TW201300380A - Oxadiazole compounds which inhibit beta-secretase activity and methods of use thereof - Google Patents

Abstract

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

Description

Oxadiazole compound inhibiting β-secretase activity and method of use thereof Cross-reference to related applications

The present application claims priority to US Provisional Application No. 61/394,680, filed on October 19, 2010, the content of which is hereby incorporated by reference.

Alzheimer's disease is a progressive mental decline in humans, especially leading to memory loss, mental confusion, and disorientation. Alzheimer's disease accounts for the majority of Alzheimer's disease and is the leading cause of death in adults (Anderson, RN, Natl. Vital Stat. Rep. 49: 1-87 (2001), the teachings of which are incorporated by reference in its entirety. In this article). Histologically, the brain of a person suffering from Alzheimer's disease is characterized by intracellular neurofibrillary deformation and the presence of senile plaques composed of granular or filamentous silver-like blocks with amyloid cores, mainly due to Beta-amyloid (Aβ) accumulates in the brain. Aβ accumulation plays a role in the pathogenesis and progression of this disease (Selkoe, DJ, Nature 399: 23-31 (1999)) and is a proteolytic fragment of amyloid precursor protein (APP). APP is initially cleaved by β-secretase and subsequently cleaved by γ-secretase to produce Aβ (Lin, X. et al., Proc. Natl. Acad Sci. USA 97 : 1456-1460 (2000); De Stropper, B. et al. People, Nature 397:387-390 (1998)). Inhibitors of beta-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; /050073; WO 2003/072535; WO 2004/043916; WO 2004/050619; WO 2004/080376; WO 2005/030709; WO2005/103020; WO 2006/034296; WO 2006/110668; WO 2009/015369; 042694; Stachel, SJ, J. Med. Chem . 47, 6447-6450 (2004); Stachel, SJ, Bioorg. Med. Chem. Lett . 16, 641-644 (2006); and Varghese, J., Curr. Med. Chem . 6: 569-578 (2006).

There is a need to develop effective compounds and methods for treating Alzheimer's disease. The present invention fulfills these and other needs.

Novel beta-secretase inhibitors and methods of use thereof are disclosed, including methods of treating Alzheimer's disease.

In one aspect, the invention provides a compound of formula (I):

Wherein R ¹ is A ¹ -L ¹ - or R together with the nitrogen and are attached form a ² together with A ¹ -L ¹ -, substituents of ^{R. 6A} and R ^6B 5 or 6-membered heterocycloalkyl ring; R ² is Hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, Optionally substituted portion of a heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl group, or together with R ¹ and the nitrogen to which it is attached, form A ¹ -L ¹ - a 5 or 6 membered heterocycloalkyl ring substituted with R ^6A and R ^6B ; A ¹ is optionally substituted heteroaryl; L ¹ is a bond, -N(R ¹⁷ )-, -S-, -S (O)-, -S(O) ₂ - or optionally substituted alkyl; R ^6A and R ^{6B are} independently hydrogen, halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl- Alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion substituted as the case may be; A ² is selected from the group consisting of a cycloalkyl group, a heterocycloalkyl group, an exoaryl group and a heteroaryl group. a portion substituted; X ¹ and X ^{2 are} independently N or CH; R ³ is hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or Substituted from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl Part; R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaryl a portion of the alkyl group which is optionally substituted; R ^7A is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycle Optionally substituted portion of alkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, or together with R ^7B and the carbon to which it is attached, form R ⁴ - L ⁴ -substituted cycloalkyl ring; R ^7B is R ⁴ -L ⁴ - or together with R ^7A and the carbon to which they are attached form an R ⁴ -L ⁴ -substituted cycloalkyl ring; R ⁴ is hydrogen, Halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O ) R ^12, or selected from alkyl, cycloalkyl, cycloalkyl - Group, - alkyl -OR ^10, - alkyl -N (R ⁸⁾ R ^9, heterocycloalkyl, heterocycloalkyl-alkyl - alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl of a portion substituted as appropriate; L ⁴ is a bond or an optionally substituted alkyl; R ^{8 is} independently hydrogen, -C(O)R ¹³ , -S(O) ₂ R ¹⁴ , or is selected from an alkane Optionally substituted portion of a group, a cycloalkyl group, a cycloalkyl-alkyl group, a heterocycloalkyl group, a heterocycloalkyl-alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; ⁹ independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl a moiety substituted as appropriate; R ^{10 is} independently -C(O)R ¹³ or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkane Optionally substituted as a base, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{11 is} independently selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl a heterocyclic alkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl group optionally substituted, wherein if attached to S(O) ₂ , then R ¹¹ may also be -NR ¹⁵ R ¹⁶ ; R ¹² and R ^{13 are} each independently hydrogen, -N(R ¹⁸ )R ¹⁹ , -OR ¹⁹ , or selected from alkyl, cycloalkyl, or ring. Optionally substituted for alkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{14 is} independently hydrogen, - N(R ¹⁸ )R ¹⁹ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl or hetero a substituted portion of the aralkyl group; and R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ^{19 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hetero a optionally substituted portion of a cycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl group; the restriction is that when both R ³ and R ⁵ are hydrogen, One of R ^7A and R ^7B is a methyl group and the other is a benzyl group, X ¹ and X ^{2 are} each N, and A ² is a substituted 1,3-phenylene group at the 5-position and R ¹ together 5 heterocycloalkyl ring formed R ² together with the nitrogen and connected by five heterocycloalkyl formed by ^{R. 1} together with R ² and the nitrogen of the ring are attached to two other a substituted moiety other than a pyrrolidinyl group substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo-3-pyridyl; or a medicinal thereof An acceptable salt or solvate.

In one embodiment, the beta-secretase inhibitor compound comprises 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 membrane aspartic acid protease 2 K _{i is} less than about 300 nM. In some embodiments, the compound has an apparent membrane aspartic acid protease 2 K _{i of} less than about 300 nM, such as by membrane aspartic acid protease 2 versus fluorescent receptor FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2) Measurement of inhibition of catalytic activity. In some embodiments, the compound can be less than about 1.5 μM, or less than about 500 nM IC ₅₀ of inhibition of cell Aβ generation. In some embodiments, the compound membrane aspartic acid protease 1 K _i and/or cathepsin DK _{i is} greater than about 300 nM. In some embodiments, the compound has an apparent membrane aspartic acid protease 1 K _i and/or an apparent cathepsin DK _i greater than about 300 nM, such as by the receptor peptide MCA-GKPILFFRLK(DNP)-dR (SEQ ID NO) .: 1) Measured. In some embodiments, the compound has a CYP 3A K _i greater than about 1 μM, or greater than 5 μM, or greater than 10 μM, as determined by metabolism of midazolam. In some embodiments, the compound is capable of selectively reducing membrane aspartic protease 2 catalytic activity relative to membrane aspartic protease 1 catalytic activity. In some embodiments, the compound is capable of selectively reducing membrane aspartic protease 2 catalytic activity relative to cathepsin D catalytic activity. In some embodiments, the compound is capable of selectively reducing membrane aspartic protease 2 catalytic activity relative to CYP3A catalytic activity. In some of these embodiments, the relative reduction is more than about 5 times. In other embodiments, the reduction is more than about 10 times. In another embodiment, the beta-secretase inhibitor compound (a) membrane aspartic protease 2 K _{i is} less than about 750 nM (or less than about 500 nM, 300 nM, 250 nM, 100 nM, 50 nM or 10) any nM in the one); (B) can be of less than about 1.5 μM (or less than about 1 μM, 500 nM, 250 nM , 100 nM, 40 nM or any of 10 nM in the one of) the IC ₅₀ inhibition of cell Aβ Producing; (c) capable of selectively reducing membrane catalytic aspartic protease 2 catalytic activity by more than about 5 times (or more than about 10 times or about 100 times) relative to membrane aspartic acid protease 1 or cathepsin D catalytic activity; / or (d) capable of selectively reducing membrane aspartic protease 2 catalytic activity by more than about 5 times (or more than about 10 times or about 100 times) relative to CYP3A catalytic activity. In some embodiments, the compound has a liver intrinsic clearance of less than about 700 mL/min/kg or less than about 400 mL/min/kg in liver microsomes as measured by LC/MS/MS. In some embodiments, the AUC of the compound is greater than 50 hr ng/ml or greater than 500 hr ng/ml, as measured after administration of a 10 mg/kg oral dose of the drug in a rat.

In another aspect, any β-secretase inhibitor compound is provided that is present in substantially pure form.

In another aspect, a formulation comprising any of the beta-secretase inhibitor compounds described herein and a carrier (eg, a pharmaceutically acceptable carrier) is provided. In some embodiments, the formulation is suitable for administration to an individual.

In another aspect, a formulation comprising any of the beta-secretase inhibitor compounds described herein and a carrier (eg, a pharmaceutically acceptable carrier) is provided.

In another aspect, a pharmaceutical formulation comprising a beta-secretase inhibitor compound or a beta-secretase inhibitor compound and a pharmaceutically acceptable carrier is provided.

In another aspect, a method of treating Alzheimer's disease in an individual in need thereof, comprising administering to the individual an effective amount of any of the β-secretase inhibitor compounds described herein (eg, I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc) , (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, Example 2 and/or Table 1. Any compound) 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.

In another aspect, a method of treating a condition mediated by membrane aspartic protease 2 catalytic activity comprising administering to the individual an effective amount of any 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 a condition mediated by membrane aspartic protease 2 catalytic activity. In some embodiments, the individual has been diagnosed with a condition mediated by membrane aspartic protease 2 catalytic activity.

In another aspect, a method of reducing membrane aspartic protease 2 catalytic activity comprising contacting membrane aspartic protease 2 with an effective amount of any of the beta-secretase inhibitor compounds described herein. In some variations, the membrane aspartate 2[beta]-secretase is contacted in the cell. In some embodiments, the cells are contacted in vivo. In some embodiments, the cells are contacted in vitro.

In another aspect, there is provided a method of selectively reducing the catalytic activity of membrane aspartic protease 2 relative to membrane aspartic acid protease 1 catalytic activity comprising effecting membrane wintering in the presence of membrane aspartic acid protease 1 Amino acid protease 2 is contacted with an effective amount of any of the β-secretase inhibitor compounds described herein.

In another aspect, a method for selectively reducing the catalytic activity of membrane aspartic protease 2 relative to cathepsin D catalytic activity comprising providing membrane aspartic protease 2 with an effective amount in the presence of cathepsin D Any of the β-secretase inhibitor compounds described herein are contacted.

In another aspect, a method for selectively reducing the catalytic activity of membrane aspartic protease 2 relative to membrane aspartic acid protease 1 catalytic activity and cathepsin D catalytic activity, comprising aspartic acid protease 1 Membrane aspartic acid protease 2 is contacted with an effective amount of any of the β-secretase inhibitor compounds described herein in the presence of cathepsin D.

In another aspect, there is provided a method of selectively reducing membrane aspartic protease 2 catalytic activity relative to CYP3A4 catalytic activity, comprising subjecting membrane aspartic acid protease 2 to an effective amount as described herein in the presence of CYP3A4 Any β-secretase inhibitor compound is contacted.

In another aspect, a method for selectively reducing membrane catalytic activity of membrane aspartic protease 2 relative to membrane aspartic acid protease 1 catalytic activity, cathepsin D catalytic activity, and CYP3A4 catalytic activity is provided, which comprises Membrane aspartic protease 2 is contacted with an effective amount of any of the β-secretase inhibitor compounds described herein in the presence of aminase 1, cathepsin D and CYP3A4.

In another aspect, a method of treating glaucoma in an individual in need thereof, comprising administering to the individual an effective amount of any of the beta-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.

In another aspect, any of the β-secretase inhibitor compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament is provided. Also provided is any 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.

Another aspect provides the use of any of the β-secretase inhibitor compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or prevention of a membrane aspartic protease 2 An agent that catalyzes a path mediated by a catalytic activity. In another aspect, the use of one or more of the beta-secretase inhibitor compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a membrane aspartame The condition mediated by acid protease 2 catalytic activity. In some variations, the condition is Alzheimer's disease.

In another aspect, a kit for treating or preventing an individual having Alzheimer's disease, comprising any of the beta-secretase inhibitor compounds described herein or a pharmaceutically acceptable thereof Salt or solvate; and packaging. In some embodiments, the kit comprises a formulation of any of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof; and a package.

In another aspect, a kit for treating or preventing a subject having a condition mediated by membrane aspartic protease 2 catalytic activity, comprising any of the beta-secretase inhibitors described herein a compound or a pharmaceutically acceptable salt or solvate thereof; and a package. In some embodiments, the kit comprises a formulation of any of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof; and a package.

In another aspect, a beta-secretase inhibitor compound can be used in the method to mediate membrane aspartate 2 activity, for example, in contrast to the absence of a membrane aspartic protease in a beta-secretase inhibitor, respectively. 2 The amount of activity, hydrolysis of β-secretase site and accumulation of β-amyloid protein decrease membrane aspartyl protease 2 activity and reduce hydrolysis of β-secretase site of membrane aspartate 2 And/or reduce the accumulation of β-amyloid.

In another aspect, the β-secretase inhibitor compound is useful for treating a β-secretase activity, a hydrolysis of a β-secretase site of a β-amyloid precursor protein, and/or a β-amyloid accumulation. Disease or condition. The disease or condition of a mammal is typically treated. In an exemplary embodiment, the condition is Alzheimer's disease.

The present invention provides compositions of beta-secretase inhibitors and methods of use thereof, such as methods of treating Alzheimer's disease.

Abbreviations and definitions

Abbreviations as used herein have their conventional meanings in chemistry and biotechnology, unless otherwise specified.

The nomenclature of some of the compounds described herein (such as those described in Example 2 and Table 1) can be identified using IUPAC or other nomenclature rules, including from CambridgeSoft. ChemDraw Ultra version 12.0.

When a substituent is specified by a conventional chemical formula written from left to right, it also encompasses chemically identical substituents derived from a right-to-left writing structure, for example, -CH ₂ O- is equivalent to -OCH ₂ -.

Unless otherwise specified, the term "alkyl", by itself or as part of another substituent, means a straight chain (ie, unbranched) or branched chain hydrocarbon chain, or a combination thereof, which may be fully saturated, monosaturated or unsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C ₁ -C ₁₀ means one to ten carbons). Examples of saturated hydrocarbon groups include, but are not limited to, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, t-butyl, (cyclohexyl)methyl A group such as a homologue and an isomer of n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The unsaturated alkyl group is a group having one or more double bonds or a bond. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl and higher carbon homologs and isomers. An alkoxy group is an alkyl group attached to the remainder of the molecule via an oxygen linking group (-O-).

Means a divalent group derived from the alkyl The term "alkylene" by itself or as part of another group of, for example (but not limited _{to) -CH 2 CH 2 CH 2 CH} 2 -. Typically, an alkyl group (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 group is a methylene group and a methylmethylene group.

Unless otherwise specified, the term "cycloalkyl", by itself or in conjunction with other terms, refers to a cyclic form of "alkyl". Further, the cycloalkyl group may contain a plurality of rings, but does not include an aryl group and a heteroaryl group. Examples of cycloalkyl groups are 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 group derived from an alkyl group such as, but not limited to, -cyclohexyl-.

The term "heterocycloalkyl", by itself or in combination with other terms, denotes a stable saturated or unsaturated cyclic hydrocarbon group containing at least one carbon atom and at least one ring heteroatom selected from the group consisting of O, N, P, Si and S, and wherein The nitrogen and sulfur atoms may be oxidized as appropriate and the nitrogen heteroatoms may be ammonium quaternized as appropriate. The heteroatoms O, N, P, S and Si may be located at any internal position of the heterocycloalkyl group or at a position where the heterocycloalkyl group is attached to the remainder of the molecule. Further, the heterocycloalkyl group may contain a plurality of rings, but does not include an aryl group and a heteroaryl group. Examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-? Phytyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl and Similar group. The term "heterocycloalkyl", by itself or as part of another substituent, means a divalent group derived from a heterocycloalkyl group, such as, but not limited to, .

The terms "cycloalkyl-alkyl" and "heterocycloalkyl-alkyl" denote an alkyl-substituted cycloalkyl group and an alkyl-substituted heterocycloalkyl group, respectively, wherein the alkyl moiety is attached to the parent structure. Non-limiting examples include cyclopropyl-ethyl, cyclobutyl-propyl, cyclopentyl-hexyl, cyclohexyl-isopropyl, 1-cyclohexenyl-propyl, 3-cyclohexenyl- Tributyl, cycloheptyl-heptyl, norbornyl-methyl, 1-piperidinyl-ethyl, 4-morpholinyl-propyl, 3-morpholinyl-tert-butyl, tetrahydrofuran-2 -yl-hexyl, tetrahydrofuran-3-yl-isopropyl and the like. Cycloalkyl-alkyl and heterocycloalkyl-alkyl also include substituents in which a carbon atom of an alkyl group (e.g., methylene) has been replaced with, for example, an oxygen atom (e.g., cyclopropoxymethyl, 2-piperidinyloxy) Base-t-butyl group and the like.

Unless otherwise specified, the term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent. The aryl group may contain other fused rings (e.g., 1 to 3 rings), including additional 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 an aryl (or ring) containing one to four ring heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally subjected to quaternary ammonium. Chemical. A heteroaryl group can be attached to the remainder of the molecule by a ring carbon or ring atom. Heteroaryl groups can contain other fused rings (e.g., 1 to 3 rings), including additional 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-pyrimidinyl, 4 -pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5- Quinoxalinyl, 3-quinolyl and 6-quinolinyl. Substituents for substituted aryl and heteroaryl ring systems are described below.

The terms "extended aryl" and "heteroaryl" mean a divalent group derived from an aryl group and a heteroaryl group, respectively. The two valences of the aryl and heteroaryl groups can each be located in any part of the ring (eg and ). Non-limiting examples of aryl groups include phenyl, exophenyl, anthranyl and the like. Examples of heteroaryl groups include, but are not limited to, pyridyl, oxazolyl, thiazolyl, pyrazolyl, piperidyl, imidazolyl, and furanyl.

The term "aralkyl" denotes an alkyl substituted aryl group wherein the alkyl moiety is attached to the parent structure. Examples are benzyl, phenethyl, phenylvinyl, phenylallyl, pyridylmethyl and the like. "Heteroaralkyl" means a heteroaryl moiety attached to the parent structure via an alkyl residue. Examples include furylmethyl, pyridylmethyl, pyrimidinylethyl and the like. Aralkyl and heteroarylalkyl also include substituents in which the carbon atom of the alkyl group (e.g., methylene) has been replaced with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1) -naphthyloxy)propyl and the like.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl Base and its like.

The term "substituted" refers to the replacement of one or more hydrogen atoms with a monovalent or divalent group. "Substituting as appropriate" indicates that the part may be replaced or unsubstituted. Lack of the terms "substituted as appropriate" and "substituted" are intended to be unsubstituted (eg "phenyl" intended to be unsubstituted phenyl unless indicated as substituted phenyl or as appropriate Phenyl).

As used herein, the terms "pharmaceutically effective amount", "therapeutically effective amount", "effective amount" and the cognates of these terms refer to a given condition (eg, disease, condition, etc.) or one or more symptoms thereof. Producing the desired pharmacological and/or physiological effects and/or completely or partially preventing the occurrence of the condition or its symptoms and/or in terms of partially or completely curing the condition and/or adverse effects attributable to the condition It has a therapeutic amount. Regarding the condition mediated by the membrane aspartate 2[beta]-secretase, the pharmaceutically or therapeutically effective amount comprises an amount sufficient to cause antagonism of the membrane aspartate 2[beta]-secretase. With regard to glaucoma, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to reduce intraocular pressure and/or to stop, reverse and/or reduce the loss of retinal ganglion cells (RGC). In certain embodiments, the pharmaceutically effective amount is sufficient to prevent the condition, such as prophylactic administration to an individual.

"Pharmaceutically effective amount" or "therapeutically effective amount" will depend on the composition to be administered, the condition to be treated/prevented, the severity of the condition being treated/prevented, the age and relative health of the individual, the route of administration and The judgment of the practitioner of the form, attending medicine or veterinary medicine and other factors known to those skilled in the art in view of the teachings provided herein.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" means a pharmaceutical excipient, for example suitable for enteral or parenteral application and will not be produced with extracts. A pharmaceutically and physiologically acceptable organic or inorganic carrier material that is detrimental to the reaction.

When used in connection with a method of treatment/prevention and the use of the compounds and compositions thereof described herein, the "in need" individual can be an individual who has been diagnosed with the condition to be treated or has previously been treated for the condition. For prevention, an individual in need may also be an individual at risk of developing a condition (eg, a family history of the condition, a lifestyle factor indicative of a risk of developing the condition, etc.).

In some variations, an individual has been identified as having one or more of the conditions described herein. Identification of a condition as described herein by a skilled physician is routine in the art and can also be suspected by an individual or other person, for example, due to memory loss in the case of Alzheimer's disease, exhibiting schizophrenia Symptoms, etc., and because of the reduction and/or loss of contrast sensitivity or visual acuity in the case of glaucoma.

In some embodiments, an individual has been identified as susceptible to one or more conditions as described herein. The susceptibility of an individual can be based on any one or more of a variety of risk factors and/or diagnostic methods known to those skilled in the art, including but not limited to genetic identification, family history, medical history (eg, occurrence of correlation) Condition, lifestyle or habit.

In some embodiments, the individual is a mammal, including but not limited to a cow, horse, cat, rabbit, dog, 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 a human, including adults, children, and premature babies. In some embodiments, the individual is a non-mammal. In some variations, primates are non-human primates, such as chimpanzees and other apes and monkeys. In some embodiments, the mammal is a farm animal, such as cattle, horses, sheep, goats, and pigs; pets, such as rabbits, dogs, and cats; experimental animals, including rodents, such as rats, mice, and guinea pigs; Similar to animals. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" does not mean a specific age or gender.

A "pharmaceutically acceptable salt" is a salt that retains biological activity and which can be administered to an individual (e.g., a human) as a drug or agent.

As used herein, "isomer" includes all stereoisomers as referred to in the formula, including enantiomers, diastereomers, and all conformational isomers, rotamers, and Tautomers.

As used herein, "amyloid precursor protein" or "APP" refers to a beta-amyloid precursor comprising a beta-secretase site.

As used herein, "membrane aspartic protease-2" refers to a protein identified by the National Center for Biotechnology Information ("NCBI") accession number NP_036236 (sometimes referred to as "beta-position"). Point APP lyase 1" or "BACE-1" or generally referred to as "β-secretase", including homologs, isoforms and subdomains that retain proteolytic activity. The sequence identity of the active membrane aspartic acid protease 2 protein and protein fragments (and their nucleic acid coding sequences) has been previously disclosed and discussed in detail in U.S. Application No. 20040121947 and International Application No. PCT/US02/34324 (published In the case of WO 03/039454, the patents are hereby incorporated by reference in their entirety for all purposes.

As used herein, "membrane aspartic acid protease-1" refers to a protein identified by the National Center for Biotechnology Information ("NCBI") accession number NP_036237 (sometimes referred to as "beta site APP lyase 2" or "BACE-2") and/or previously disclosed and discussed in detail in U.S. Patent Application Publication No. 20040112947 and International Application No. PCT/US02/34324 (Publication No. WO 03/039454) The proteins incorporated herein by reference in their entirety for all purposes include homologs, isoforms and subdomains which retain proteolytic activity.

As used herein, "Cathepsin D" refers to a protein identified by the National Center for Biotechnology Information ("NCBI") (eg, accession number NP-599161) and/or by the Enzyme Commission number EC3. 4.23.5 Identification of proteins, including proteins from any substance, homologs, isoforms and subdomains that retain proteolytic activity.

The "β-secretase site" is an amino acid sequence which is cleaved by the active membrane aspartic acid protease 2 or an active fragment thereof. Specific β-secretase sites have also been previously described and described in detail in U.S. Application No. 20040121947 and International Application No. PCT/US02/34324 (Publication No. WO 03/039454), which are incorporated herein by reference. It is incorporated herein by reference in its entirety for all purposes, and includes a Swedish mutation sequence and a native beta-amyloid precursor protein cleavage sequence. Therefore, the β-secretase inhibitor can be tested to reduce the hydrolysis of the β-secretase site of the substrate (such as a β-amyloid precursor protein, a β-amyloid precursor protein compound or a β-amyloid precursor protein fragment). ability.

"β-secretase inhibitor" means a compound capable of reducing the proteolytic activity of membrane aspartic protease 2 relative to the activity in the absence of an inhibitor.

As used herein, "cytochrome P450 3A4" or "CYP3A4" refers to a protein identified by Genbank Serial Accession Number: AF280107; HGNC: 2637; Enzymology ID: 1.1.1.161, which can be found in products from Celsis, InVitro CYP ^TM M-class ^{TM in} human liver microsomes.

References to "about", the values or parameters herein include (and describe) changes to the value or parameter itself. For example, the description referring to "about X" includes the description of "X".

As used herein, the term "a" means one or more.

I. β-secretase inhibitor

In one aspect, a compound that mediates (eg, inhibits) the catalytic activity of beta-secretase (membrane aspartic protease 2) is provided. Such compounds may be referred to herein as "beta-secretase inhibitor compounds" or "membrane aspartic protease 2[beta]-secretase inhibitors". In this aspect, the compound has the formula (I):

Wherein R ¹ is A ¹ -L ¹ - or and R together with the attached nitrogen form a ² together with A ¹ -L ¹ -, substituents of ^{R. 6A} and R ^6B 5 or 6-membered heterocycloalkyl ring; R ² is Hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, Optionally substituted portion of a heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl group, or together with R ¹ and the nitrogen to which it is attached, form A ¹ -L ¹ - a 5 or 6 membered heterocycloalkyl ring substituted with R ^6A and R ^6B ; A ¹ is optionally substituted heteroaryl; L ¹ is a bond, -N(R ¹⁷ )-, -S-, -S (O)-, -S(O) ₂ - or optionally substituted alkyl; R ⁶ A and R ^{6B are} independently hydrogen, halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl -alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl the base portion of the optionally substituted; A ² is a group selected from cycloalkyl extension, extending heterocycloalkyl, aryl and stretched extensor heteroaryl of view Status portion of substituted; X ¹ and X ^{2 are} independently N or CH; R ³ is ^{hydrogen, -N (R 8) R 9} , -S (O) 2 R 11, -C (O) R 12, or Substituted from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl Part; R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaryl a portion of the alkyl group which is optionally substituted; R ^7A is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycle Optionally substituted portion of alkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, or together with R ^7B and the carbon to which it is attached, form R ⁴ - L ⁴ -substituted cycloalkyl ring; R ^7B is R ⁴ -L ⁴ - or together with R ^7A and the carbon to which they are attached form an R ⁴ -L ⁴ -substituted cycloalkyl ring; R ⁴ is hydrogen, Halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl- Alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion substituted as appropriate; L ⁴ is a bond or an optionally substituted alkyl group; R ^{8 is} independently hydrogen, -C(O)R ¹³ , -S(O) ₂ R ¹⁴ , or selected from Optionally substituted as an alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group; R ^{9 is} independently hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaryl a substituted alkyl moiety; R ^{10 is} independently -C(O)R ¹³ or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl- Optionally substituted for alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{11 is} independently selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkane Optionally substituted as a heterocyclic alkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group, wherein if attached to S ( O) ₂ , then R ¹¹ may also be -NR ¹⁵ R ¹⁶ ; R ¹² and R ^{13 are} each independently hydrogen, -N(R ¹⁸ )R ¹⁹ , -OR ¹⁹ , or selected from alkyl, cycloalkyl, Optionally substituted for cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{14 is} independently hydrogen, -N(R ¹⁸ )R ¹⁹ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl or a substituted heteroaryl group as defined above; and R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ^{19 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, Optionally substituted portion of heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; with the proviso that when both R ³ and R ⁵ are hydrogen , one of R ^7A and R ^7B is a methyl group and the other is a benzyl group, X ¹ and X ^{2 are} each N, and A ² is a substituted 1,3-phenylene group at the 5-position and R ¹ and R ² together with the attached nitrogen form a 5-membered heterocyclic ring group, a heterocycloalkyl ring R 5 form together with ^{the. 1} and R ² are attached to the nitrogen in addition to two a substituted moiety other than a pyrrolidinyl group substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo-3-pyridyl; or a medicinal thereof An acceptable salt or solvate.

a substituent on a substituted moiety of formula (I) (eg, any optionally substituted alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, The substituent on the aryl, aralkyl, heteroaryl and/or heteroarylalkyl group may be one, two, three or more groups selected from, but not limited to, the following: hydroxyl, nitrate a group, an amine group (for example, -NH ₂ or a dialkylamino group), an imido group, a cyano group, a halogen group (such as F, Cl, Br, I), a haloalkyl group (such as -CCl ₃ or -CF ₃ ) , thio, sulfonyl, thioguanamine, indolyl, imidino, pendant oxy, oxamidino, methoxamidino, imidinyl, fluorenyl , sulfonamide, carboxyl, methionyl, alkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy (-OCOR), aminocarbonyl, arylcarbonyl, aralkyl Alkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aminecaraki (-NHCOOR- or -OCONHR-), urea (- NHCONHR-), an aryl group and the like, wherein R is any suitable group, such as an alkane Or alkylene. In some embodiments, the optionally substituted moiety is optionally substituted with only the selected group as described herein. In some embodiments, the above groups (eg, alkyl groups) are optionally substituted with, for example, an alkyl group (eg, methyl or ethyl), a haloalkyl group (eg, -CCl ₃ , -CH ₂ CHCl ₂ or - CF ₃ ), cycloalkyl (eg, -C ₃ H ₅ , -C ₄ H ₇ , -C ₅ H ₉ ), amine (eg, -NH ₂ or dialkylamino), alkoxy (eg, methoxy) a heterocycloalkyl group (e.g., morpholine, piperazine, piperidine, azetidine), a hydroxyl group, and/or a heteroaryl group (e.g., oxazolyl). In some embodiments, the substituents are themselves substituted as appropriate. In some embodiments, the substituents are not themselves substituted. The group substituted on the substituent group may be, for example, a carboxyl group, a halogen group, a nitro group, an amine group, a cyano group, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aminocarbonyl group, a -SR, a thio group. acyl group, -SO ₃ H, -SO ₂ R or cycloalkyl, where R is any suitable group of, for example, hydrogen or alkyl.

In some such embodiments, A ¹ is optionally substituted 5 to 7 membered heteroaryl (eg, wherein the heteroaryl is attached to L ¹ at 1, 2, 3, 4 or 5 positions and/or wherein The heteroaryl group is substituted at 1, 2, 3, 4 and/or 5 positions). In other embodiments, A ¹ is optionally substituted 5-membered heteroaryl (eg, wherein the heteroaryl is attached to L ¹ at 1, 2, 3, 4 or 5 and/or wherein the heteroaryl is 1, 2, 3, 4 and / or 5 positions are substituted).

In some such embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, furyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrole , pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, carbazolyl, benzimidazolyl, benzothienyl, benzo Furanyl, fluorenyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzopyrene Oxazolyl, pyrazinyl, pyrrolinyl, fluorenyl and benzodiazepine.

In some such embodiments, A ¹ is optionally substituted in the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrimidine , pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, oxazolyl, benzimidazolyl, benzothienyl, benzofuranyl, fluorenyl , quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzisoxazolyl, pyrazine Base, pyrrolinyl, fluorenyl and benzodiazepine.

In some such embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, furyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiophene , pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, carbazolyl, benzimidazolyl, benzothienyl, benzo Furanyl, fluorenyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzopyrene Oxazolyl, pyrazinyl, pyrrolinyl, fluorenyl and benzodiazepine.

In some such embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, furyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrole , pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, carbazolyl, benzimidazolyl, benzothienyl, benzo Furanyl, fluorenyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzopyrene Oxazolyl, pyrazinyl, pyrrolinyl, fluorenyl and benzodiazepine.

In some such embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thienyl, pyridyl, Pyrimidinyl, oxadiazolyl and piperidyl.

In some such embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of thiazolyl (eg, optionally substituted 2-thiazolyl or optionally substituted 4-thiazolyl, such as 2-(substituted at the 4-position) thiazolyl or 4-(substituted at the 2-position) thiazolyl), oxazolyl (for example, optionally substituted 2-oxazolyl or optionally substituted 4- Oxazolyl, such as 2-(substituted at the 4-position) oxazolyl or 4-(substituted at the 2-position) oxazolyl), imidazolyl, pyrazolyl, isoxazolyl, pyrimidinyl, ace Diazolyl and piperidyl. In some embodiments, A ¹ is an optionally substituted moiety selected from the group consisting of thiazolyl (eg, optionally substituted 2-thiazolyl or optionally substituted 4-thiazolyl, such as 2- (substituted at the 4-position) thiazolyl or 4-(substituted at the 2-position) thiazolyl), oxadiazolyl and oxazolyl (for example, optionally substituted 2-oxazolyl or optionally substituted 4-oxazolyl, such as 2-(substituted at the 4-position) oxazolyl or 4-(substituted at the 2-position) oxazolyl). In some embodiments, A ¹ is optionally substituted thiazolyl (eg, optionally substituted 2-thiazolyl or optionally substituted 4-thiazolyl, such as 2-(4-substituted) thiazole Base or 4-(substituted at the 2-position) thiazolyl). In some embodiments, A ¹ is optionally substituted oxazolyl (eg, optionally substituted 2-oxazolyl or optionally substituted 4-oxazolyl, such as 2-(4-substituted at position 4) Oroxazolyl or 4-(substituted at the 2-position) oxazolyl). In some embodiments, A ¹ is an optionally substituted oxadiazolyl group. In some embodiments, A ¹ is an optionally substituted imidazolyl group. In some embodiments, A ¹ is optionally substituted pyrazolyl. In some embodiments, A ¹ is an optionally substituted isoxazolyl group. In some embodiments, A ¹ is an optionally substituted pyrimidinyl group. In some embodiments, A ¹ is optionally substituted 2-thiazolyl. In some embodiments, A ¹ is an optionally substituted 2-oxazolyl group.

In some such embodiments, A ¹ is optionally substituted thienyl (eg, optionally substituted 2-thienyl). In some such embodiments, A ¹ is optionally substituted pyridyl (eg, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl or optionally substituted 4-pyridyl, Such as 6-methylpyridin-3-yl, 6-methylpyridin-2-yl and 4-pyridyl). In some such embodiments, A ¹ is optionally substituted pyrazinyl (eg, optionally substituted 2-pyrazinyl). In some such embodiments, A ¹ is an optionally substituted oxadiazolyl group (eg, 1,2,4-oxadiazolyl, or optionally substituted 1, 2,3-oxo, as appropriate) A oxazolyl group such as 3-methyl-1,2,4-oxadiazol-5-yl). In some such embodiments, A ¹ is optionally substituted pyrazolyl (eg, optionally substituted 3-pyrazolyl, optionally substituted 4-pyrazolyl or optionally substituted 5-- Pyrazolyl, such as 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 1-methylpyrazole-5- And 1,5-dimethylpyrazol-4-yl). In some such embodiments, A ¹ is optionally substituted oxazolyl (eg, optionally substituted 2-oxazolyl or optionally substituted 4-oxazolyl, such as 2-methyloxazole) 4-yl and 2,5-dimethyloxazol-4-yl). In some such embodiments, A ¹ is optionally substituted thiazolyl (eg, optionally substituted 2-thiazolyl or optionally substituted 4-thiazolyl, such as thiazol-2-yl, 4-methyl Thiazol-2-yl, 4-ethylthiazol-2-yl, 4-bromothiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-(methoxymethyl)thiazole-2- Base, 4,5-dimethylthiazol-2-yl and 2-methylthiazol-4-yl).

In some embodiments, R ^{1 ,} together with R ² and the nitrogen to which it is attached, form a 5-membered heterocycloalkyl ring and A ¹ is optionally substituted with a furanyl group as appropriate and a optionally substituted pyridyl group. Substituted 5 to 7 membered heteroaryl. In some such embodiments, A ¹ is optionally substituted 5-membered heteroaryl, in addition to substituted or unsubstituted furanyl. In some such embodiments, A ¹ is an optionally substituted 5-membered heteroaryl group other than a substituted furanyl group. In some such embodiments, A ¹ is optionally substituted 5-membered heteroaryl in addition to the substituted furan-2-yl at position 5. In some such embodiments, A ¹ is optionally substituted 5-membered heteroaryl in addition to 5-chlorofuran-2-yl and 5-methylfuran-2-yl. In some such embodiments, A ¹ is optionally substituted 6-membered heteroaryl in addition to substituted or unsubstituted pyridyl. In some such embodiments, A ¹ is an optionally substituted 6-membered heteroaryl group in addition to the unsubstituted pyridyl group. In some such embodiments, A ¹ is an optionally substituted 6-membered heteroaryl group other than a substituted pyridyl group. In some such embodiments, A ¹ is an optionally substituted 6-membered heteroaryl group in addition to the substituted 3-pyridyl group. In some such embodiments, A ¹ is an optionally substituted 6-membered heteroaryl group other than 3-pyridyl and 5-bromo-3-pyridyl.

The substituent on the A ¹ substituted by the formula (I) may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a nitro group, an amine group, or a subgroup. Amine, cyano, halo, haloalkyl, fluorenyl, sulfanyl, sulfonyl, thioguanamine, methionyl, pendant oxy, amidino, methylamine, imidylene, Sulfhydryl, sulfonylamino, carboxy, decyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, hetero Aryl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aminecaraki and urea.

In some embodiments, the optionally substituted substituent on A ¹ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, OCHF ₂ ). In some embodiments, A ¹ (eg, thiazolyl) is substituted with an alkyl group (such as methyl) (eg, at the ¹ , 2, 3, or 4 position of A ¹ ). In some such embodiments, the alkyl (e.g. methyl) optionally substituted with 1-3 halogens (e.g. _{-CF 3, -CHF 2, -CH 2} F).

In some such embodiments, L ¹ is a bond or an optionally substituted alkyl. In other embodiments, L ¹ is -N(R ¹⁷ )-, -S-, -S(O)-, -S(O) ₂ - or optionally substituted alkylene. In other embodiments, L ¹ is -N(R ¹⁷ )-, -S-, -S(O)- or -S(O) ₂ -. In other embodiments, L ¹ is -N(R ¹⁷ )-. In other embodiments, L ¹ is -S-, -S(O)- or -S(O) ₂ -. In other embodiments, L ¹ is a bond. In other embodiments, L ¹ is an optionally substituted alkylene group. In other embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene. In other embodiments, L ¹ is an optionally substituted methylene group. In other embodiments, L ¹ is a C ₁ -C ₆ alkylene group (eg, methylene or methylmethylene). In other embodiments, L ¹ is a branched chain C ₁ -C ₆ alkyl (eg, methylmethylene). In other embodiments, L ¹ is a methylene group. In other embodiments, L ¹ is methylmethylene.

In some embodiments, the optionally substituted substituent on L ¹ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, OCHF ₂ ).

In some such embodiments, the compound has the formula (II):

Or a pharmaceutically acceptable salt or solvate thereof; wherein A ¹ , A ² , L ¹ , X ¹ , X ² , R ² , R ³ , R ⁵ , R ^7A and R ^{7B are} as for formula (I) And any variations thereof are defined.

In some such embodiments, R ² is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, The heteroaryl and heteroarylalkyl groups are optionally substituted. In some embodiments, R ² is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, and cycloalkyl-alkyl groups as appropriate. In some embodiments, R ² is hydrogen or optionally substituted alkyl. In some embodiments, R ² is hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ² is optionally substituted C ₁ -C ₃ alkyl. In some embodiments, R ² is optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is methyl.

In some such embodiments, R ² is hydrogen, optionally substituted C ₁ -C ₆ alkyl or optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ² is optionally substituted C ₁ -C ₆ alkyl, such as methyl, ethyl, 2-fluoroethyl, propyl (eg, n-propyl or isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl or tert-butyl). In some embodiments, R ² is optionally substituted C ₃ -C ₆ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, the optionally substituted substituent on R ² may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, -OCHF ₂ ). In some embodiments, the substituent on R ² , as appropriate, is selected from the group consisting of methyl and cyclopropyl.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein: W is -CH ₂ -, -O-, -N(R ¹⁷ )-, -S-, -S(O)- or -S(O ₂ -, or wherein W is -CH- or -N- and is substituted by R ^6A or R ^6B , or wherein W is -C- and substituted by R ^6A and R ^6B ; m is 1 or 2; and A ¹ , A ² , L ¹ , X ¹ , X ² , R ² , R ³ , R ⁵ , R ^6A , R ^6B , R ^7A , R ^7B and R ¹⁷ are as defined above in the discussion of formula (I).

In some variations of formula (III), W is -O-. In some variations, W is -S-, -S(O)- or -S(O) ₂ . In some variations, W is -S-. In some variations, W is -N (R ¹⁷⁾ -. In some variations, W is -N( ^R6A )- or -N( ^R6B )-. In some variations, W is -CH ₂ -. In some variations, W is -CH( ^R6A )- or -CH( ^R6B )-. In some variations, W is -C(R ^6A )(R ^6B )-. In some variations, m is one. 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.

In some embodiments, the compound has the formula (IIIa):

Or a pharmaceutically acceptable salt or solvate thereof; wherein A ¹ , A ² , L ¹ , X ¹ , X ² , R ² , R ³ , R ⁵ , R ^6A , R ^6B , R ^7A and R ^7B As defined above in the discussion of formula (I).

In some embodiments, the A ¹ -L ¹ - moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula: , such as .

In some such embodiments, L ¹ is a bond and A ^{1 is} substituted on the pyrrolidine heterocycloalkyl ring according to the formula: , such as .

In some embodiments, the A ¹ -L ¹ - moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula: , such as .

In some embodiments, L ¹ is a bond, and A ^{1 is} substituted on the pyrrolidine heterocycloalkyl ring according to the formula: , such as .

In some embodiments, L ¹ is a bond, and A ¹ , R ^{6A ,} and R ^{6B are} substituted on a pyrrolidinylcycloalkyl ring according to the formula: , such as .

In some embodiments, the A ¹ -L ¹ - moiety, R ^6A and R ^{6B are} substituted for a pyrrolidine heterocycloalkyl ring wherein R ^6A and R ^6B may be substituted on different carbon atoms, for example , or R ^6A and R ^6B may be substituted on the same carbon atom, for example or

In some embodiments, R ^6A and R ^{6B are,} independently, hydrogen, halogen, —OH, —N(R ⁸ )R ⁹ , —OR ¹⁰ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl. Optionally substituted as a heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group. In some embodiments, R ^6A is hydrogen or is selected from the group consisting of aryl, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, R ^6A is hydrogen, halogen (eg, F or Cl), optionally substituted alkyl (eg haloalkyl) or optionally substituted -OR ¹⁰ (eg, optionally substituted -O) An alkyl group such as methoxy, ethoxy, propoxy, isopropoxy or a halogenated variant thereof. In some embodiments, R ^6A is hydrogen, F, optionally substituted (C ₁ -C ₄ )alkyl (eg, methyl, ethyl, propyl, butyl, -CF ₃ , -CHF ₂ , - CH ₂ F), optionally substituted -O-(C ₁ -C ₄ )alkyl (for example -O-(C ₁ -C ₄ )alkyl substituted by 1, 2 or 3 fluoro groups (such as A Oxy, ethoxy, propoxy or isopropoxy), such as -OCH ₂ F, -OCHF ₂ ). In some embodiments, R ^6A is hydrogen or halogen. In some embodiments, R ^6A is halo, such as fluoro. In some embodiments, R ^6A is hydrogen. In some variations of these embodiments, R ^6B is hydrogen. In some variations of these embodiments, R ^6B is an optionally substituted alkyl group. In some variations of these embodiments, R ^6B is halo (eg, fluoro). In some particular variations, R ^6A and R ^{6B are} independently halogen. In some particular variations, each of R ^6A and R ^6B is a fluoro group.

In some embodiments, the compound has Formula I, II, III, IV, V, VI, or any variation thereof, wherein A ² is optionally substituted aryl or optionally substituted aryl. In some embodiments, A ² is an optionally substituted moiety selected from the group consisting of phenyl, exopyridyl, oxazolyl, thiazolyl, pyrazolyl, piperidyl, Imidazole group and furanyl group. In some variations, A ² is an extended aryl group having at least two substituents and the two substituents may together form another heterocyclic ring fused to an extended aryl group, such as Alkyl or dihydrobenzofuranyl. In some variations, A ² is an optionally substituted pyridone group.

In some such embodiments, A ² has the formula:

Wherein L ² and L ^{3 are} independently a bond or optionally substituted C ₁ -C ₅ alkyl; R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen, halogen, -N(R ²⁴ )R ²⁵ , Or optionally selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion; and Y is -N= or -C(R ²³ )=, wherein R ²³ is hydrogen, halogen, —NO ₂ , —N(R ²⁴ )R ²⁵ , —OR ²⁶ , —SR ²⁷ , —S ( O) R ²⁷ , -S(O) ₂ R ²⁷ or -C(O)R ²⁸ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkane Optionally substituted for a aryl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; wherein R ²⁴ and R ^{25 are} independently hydrogen, -C(O)R ²⁹ or -S(O) ₂ R ³⁰ , or selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a substituted portion; wherein R ^{29 is} independently hydrogen, -N(R ³¹ )R ³² or -OR ³³ , selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycle Alkyl-alkyl, aryl, aralkyl, heteroaryl And optionally substituted moieties; wherein R ³¹ , R ³² and R ^{33 are} independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl - optionally alkyl, aryl, aralkyl, heteroaryl and substituted heteroaryl groups of the moiety; and R ³⁰ is selected from alkyl, cycloalkyl, cycloalkyl - group, Optionally substituted portion of heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ²⁶ is hydrogen or selected from alkyl, cycloalkyl , optionally substituted portion of cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ²⁷ is -N ( R ³⁴ )R ³⁵ , or selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl a moiety substituted as appropriate; wherein R ³⁴ and R ^{35 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl a substituted portion of an aryl group, an aralkyl group, a heteroaryl group, and a heteroarylalkyl group; and R ²⁸ Is -OR ³⁶ , -N(R ³⁷ )R ³⁸ , or is selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl And optionally substituted moieties of heteroaryl and heteroarylalkyl; wherein R ³⁶ , R ³⁷ and R ^{38 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hetero Optionally substituted as a cycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group.

In some such embodiments, A ² has the formula:

Wherein L ² and L ^{3 are} independently a bond or optionally substituted C ₁ -C ₅ alkyl; R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen, halogen, -N(R ²⁴ )R ²⁵ , Or optionally selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion; each R ^{23 is} independently hydrogen, halogen, cyano, -NO ₂ , -N(R ²⁴ )R ²⁵ , -OR ²⁶ , -SR ²⁷ , -S(O)R ²⁷ , -S(O) ₂ R ²⁷ or -C(O)R ²⁸ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, hetero a portion of the aryl and heteroarylalkyl which is optionally substituted; and Y is -N= or -C(R ²³ )=; wherein R ²⁴ and R ^{25 are} each independently hydrogen, -C(O)R ²⁹ or -S(O) ₂ R ³⁰ , or selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and a substituted portion of a heteroaralkyl group; wherein R ^{29 is} independently hydrogen, -N(R ³¹ )R ³² or -OR ³³ , selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hetero Cycloalkyl, heterocycloalkyl-alkyl, aryl, Optionally substituted according to aralkyl, heteroaryl and heteroarylalkyl; wherein R ³¹ , R ³² and R ^{33 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkane Optionally substituted moieties, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; and R ^{30 is} independently selected from alkyl, halo Optionally substituted for alkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ²⁶ independently Is hydrogen, or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a substituted portion; R ^{27 is} independently -N(R ³⁴ )R ³⁵ , or is selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, Optionally substituted for aryl, aralkyl, heteroaryl and heteroarylalkyl; wherein R ³⁴ and R ^{35 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkane Base, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and Optionally substituted aralkyl group of the moiety; and R ²⁸ is independently ^{-OR 36, -N (R 37)} R 38, or selected from alkyl, cycloalkyl, cycloalkyl - alkyl, heterocycloalkyl Optionally substituted as a heterocyclic alkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group; wherein R ³⁶ , R ³⁷ and R ^{38 are} each independently hydrogen, or Optionally substituted for alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups .

In other such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In other such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In some such embodiments, A ² has the formula:

Wherein R ^{23 is} as defined herein.

In other such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In some such embodiments, Y is -C(R ²³ )=. In other embodiments, Y is -N=.

In some such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In other such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In other such embodiments, A ² has the formula:

Wherein R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In other such embodiments, A ² has the formula:

Wherein R ²⁰ and R ^{22 are} as defined herein.

In some such embodiments, A ² has the formula:

Wherein R ^{23 is} as defined herein.

In some such embodiments, A ² has the formula:

Wherein R ^{23 is} as defined herein.

In some embodiments, R ²³ is hydrogen, halogen, cyano, —NO ₂ , —N(R ²⁴ )R ²⁵ , —OR ²⁶ , —SR ²⁷ , —S(O)R ²⁷ , —S(O) ₂ R ²⁷ or -C(O)R ²⁸ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, hetero The aryl and heteroarylalkyl groups are optionally substituted. In some embodiments, R ²³ is halo, cyano, or —NO ₂ . In some embodiments, R ²³ is halo (eg, F, Cl, Br, or I). In some embodiments, R ²³ is cyano. In some embodiments, R ²³ is -NO ₂ .

In some embodiments, R ²³ is —N(R ²⁴ )R ²⁵ , wherein R ²⁴ and R ^{25 are} each independently hydrogen, optionally substituted C ₁ -C ₆ alkyl (eg, methyl, ethyl, and 2-methoxyethyl) or -C(O)R ²⁹ , wherein R ²⁹ is hydrogen, optionally substituted C ₁ -C ₆ alkyl (eg methyl). In some embodiments, R ²³ is —NH ₂ . In some embodiments, R ²³ is —NH(CH ₂ CH ₃ ). In some embodiments, R ²³ is —NH(CH ₂ CH ₂ OCH ₃ ). In some embodiments, R ²³ is —N(CH ₃ )(CH ₂ CH ₂ OCH ₃ ). In some embodiments, R ²³ is —N(CH ₃ )C(O)CH ₃ .

In some embodiments, R ²³ is -OR ²⁶ . In some embodiments, R ²⁶ is hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ²⁶ unsubstituted C ₁ -C ₆ alkyl (eg, methyl) or substituted C ₁ -C ₆ alkyl (eg, C ₁ -C substituted with one or more halogen atoms) ₆ alkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl). In some embodiments, R ²³ is -OH. In some embodiments, R ²³ is -OCH ₃ . In some embodiments, R ²³ is -OCH ₂ CH ₂ . In some embodiments, R ²³ is -OCHF ₂ . In some embodiments, R ²³ is -OCF ₃ .

In some embodiments, R ²³ is —C(O)R ²⁸ . In some embodiments, R ²⁸ is optionally substituted alkyl of C ₁ -C ₆ (e.g. methyl) or optionally substituted alkyl of C ₁ -C _6. In some embodiments, R ²⁸ is —OR ³⁶ , wherein R ³⁶ is hydrogen or optionally substituted C ₁ -C ₆ alkyl (eg, methyl or ethyl). In some embodiments, R ²⁸ is -N(R ³⁷ )R ³⁸ , wherein R ³⁷ and R ^{38 are} each independently hydrogen or optionally substituted C ₁ -C ₆ alkyl (eg, methyl and ethyl) . In some embodiments, R ²³ is —C(O)OH. In some embodiments, R ²³ is -C(O)OCH ₂ CH ₃ . In some embodiments, R ²³ is —C(O)NH ₂ . In some embodiments, R ²³ is —C(O)NHCH ₃ . In some embodiments, R ²³ is —C(O)N(CH ₃ ) ₂ .

In some embodiments, R ²³ is hydrogen, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ²³ is unsubstituted C ₁ -C ₆ alkyl (eg, methyl) or substituted C ₁ -C ₆ alkyl (eg, C ₁ - substituted with one or more halogen atoms) C ₆ alkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl and 2,2,2-trifluoroethyl base). In some embodiments, R ²³ is optionally substituted C ₃ -C ₆ cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

In some such embodiments, R ²³ is hydrogen, halogen, -N(R ²⁴ )R ²⁵ , -OR ²⁶ , -SR ²⁷ , -S(O)R ²⁷ , -S(O) ₂ R ²⁷ ,- C(O)R ²⁸ or optionally substituted heterocycloalkyl. In other embodiments, R ²³ is hydrogen, -N(R ²⁴ )R ²⁵ (eg, -N(alkyl)alkylsulfonylamino, such as N-methyl-methanesulfonylamino) or, as appropriate, Substituted heterocycloalkyl (e.g., optionally substituted cyclic sulfonamide). In other embodiments, R ²³ is hydrogen or -N(R ²⁴ )R ²⁵ (eg, -N(alkyl)alkylsulfonylamino, such as N-methyl-methanesulfonylamino). In other embodiments, R ²³ is hydrogen. In other embodiments, R ²³ is -N(R ²⁴ )R ²⁵ (eg, -N(alkyl)alkylsulfonylamino, such as N-methyl-methanesulfonylamino) or optionally substituted Heterocycloalkyl (e.g., cyclic sulfonylamino). In other embodiments, R<^23> is -N(R<^24>)R<^25> (eg, -N(alkyl)alkylsulfonylamino, such as N-methyl-methanesulfonylamino). In other embodiments, R ²³ is optionally substituted heterocycloalkyl (eg, optionally substituted cyclic sulfonamide, such as optionally substituted ). In some embodiments, R ²³ is . In some embodiments, R ²³ is . In some embodiments, R ²³ is . In other embodiments, R ²³ is -OR ²⁶ . In other embodiments, R ²³ is -SR ²⁷ , -S(O)R ²⁷ or -S(O) ₂ R ²⁷ . In other embodiments, R ²³ is -C(O)R ²⁸ . In some embodiments, R ²³ is hydrogen, selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl And the heteroaryl group is replaced as appropriate. In some embodiments, R ²³ is an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, R ²³ is an optionally substituted alkyl. In some embodiments, R ²³ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ²³ is methyl. In some embodiments, R ²³ is optionally substituted cycloalkyl. In some embodiments, R ²³ is optionally substituted heterocycloalkyl. In some embodiments, R ²³ is selected from the group consisting of cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl The part that has been replaced as appropriate. In some embodiments, R ²³ is an optionally substituted moiety selected from the group consisting of aryl, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, R ²³ is an optionally substituted moiety selected from the group consisting of aryl and heteroaryl. In some embodiments, R ²³ is an optionally substituted aryl. In some embodiments, R ²³ is optionally substituted heteroaryl.

In some embodiments, R ²³ is optionally substituted heterocycloalkyl. In some embodiments, R ²³ is optionally substituted pyrrolidinyl (eg, 1-pyrrolididyl or pendant oxy-substituted pyrrolidinyl, such as and ). In some embodiments, R ²³ is optionally substituted oxazolidinyl (eg, oxazolidinyl substituted by pendant oxy group, such as ). In some embodiments, R ²³ is an optionally substituted oxadiazolyl group (eg, a oxadiazolyl substituted with a pendant oxy group, such as ). In some embodiments, R ²³ is optionally substituted piperidinyl (eg, 1-piperidinyl or piperidinyl substituted by pendant oxy group, such as ).

In some embodiments, R ²³ is selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidinyl group, pyran, pyrazine The substituted portion of the group, pyrrolyl group and furyl group as appropriate. In some embodiments, R ²³ is an optionally substituted moiety selected from the group consisting of thiazolyl, oxadiazolyl, oxazolyl, imidazolyl, pyrrolyl, and pyrazinyl. In some embodiments, R ²³ is optionally substituted phenyl. In some embodiments, R ²³ is optionally substituted pyridyl. In some embodiments, R ²³ is optionally substituted thiazolyl. In some embodiments, R ²³ is an optionally substituted oxazolyl group. In some embodiments, R ²³ is an optionally substituted oxadiazolyl. In some embodiments, R ²³ is an optionally substituted imidazolyl group. In some embodiments, R ²³ is optionally substituted pyrazolyl. In some embodiments, R ²³ is an optionally substituted isoxazolyl group. In some embodiments, R ²³ is optionally substituted pyrimidinyl. In some embodiments, R ²³ is optionally substituted pyrazinyl. In some embodiments, R ²³ is optionally substituted piperidyl. In some embodiments, R ²³ is optionally substituted furanyl. In some embodiments, R ²³ is optionally substituted 2-thiazolyl. In some embodiments, R ²³ is optionally substituted 2-oxazolyl. In some embodiments, R ²³ is optionally substituted 5-oxazolyl.

In some embodiments, R ²³ is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R ²³ is optionally substituted phenyl (eg, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 2-cyanophenyl). In some embodiments, R ²³ is optionally substituted furanyl (eg, 2-furyl or 3-furanyl). In some embodiments, R ²³ is optionally substituted thienyl (eg, 2-thienyl or 3-thienyl). In some embodiments, R ²³ is optionally substituted pyrrolyl (eg, 1-pyrrolyl or 1-methylpyrrol-2-yl). In some embodiments, R ²³ is optionally substituted oxazolyl (eg, 2-oxazolyl or 5-oxazolyl). In some embodiments, R ²³ is an optionally substituted isoxazolyl (eg, 3-isoxazolyl or 5-isoxazolyl). In some embodiments, R ²³ is optionally substituted thiazolyl (eg, 2-thiazolyl, 2-methylthiazol-4-yl or 4,5-dimethylthiazol-2-yl). In some embodiments, R ²³ is optionally substituted pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methylpyrazol-3-yl, 1- Methylpyrazol-4-yl or 1-methylpyrazol-5-yl). In some embodiments, R ²³ is optionally substituted imidazolyl (eg, 1-imidazolyl, 2-imidazolyl or 1-methylimidazol-2-yl). In some embodiments, R ²³ is optionally substituted oxadiazolyl (eg, 1,3,4-oxadiazol-2-yl or 5-methyl-1,3,4-oxadiazole-2) -base). In some embodiments, R ²³ is optionally substituted triazolyl (eg, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl or 1,2,5 - Triazol-1-yl). In some embodiments, R ²³ is optionally substituted pyridyl (eg, 2-pyridyl, 3-pyridyl or 4-pyridyl). In some embodiments, R ²³ is optionally substituted pyrimidinyl (eg, 5-pyrimidinyl). In some embodiments, R ²³ is optionally substituted pyrazinyl (eg, 2-pyrazinyl).

The substituent on R ²³ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a nitro group, an amine group, an imido group, a cyano group. , halo, haloalkyl, fluorenyl, sulfanyl, sulfonyl, thioguanamine, formazan, pendant oxy, amidoxime, methylamine, imidazolyl, fluorenyl, sulfonium Amine, carboxyl, methionyl, alkyl, cycloalkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy, aminocarbonyl, aryl, heteroaryl, aryl Carbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aminecaraki and urea.

In some embodiments, the optionally substituted substituent on R ²³ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, OCHF ₂ ).

In some embodiments, A ² has the formula:

Wherein L ² , L ³ , R ²⁰ , R ²¹ and R ^{22 are} as defined herein.

In some embodiments, L ² is optionally substituted C ₂ -C ₅ alkyl and L ³ is a bond. In a variation, L ² is optionally substituted C ₂ -C ₄ alkyl and L ³ is a bond. In another variation, L ² is an optionally substituted ethyl group and L ³ is a bond. In another variation, L ² is an optionally substituted propyl group and L ³ is a bond. In another variation, L ² is an optionally substituted butyl group and L ³ is a bond. In a variation, L ² is C ₂ -C ₄ alkyl and L ³ is a bond. In another variation, L ² is an exoethyl, propyl or butyl group and L ³ is a bond. In another variation, L ² is a propyl group and L ³ is a bond. In another variation, L ² is a butyl group and L ³ is a bond.

In some embodiments, L ² is optionally substituted C ₁ -C ₄ alkylene and L ³ is optionally substituted methylene. In a variation, L ² is optionally substituted C ₂ -C ₄ alkyl and L ³ is optionally substituted methylene. In another variation, L ² is an optionally substituted ethyl group and L ³ is an optionally substituted methylene group. In another variation, L ² is an optionally substituted propyl group and L ³ is an optionally substituted methylene group. In a variation, L ² is a C ₁ -C ₃ alkylene group and L ³ is a methylene group. In another variation, L ² is methylene or ethyl and L ³ is methylene. In a particular variation, each of L ² and L ³ is a methylene group.

In some embodiments, L ² is optionally substituted C ₁ -C ₃ alkyl and L ³ is optionally substituted ethyl. In some variations, L ² is optionally substituted methylene or ethyl and L ³ is optionally substituted propyl. In some variations, L ² is an optionally substituted propyl group and L ³ is an optionally substituted butyl group.

In some embodiments, L ² is a bond and L ³ is optionally substituted C ₂ -C ₅ alkyl. In a variation, L ² is a bond and L ³ is optionally substituted C ₂ -C ₄ alkyl. In another variation, L ² is a bond and L ³ is an optionally substituted ethyl group. In another variation, L ² is a bond and L ³ is an optionally substituted propyl group. In another variation, L ² is a bond and L ³ is an optionally substituted butyl group.

In some embodiments, A ² has the formula:

Wherein R ²⁰ and R ^{22 are} as defined herein.

In some embodiments, A ² has the formula:

Wherein R ²⁰ and R ^{22 are} as defined herein. In a variation, each of R ²⁰ and R ²² is hydrogen.

In some embodiments, A ² has the formula:

Wherein R ²¹ and R ^{22 are} as defined herein.

In some embodiments, A ² has the formula:

Wherein R ²¹ and R ^{22 are} as defined herein. In a variation, R ²¹ and R ^{22 are} each hydrogen.

In some such embodiments, R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen or optionally substituted C ₁ -C ₁₀ alkyl. In some embodiments, R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, at least one of R ²⁰ , R ²¹ and R ²² is hydrogen. In some embodiments, R ²⁰ , R ²¹ and R ²² are hydrogen.

In some such embodiments, R ²² is hydrogen. In some embodiments, R ²² is hydrogen; and, where applicable, R ²⁰ or R ²¹ is hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ²² is hydrogen; and where applicable R ²⁰ and R ²¹ are hydrogen or methyl. In some embodiments, R ²² is hydrogen and, where applicable, R ²⁰ or R ²¹ is methyl. In some embodiments, at least one of R ²⁰ , R ²¹ or R ²² is —N(R ²⁴ )R ²⁵ . In some embodiments, R ²⁰ or R ²¹ is -N(R ²⁴ )R ²⁵ when applicable. In some embodiments, R ²² is —N(R ²⁴ )R ²⁵ .

In some such embodiments, R ²⁴ and R ^{25 are} independently hydrogen or are optionally substituted from alkyl and heteroalkyl. In some embodiments, R ²⁴ and R ^{25 are} independently hydrogen or 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 embodiments, at least one of R ²⁴ and R ²⁵ is an optionally substituted alkyl. In some embodiments, R ²⁴ and R ^{25 are} independently alkyl as appropriate. In some embodiments, at least one of R ²⁴ and R ²⁵ is methyl. In some embodiments, R ²⁴ and R ^{25 are} independently hydrogen, optionally substituted alkyl, -C(O)R ²⁹ or -S(O) ₂ R ³⁰ . In some embodiments, one of R ²⁴ and R ²⁵ is -C(O)R ²⁹ or -S(O) ₂ R ³⁰ . In some embodiments, one of R ²⁴ and R ²⁵ is -C(O)R ²⁹ . In some embodiments, one of R ²⁴ and R ²⁵ is -S(O) ₂ R ³⁰ .

In some such embodiments, R ^{29 is} independently hydrogen, optionally substituted alkyl, -N(R ³¹ )R ³² or -OR ³³ . In some embodiments, R ^{29 is} independently hydrogen or optionally substituted alkyl. In some embodiments, R ²⁹ is hydrogen. In some embodiments, R ²⁹ is an optionally substituted alkyl. In some embodiments, R ²⁹ is methyl. In some embodiments, R ^{29 is} independently -N(R ³¹ )R ³² or -OR ³³ . In some embodiments, R ²⁹ is —N(R ³¹ )R ³² . In some embodiments, R ²⁹ is -OR ³³ .

In some such embodiments, R ³¹ , R ³² and R ^{33 are,} independently, hydrogen or optionally substituted alkyl.

In some embodiments, R ³⁰ is an optionally substituted alkyl. In some embodiments, R ³⁰ is methyl.

In some such embodiments, A ² has the formula:

Wherein R ²³ is halogen (for example F, Cl, Br or I) or an optionally substituted alkoxy group (for example methoxy or trifluoromethoxy).

In some embodiments, A ² has the formula:

Wherein each R ^{39 is} independently hydrogen or optionally substituted alkyl. In some embodiments, R ³⁹ is hydrogen. In some embodiments, R ³⁹ is an optionally substituted alkyl. In some embodiments, R ³⁹ is optionally substituted C ₁ -C ₆ alkyl (eg, methyl or ethyl).

In some embodiments, A ² has the formula:

Wherein each R ^{40 is} independently halogen or optionally substituted alkyl. In some embodiments, R ⁴⁰ is halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁴⁰ is optionally substituted alkoxy (eg, methoxy or trifluoromethoxy).

In some embodiments, the compound has the formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), ( Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variations Form, wherein X ¹ and X ^{2 are} independently N or CH. In some embodiments, X ¹ is N. In some embodiments, X ² is N. In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, X ¹ is CH. In some embodiments, X ² is CH. In some embodiments, X ¹ and X ^{2 are} each CH. In some embodiments, X ¹ is N and X ² is CH. In some embodiments, X ¹ is CH and X ² is N.

In some embodiments, the compound has Formula I, II, III, IV, or any variation thereof, wherein R ³ is hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O R ¹² , or selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl The part that has been replaced as appropriate. In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is —N(R ⁸ )R ⁹ , —S(O) ₂ R ¹¹ , —C(O)R ¹² . In some embodiments, R ³ is selected from alkyl, cycloalkyl, cycloalkyl - alkyl, heterocycloalkyl, heterocycloalkyl-alkyl - alkyl, aryl, arylalkyl, heteroaryl, and heteroaryl The part of the alkyl group that has been replaced as appropriate.

In some such embodiments, R ³ is hydrogen, -C(O) ^t Bu, or is selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl The aryl, aralkyl, heteroaryl and heteroarylalkyl groups are optionally substituted. In some embodiments, R ³ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, and cycloalkyl-alkyl groups as appropriate. In some embodiments, R ³ is hydrogen or an optionally substituted alkyl. In some embodiments, R ³ is hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is methyl. In some embodiments, R ³ is —C(O) ^t Bu.

In some embodiments, the optionally substituted substituent on R ³ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, OCHF ₂ ).

In some embodiments, the compound has Formula I, II, III, IV, or any variation thereof, wherein R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, hetero Optionally substituted as a cycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group. In some embodiments, R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, and cycloalkyl-alkyl groups as appropriate. In some embodiments, R ⁵ is hydrogen or optionally substituted alkyl. In some embodiments, R ⁵ is hydrogen or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is optionally substituted C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is methyl.

In some embodiments, the optionally substituted R ⁵ substituent may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, -OCHF ₂ ).

In some embodiments, the compound has the formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), ( Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variations a form wherein R ^{7A is} selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycloalkyl, heterocycloalkyl- Optionally substituted for alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups. In some embodiments, R ^7A is an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl, and cycloalkyl-alkyl. In some embodiments, R ^7A is an optionally substituted alkyl. In some embodiments, R ^7A is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^7A is methyl.

In some embodiments, R ^7A is an optionally substituted moiety selected from the group consisting of -alkyl-OR ¹⁰ and -alkyl-N(R ⁸ )R ⁹ . In some embodiments, R ^7A is optionally substituted alkyl-OR ¹⁰ . In some embodiments, R ^7A is —CH ₂ OCH ₃ .

In some embodiments, R ^7A is an optionally substituted moiety selected from the group consisting of heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, R ^7A is optionally substituted aralkyl. In some embodiments, R ^7A is optionally substituted alkyl-phenyl (eg, benzyl or 3-phenylpropyl).

In some embodiments, R ^7A is an optionally substituted moiety selected from the group consisting of phenyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, Pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienophenyl, thioxyl, oxazolyl, benzimidazolyl, benzothienyl, benzofuranyl, Mercapto, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzisoxazole , dimethyl endocarbazide, pyrazinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, fluorenyl, diazenium, aziridine, thioxyl, piperidinyl and oxindole base. In some embodiments, R ^7A is selected from pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, and furanyl The part that has been replaced as appropriate. In some embodiments, R ^7A is an optionally substituted moiety selected from the group consisting of pyridyl and imidazolyl (eg, 1-methylimidazol-2-yl).

In some embodiments, the optionally substituted substituent on R ^7A may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, -OCHF ₂ ).

In some embodiments, the compound has Formula I, II, III, IV, or any variation thereof, wherein R ^7A, together with R ⁵ , forms an optionally substituted propyl group. In some embodiments, R ^7A together with R ⁵ form an unsubstituted extended propyl group. In some embodiments, R ^7A, together with R ⁵ , form a stretched propyl group, optionally substituted with one, two, three or more, selected from the group consisting of, but not limited to, a hydroxy group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propyl Oxyl, isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted with 1-3 halogens (eg, -CF ₃ , -CHF ₂ , -CH ₂ F , -OCH ₂ F, -OCHF ₂ ).

In some embodiments, the compound has Formula I, II, III, or any variation thereof, wherein R ^7B is R ⁴ -L ⁴ - or together with R ^7A and the carbon to which they are attached form an R ⁴ -L ⁴ - substitution a cycloalkyl ring.

In some such embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is an optionally substituted moiety selected from the group consisting of alkyl and heteroalkyl. In some embodiments, R ⁴ is an optionally substituted moiety selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments, R ⁴ is an optionally substituted moiety selected from the group consisting of cycloalkyl and heterocycloalkyl. In some embodiments, R ⁴ is an optionally substituted moiety selected from the group consisting of aryl and heteroaryl. In some embodiments, R ⁴ is an optionally substituted aryl (eg, phenyl, 4-fluorophenyl, 3,5-difluorophenyl or 3-fluorophenyl). In some embodiments, R ⁴ is optionally substituted heteroaryl. In some embodiments, R ⁴ is phenyl, optionally substituted with one or more halogens. In some embodiments, R ⁴ is phenyl, 4-fluorophenyl, 3,5-difluorophenyl or 3-fluorophenyl. In some embodiments, R ⁴ is phenyl or 4-fluorophenyl. In some embodiments, R ⁴ is phenyl. In some embodiments, R ⁴ is 3,5-difluorophenyl. In some embodiments, R ⁴ is 4-fluorophenyl. In some embodiments, R ⁴ is 3-fluorophenyl.

In some embodiments, the substituent on R ⁴ optionally substituted may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, -OCHF ₂ ).

In some such embodiments, L ⁴ is a bond or an optionally substituted alkyl. In some embodiments, L ⁴ is a bond. In some embodiments, L ⁴ is an optionally substituted alkylene group. In some embodiments, L ⁴ is optionally substituted C ₁ -C ₆ alkylene. In some embodiments, L ⁴ is C ₁ -C ₆ alkylene. In some embodiments, L ⁴ is a methylene group (eg, when L ⁴ -R ⁴ is, for example, -CH ₂ -phenyl or -CH ₂ -difluorophenyl).

In some embodiments, the optionally substituted substituent on L ⁴ may be one, two, three or more selected from the group consisting of, but not limited to, a hydroxyl group, a halogen group (such as F, Cl, Br, I), C ₁ -C ₆ alkyl (eg methyl, ethyl, propyl, isopropyl) or C ₁ -C ₆ alkoxy (methoxy, ethoxy, propoxy) , isopropoxy), wherein C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted by 1-3 halogens (for example -CF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F, -OCHF ₂ ).

In some such embodiments, the compound has the formula (IV):

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ² , L ⁴ , X ¹ , X ² , R ¹ , R ² , R ^J , R ⁴ , R ⁵ and R ^{7A are} as ^defined for formula (I) And any variations thereof are defined.

In some such 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 , X ¹ , X ² , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^7A and R ^{7B are} as defined for formula (I) and any variants thereof. In some such embodiments, the compound has the formula (IVa-1):

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

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

In some embodiments, the compound has the formula (V)

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , X ¹ , X ² , R ^6A , R ^6B , R ^7A and R ^{7B are} as ^defined for formula (I) and any variant thereof definition. In some embodiments, R ^6A is hydrogen. In some embodiments, R ^6A is halo (eg, fluoro). In some embodiments, R ^6B is hydrogen. In some embodiments, R ^6B is halo (eg, 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, A ¹ is optionally substituted thiazolyl (eg, 4-methylthiazol-2-yl or 4-(fluoromethyl)thiazol-2-yl). In some embodiments, A ¹ is optionally substituted oxazolyl (eg, 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 X ² are N. In some embodiments, X ¹ is N and X ² is CH. In some embodiments, X ¹ is CH and X ² is N. In some embodiments, both X ¹ and X ² are CH. In some embodiments, R ^7A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, R ^7A is methyl. In some embodiments, R ^7B is optionally substituted alkyl-phenyl (eg, benzyl or 4-fluorobenzyl).

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , X ¹ , X ² , R ^6A , R ^6B , R ^7A and R ^{7B are} as defined for formula (V).

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^6B and R ^{7A are} as ^defined for formula (I) and any The variant is defined. In some embodiments, A ¹ , A ² , L ⁴ , X ¹ , X ₂ , R ^6A , R ^{6B ,} and R ^{7A are} as defined for formula (V). In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ is 4-methylthiazol-2-yl, 4-(fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl and R ⁴ is phenyl or 4 - Fluorophenyl.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , L ⁴ , X ¹ , X ² , Y, R ⁴ , R ^6A , R ^6B , R ⁷ A, R ²⁰ , R ²¹ And R ^{22 is} as defined for formula (I). In some embodiments, A ¹ , A ² , L ⁴ , X ¹ , X ² , Y, R ⁴ , R ^6A , R ^6B , R ^7A , R ²⁰ , R ²¹ and R ^{22 are} as detailed herein. Any suitable variation of formula (I) is described as if each variant was described individually. In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^{6B ,} and R ^{7A are} as defined for formula (V). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, 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 a fluoro group. In some embodiments, R ^6A and R ^{6B are} each hydrogen. In some embodiments, each of R ^6A and R ^6B is a fluoro group. In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ 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-methyloxazole-2- And R ⁴ is phenyl or 4-fluorophenyl. In some embodiments, R ^{23 is} as described for any of the applicable variations of Formula (I) detailed herein, as is each individual variant described.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , L ⁴ , X ¹ , X ² , Y, R ⁴ , R ^6A , R ^6B , R ^7A , R ²⁰ , R ²¹ and R ^{22 is} as defined for formula (I). In some embodiments, A ¹ , A ² , L ⁴ , X ¹ , X ² , Y, R ⁴ , R ^6A , R ^6B , R ^7A , R ²⁰ , R ²¹ and R ^{22 are} as detailed herein. Any suitable variation of formula (I) is described as if each variant was described individually. In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^{6B ,} and R ^{7A are} as defined for formula (V). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, 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 a fluoro group. In some embodiments, R ^6A and R ^{6B are} each hydrogen. In some embodiments, each of R ^6A and R ^6B is a fluoro group. In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ 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-methyloxazole-2- And R ⁴ is phenyl or 4-fluorophenyl. In some embodiments, R ^{23 is} as described for any of the applicable variations of Formula (I) detailed herein, as is each individual variant described.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^6B , R ^7A and R ^{23 are} as defined for formula (I). In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^6B , R ^7A and R ^{23 are} as described for any suitable variation of formula (I) as detailed herein. Just like each variant is described individually. In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^{6B ,} and R ^{7A are} as defined for formula (V). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, 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 a fluoro group. In some embodiments, R ^6A and R ^{6B are} each hydrogen. In some embodiments, each of R ^6A and R ^6B is a fluoro group. In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ 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-methyloxazole-2- And R ⁴ is phenyl or 4-fluorophenyl. In some embodiments, R ^{23 is} as described for any of the applicable variations of Formula (I) detailed herein, as is each individual variant described.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^6B and R ^{7A are} as defined for formula (I), and Y is N Or CH, R ⁴⁰ is halogen or optionally substituted alkoxy. In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R ⁴⁰ is optionally substituted C ₁ -C ₆ alkoxy (eg, methoxy). In some embodiments, R ⁴⁰ is halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁴⁰ is a fluoro group. In some embodiments, R ⁴⁰ is a chloro group. In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^6B and R ^{7A are} as described for any suitable variation of formula (I) as detailed herein. Each variation is described in detail individually. In some embodiments, A ¹ , L ⁴ , X ¹ , X ² , R ⁴ , R ^6A , R ^{6B ,} and R ^{7A are} as defined for formula (V). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, 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 a fluoro group. In some embodiments, R ^6A and R ^{6B are} each hydrogen. In some embodiments, each of R ^6A and R ^6B is a fluoro group. In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ 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-methyloxazole-2- And R ⁴ is phenyl or 4-fluorophenyl.

In some embodiments, the compound has the formula (VI):

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , L ¹ , X ¹ , X ² , R ² , R ^7A and R ^{7B are} as ^defined for formula (I) and any variant thereof definition. In some embodiments, A ¹ is optionally substituted thiazolyl (eg, 4-methylthiazol-2-yl or 4-(fluoromethyl)thiazol-2-yl). In some embodiments, A ¹ is optionally substituted oxazolyl (eg, 4-methyloxazol-2-yl). In some embodiments, L ¹ is a methylene group. In some embodiments, R ² is H or optionally substituted alkyl. In some embodiments, R ² is H. In some embodiments, R ² is an optionally substituted alkyl (eg, methyl). In some embodiments, R ² is optionally substituted cycloalkyl (eg, cyclopropyl or cyclopentyl). In some embodiments, X ¹ is N. In some embodiments, X ² is N. In some embodiments, both X ¹ and X ² are N. In some embodiments, X ¹ is N and X ² is CH. In some embodiments, X ¹ is CH and X ² is N. In some embodiments, both X ¹ and X ² are CH. In some embodiments, R ^7A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, R ^7A is methyl. In some embodiments, R ^7B is optionally substituted alkyl-phenyl (eg, benzyl or 4-fluorobenzyl).

In some embodiments, the compound has the formula (VIa):

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , A ² , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ⁴ and R ^{7A are} as ^defined for formula (I) and any The variant is defined. In some embodiments, A ¹ , A ² , L ¹ , X ¹ , X ² , R ² and R ^{7A are} as defined for formula (VI). In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ is optionally substituted thiazolyl and R ⁴ is optionally substituted phenyl. In some embodiments, A ¹ is 4-methylthiazol-2-yl, 4-(fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl and R ⁴ is phenyl or 4 - Fluorophenyl.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ¹ , L ⁴ , X ¹ , X ² , Y, R ² , R ⁴ , R ^7A , R ²⁰ , R ²¹ and R ^{22 are} as defined It is defined for formula (I) and any variations thereof. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ^{4 ,} 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, both R ²⁰ and R ²² are hydrogen. In some embodiments, R ²¹ is hydrogen.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ¹ , L ⁴ , X ¹ , X ² , Y, R ² , R ⁴ , R ^7A , R ²⁰ , R ²¹ and R ^{22 are} as defined It is defined for formula (I) and any variations thereof. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ^{4 ,} 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, both R ²⁰ and R ²² are hydrogen. In some embodiments, R ²¹ is hydrogen.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ⁴ , R ^7A and R ^{23 are} as defined for formula (I) and any The variant is defined. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ⁴ , R ^7A and R ^{23 are} as described for any suitable variation of formula (I) as detailed herein. Just like each variant is described individually. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ^{4 ,} and R ^{7A are} as defined for formula (VI) or (VIa). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, methyl). In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, A ¹ optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted thienyl, optionally substituted oxadiazole A pyridyl group substituted or optionally substituted pyrazinyl, as appropriate. In some embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene (eg, methylene or methylmethylene). In some embodiments, A ¹ is 2-methyloxazol-4-yl and 2,5-dimethyloxazol-4-yl. In some embodiments, A ¹ is thiazol-2-yl, 4-methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4-bromothiazol-2-yl, 4-cyclopropylthiazole 2-yl, 4-(methoxymethyl)thiazol-2-yl, 4,5-dimethylthiazol-2-yl and 2-methylthiazol-4-yl. In some embodiments, A ¹ is 2-thienyl. In some embodiments, A ¹ is 3-methyl-1,2,4-oxadiazol-5-yl. In some embodiments, A ¹ is 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 1-methylpyridyl Zyrid-5-yl and 1,5-dimethylpyrazol-4-yl. In some embodiments, A ¹ is 6-methylpyridin-3-yl, 6-methylpyridin-2-yl or 4-pyridyl. In some embodiments, A ¹ is 2-pyrazinyl. In some embodiments, R ² is hydrogen, optionally substituted C ₁ -C ₆ alkyl or optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is methyl, ethyl, 2-fluoroethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or t-butyl. In some embodiments, R ² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ^{23 is} as described for any of the applicable variations of Formula (I) detailed herein, as is each individual variant described.

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

Or a pharmaceutically acceptable salt or solvate thereof, wherein A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ⁴ and R ^{7A are} as defined for formula (I), and Y is N Or CH, R ⁴⁰ is halogen or optionally substituted alkoxy. In some embodiments, Y is CH. In some embodiments, Y is N. In some embodiments, R ⁴⁰ is optionally substituted C ₁ -C ₆ alkoxy (eg, methoxy). In some embodiments, R ⁴⁰ is halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁴⁰ is a fluoro group. In some embodiments, R ⁴⁰ is a chloro group. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ⁴ and R ^{7A are} as described for any suitable variation of formula (I) as detailed herein. Each variation is described in detail individually. In some embodiments, A ¹ , L ¹ , L ⁴ , X ¹ , X ² , R ² , R ^{4 ,} and R ^{7A are} as defined for formula (VI) or (VIa). In some embodiments, X ¹ and X ^{2 are} each N. In some embodiments, one of X ¹ and X ² is N and the other is CH. In some embodiments, R ^7A is C ₁ -C ₆ alkyl (eg, methyl). In some embodiments, L ⁴ is a methylene group. In some embodiments, R ⁴ is substituted or unsubstituted aryl (eg, phenyl or 4-fluorophenyl). In some embodiments, L ¹ is optionally substituted C ₁ -C ₆ alkylene (eg, methylene or methylmethylene). In some embodiments, A ¹ optionally substituted thiazolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted thienyl, optionally substituted oxadiazole A pyridyl group substituted or optionally substituted pyrazinyl, as appropriate. In some embodiments, A ¹ is 2-methyloxazol-4-yl and 2,5-dimethyloxazol-4-yl. In some embodiments, A ¹ is thiazol-2-yl, 4-methylthiazol-2-yl, 4-ethylthiazol-2-yl, 4-bromothiazol-2-yl, 4-cyclopropylthiazole 2-yl, 4-(methoxymethyl)thiazol-2-yl, 4,5-dimethylthiazol-2-yl and 2-methylthiazol-4-yl. In some embodiments, A ¹ is 2-thienyl. In some embodiments, A ¹ is 3-methyl-1,2,4-oxadiazol-5-yl. In some embodiments, A ¹ is 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 1-methylpyridyl Zyrid-5-yl and 1,5-dimethylpyrazol-4-yl. In some embodiments, A ¹ is 6-methylpyridin-3-yl, 6-methylpyridin-2-yl or 4-pyridyl. In some embodiments, A ¹ is 2-pyrazinyl. In some embodiments, R ² is hydrogen, optionally substituted C ₁ -C ₆ alkyl or optionally substituted C ₃ -C ₆ cycloalkyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is methyl, ethyl, 2-fluoroethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or t-butyl. In some embodiments, R ² is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

In some embodiments, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any variation thereof, any of the compounds of Example 2 and/or Table 1 in a substantially pure form. Unless otherwise specified, "substantially pure" is intended to mean a formulation containing no more than 15% of an impurity, wherein the impurity is intended to be a compound other than the indicated inhibitor compound, but does not include other forms of the inhibitor compound ( For example, different salt forms of the compounds or different stereoisomers, conformers, rotamers or tautomers). In a variation, a formulation of substantially pure compound is provided, wherein the formulation contains no more than 25% impurities, or no more than 20% impurities, or no more than 10% impurities, or no more than 5% impurities, or no more than 3% Impurities, or no more than 1% impurities, or no more than 0.5% impurities. In some embodiments, the compound is present in an amount of no greater than 15% or no greater than 10% or no greater than 5% or no greater than 3% or no greater than 1% of the total amount of the compound in different stereochemical forms (eg, when present) The total R, R, S, R, R, S forms are not more than 15% or not more than 10% or not more than 5% or not more than 3% or not more than 1% of the S, S compound).

Unless otherwise specified, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any variation thereof, any of the compounds of Example 2 and/or Table 1 and methods of use thereof include all solvate and/or hydrate forms. In some embodiments, the compounds described herein can exist in unsolvated as well as solvated forms (ie, solvates). The compounds may also include hydrated forms (i.e., hydrates).

Unless otherwise specified, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any variation thereof, any of the compounds of Example 2 and/or Table 1 and methods of use thereof include all salt forms of the compounds. The compounds also include all non-salt forms of any of the salts of the compounds described herein, as well as other salts of any of the salts of the compounds described herein. In some embodiments, the salt of the compound is a pharmaceutically acceptable salt. The desired salt of the basic functional group of the compound can be prepared by treating the compound with an acid by methods known to those skilled in the art. The desired salt of the acidic functional group of the compound can be prepared by treating the compound with a base by methods known to those skilled in the art. Examples of the inorganic salt of the acid compound include, but are not limited to, alkali metal and alkaline earth metal salts such as sodium salt, potassium salt, magnesium salt, barium salt, and calcium salt; ammonium salt; and aluminum salt. Examples of organic salts of acid compounds include, but are not limited to, procaine, benzhydrylamine, N -ethylpiperidine, N,N' -dibenzylethylenediamine, trimethylamine, and Triethylamine salt. Examples of inorganic salts of base compounds include, but are not limited to, hydrochlorides and hydrobromides. Examples of organic salts of base compounds include, but are not limited to, tartrate, citrate, maleate, fumarate, and succinate. In some embodiments, the compound is in the form of the hydrochloride salt, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, antibutene Acid salt, tartrate (eg (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate and with amino acids (such as glutamic acid) ) the salt formed. In some embodiments, the compounds described herein exist as citrate (eg, monocitrate, hydrogen citrate or dihydrogen citrate) and/or mesylate (eg, dimesylate). . Such salts can be prepared by methods known to those skilled in the art.

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

In addition to the salt form, a compound in the form of a prodrug is also provided. Prodrugs of the compounds described herein are susceptible to undergoing chemical changes under physiological conditions to provide the desired compound (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII) And (VIII), (IX), (X) or any of their variations, any of the compounds of Example 2 and/or Table 1). In addition, prodrugs can be converted to the compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound described herein when placed in a transdermal patch reservoir having a suitable enzyme or chemical reagent.

Metabolites of the compounds are also covered. Metabolites can include primary metabolites and/or secondary metabolites. However, the claimed compounds do not include metabolites of substances naturally present in the individual.

Unless explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to encompass all possible stereoisomers, conformers, rotamers, and tautomers of the compound. For example, a compound containing a palmitic carbon atom is intended to encompass the ( R ) enantiomer and the ( S ) enantiomer. A compound containing a plurality of palmitic carbon atoms is intended to cover all enantiomers and diastereomers (including ( R , R ), ( S , S ), ( R , S ) and ( R , S ) isomer). When a compound is specifically indicated in a particular stereochemical arrangement (e.g., 2S, 3R), in other embodiments, the compound can be described in another particular stereochemical arrangement (e.g., 2R, 3S) and/or a mixture of stereochemical arrangements.

The composition may contain a compound in the form of a mixture of stereoisomers, wherein the mixture may be an equal or unequal amount of enantiomers (e.g., S, S and R, R) or diastereomers ( For example, S, S and R, S or S, R). The composition may contain a compound in the form of a mixture of two or three or four such stereoisomers in any ratio of stereoisomers.

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

Any one of stereochemical, enantiomeric, diastereomeric, conformational, isomerism, tautomerism, isotope, solvate, hydrate, salt, and pharmaceutically acceptable salt of the compound Or all of them are included in all uses of the compounds disclosed herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa- 2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX) , (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1).

II. General synthetic methods

The compounds herein are synthesized by appropriate combination of synthetic methods well known in the art. Techniques suitable for the synthesis of the compounds herein are apparent to those skilled in the art in light of the teachings herein. The following discussion is provided to illustrate certain different methods that can be used to assemble the compounds herein. However, this discussion is not intended to define the scope of the reactions or reaction sequences that are suitable for the preparation of the compounds herein.

The oxadiazole compounds described herein can be synthesized according to Scheme I. In an alternative, the carboxylic acid A is converted to 醯肼C , which is coupled with the carboxylic acid B to form the intermediate E. In another alternative, the carboxylic acid B is converted to 醯肼D , which is coupled with the carboxylic acid A to form the intermediate E. The intermediate E is treated with a dehydrating agent such as Burgess' Reagent to form the oxadiazole compound F. Appropriate protecting groups are used in any of the reaction steps as necessary.

Scheme 2 shows an exemplary synthesis of an oxadiazole compound described herein according to Scheme 1. The acid A' is coupled to 醯肼D' to give the intermediate E' which undergoes cyclization to form the oxadiazole F'. Removal of the protecting group of F' gives the β-secretase inhibitor compound G'.

An exemplary synthesis of one of the oxazole compounds is shown in Scheme 3.

The oxazole compound of formula (I) wherein X ¹ is CH and X ² is N can be synthesized according to Exemplary Scheme 4.

The furan compound of the formula (I) wherein both X ¹ and X ² are CH can be synthesized according to the exemplary scheme 5a or 5b.

Compounds of formula (I)-(VIII), or any variant thereof, can be synthesized according to Scheme 1, 2 or 3 using suitable starting materials which are commercially available or synthesized according to procedures described in the literature procedures or examples herein.

III. β-secretase inhibitor activity

To develop suitable beta-secretase inhibitors, candidate inhibitors capable of selectively mediating (e.g., reducing) membrane aspartyl protease 2 catalytic activity can be identified in vitro and subsequently tested for their ability to reduce A[beta] production. The activity of the inhibitor compound can be analyzed using methods known in the art and/or methods provided herein.

Compounds which reduce the catalytic activity of membrane aspartate 2 can be identified and tested using recombinant or naturally occurring bioactive membrane aspartic protease 2. Membrane aspartic acid protease 2 may be present in natural cells, isolated in vitro, or co-expressed or expressed in cells. The reduction in membrane aspartic protease 2 catalytic activity in the presence of an inhibitor can be measured using various methods known in the art with respect to activity in the absence of inhibitor.

For example, a test compound can be tested for its ability to detect a reduced decrease in the beta-secretase site of the peptide in the presence of membrane aspartate protease 2. Such information can be expressed, for example, as K _i , apparent K _i , V _i /V _o or percent inhibition. K _i is an inhibition equilibrium constant indicating the ability of a compound to inhibit specific enzymes such as membrane aspartic protease 2 , membrane aspartic protease 1 and/or cathepsin D. A lower value of K _i indicates that the compounds herein have a higher affinity for the enzyme. The K _i value is independent of the substrate concentration and is converted by the apparent K _i .

Apparent K _i is determined in the presence of a substrate according to established techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pages 463-469, Springer-Verlag, Berlin (1994)). The standard error of apparent K _i is in accordance with well-known techniques (see, for example, Bieth, J., Bayer-Symposium V: Proteinase Inhibitors, pages 463-469, Springer-Verlag, Berlin (1994), Ermolieeff, J. et al. Biochemistry 39: 12450-12456 (2000), the teachings of which are incorporated in its entirety by reference herein) (for example, from about 10 nM to about 1000 nM) as measured at the V _i / V _o data of different concentrations of compounds herein The error of nonlinear regression. V _i /V _o describes the ratio of the initial rate of conversion of the enzyme to the substrate in the absence (V _o ) or presence of (V _i ) inhibitor (Ermolieff et al, Biochemistry 40: 12450-12456 (2000)). A V _i /V _o value of 1.0 indicates that the compound does not inhibit the enzyme at the concentrations tested. A V _i /V _o value of less than 1.0 indicates that the compounds herein inhibit enzyme activity.

In some embodiments, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any of its variations, any of the compounds of Example 2 and/or Table 1, is capable of reducing membrane aspartate 2[beta]-secretase activity. In some embodiments, the compound of the film-aspartate protease K _i 2β- -secretase and / or apparent K _i (e.g. using any of the herein inhibitory analysis) less than about 10 μM, 5 μM, 1 μM in Either or less than about 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2 or 1 nM; or about 1 to 5 nM, 1 to 10 nM 1 to 100 nM, 1 to 300 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM, 200 to 750 nM, 300 to 750 nM 400 to 750 nM, 500 to 750 nM, 100 to 1000 nM, 250 to 1000 nM, 500 to 1000 nM or 750 to 1000 nM. In some embodiments, the compound of the film-aspartate protease K _i 2β- -secretase and / or apparent K _i (e.g. using any of the herein inhibitory analysis) of less than about 300 nM, or 500 nM to 301 Greater than 501 nM.

Once a compound capable of mediating (eg, reducing) the hydrolysis of the β-secretase site of the peptide in the presence of membrane aspartate 2 is identified, the compounds can be further tested for selective inhibition of membrane aspartate relative to other enzymes. The ability of acid protease 2. Typically, another enzyme is a peptide hydrolase, such as membrane aspartic acid protease 1 or cathepsin D; or from another family of interest, such as cytochrome P450 3A4 (CYP3A4). Compounds that reduce cathepsin D catalytic activity or membrane aspartic protease 1 catalytic activity are tested using recombinant or naturally occurring biologically active enzymes. The catalytic activity of cathepsin D or membrane aspartate 1 may be present in natural cells, isolated in vitro, or co-expressed or expressed in cells. Inhibitions achieved by the compounds described herein are measured using standard in vitro or in vivo assays, such as those well known in the art or as otherwise described herein.

For example, the selectivity of the compound can be determined by measuring the degree of inhibition of membrane aspartic protease 1 and/or cathepsin D by the same compound in the presence of the compound. The extent of the peptide is measured. Exemplary receptor peptides suitable for determining the activity of membrane aspartic protease 2 and/or membrane aspartate protease 1 include APP and its derivatives, such as FS-2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO. : 2) (Bachem Americas, Torrance, CA). Exemplary receptor peptides suitable for determining the activity of cathepsin D include, for example, peptides comprising the sequence MCA-GKPILFFRLK(DNP)-dR (SEQ ID NO.: 1). These receptor peptides can be synthesized using known peptide synthesis methods, such as solid phase peptide synthesis (e.g., FMOC amino acid coupling, etc.). Such data can be expressed, for example, as K _i , apparent K _i , V _i /V _o or percent inhibition and describe the catalysis of membrane aspartic protease 2 relative to membrane aspartic acid protease 1 or cathepsin D catalytically active compound Inhibition of activity. For example, K _i of the reaction between the inhibitor compound described herein if the film 1 or aspartic acid protease cathepsin D 1000 and K of the reaction between the inhibitor compounds described herein with the membrane aspartic protease _i At 100, the inhibitor compound inhibits the β-secretase activity of membrane aspartic protease 2 with a selectivity ten times that relative to membrane aspartic acid protease 1 or cathepsin D.

The compounds described herein are capable of selectively inhibiting membrane aspartic protease 2 relative to cytochrome P450 3A4 (CYP3A4). CYP3A4 plays an important role in the metabolism of foreign organisms. Inhibition of CYP3A4 can result in inappropriate drug-drug interactions by modulating the metabolism of other therapeutic agents. Many patients, especially elderly patients seeking treatment for conditions such as Alzheimer's disease, are prescribed a variety of therapeutic agents for various conditions, among which the interdrug interaction caused by inhibition of CYPAA4 will be highly undesirable. Thus, the ability to selectively inhibit membrane aspartate 2 relative to CYP3A4 (eg, without affecting or minimally affecting CYP3A4) can help reduce inappropriate drug-drug interactions, thereby reducing the toxicity of beta-secretase inhibitors and Increased effectiveness. Some of the compounds described herein have been shown to exhibit prominent selective inhibition of membrane aspartic protease 2 in the presence of cytochrome P450 3A4.

In some embodiments, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any variation thereof, any of the compounds of Example 2 and/or Table 1 can selectively reduce membrane aspartic protease 2 relative to membrane aspartic acid protease 1, cathepsin D and/or CYP3A4. In some embodiments, the compound is capable of selectively reducing membrane aspartic protease 2 relative to membrane aspartic acid protease 1, cathepsin D and/or CYP3A4, with a selectivity greater than about 2 fold, or a selectivity greater than about Any of 3, 5, 7, 10, 25, 50, 75, 100, 300, 200, 500, 750, 1000, 2000, 5000 or 10000 times. (E.g. using any inhibitory analysis of the herein) In some embodiments, a film of a compound of aspartate protease K _i 2β- -secretase and / or apparent K _i of less than about 10 μM, 5 μM, 1 μM , Or less than about 750, 500, 400, 300, 250, 200, 100, 75, 50, 25, 10, 5, 2 or 1 nM, or about 1 to 5 nM, 1 to 10 nM, 1 to 100 nM, 1 to 250 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM, 200 to 750 nM, 250 to 750 nM, Any of 300 to 750 nM, 400 to 750 nM, 500 to 750 nM, 100 to 1000 nM, 250 to 1000 nM, 500 to 1000 nM, or 750 to 1000 nM; and membrane aspartic acid protease 1 and/or The cathepsin DK _i and/or the apparent K _{i is} greater than about 10 μM, 5 μM, 1 μM, or greater than about 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM. Any of, or about 1 to 5 nM, 1 to 10 nM, 1 to 100 nM, 1 to 300 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM, 200 to 750 nM, 300 to 750 nM, 400 to 750 nM, 500 to 750 nM, 100 to 1000 nM, 250 Up to 1000 nM, 500 to 1000 nM or 750 to 1000 nM. In some embodiments, a film of the compound of aspartate protease K _i 2 β- -secretase and / or apparent K _i (e.g. using any of the herein inhibitory analysis) less than about 10 μM, 5 μM, 1 μM Or less than about 750, 500, 400, 300, 250, 200, 100, 50, 25, 10, 5, 2 or 1 nM, or about 1 to 5 nM, 1 to 10 nM, 1 Up to 100 nM, 1 to 250 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM, 200 to 750 nM, 250 to 750 nM, 400 Up to any of 750 nM, 500 to 750 nM, 100 to 1000 nM, 250 to 1000 nM, 500 to 1000 nM, or 750 to 1000 nM; and CYP3A4 K _i and/or apparent K _{i is} greater than about 100 μM, Any of 50 μM, 25 μM, 10 μM, 5 μM, 1 μM, or greater than about 750, 500, 400, 300, 200, 100, 50, 25, 10, 5, 2, or 1 nM, or About 1 to 5 nM, 1 to 10 nM, 1 to 100 nM, 1 to 300 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM 200 to 750 nM, 300 to 750 nM, 400 to 750 nM, 500 to 750 nM, 100 to 1000 nM, 250 to 1000 nM, 500 to 1000 nM or 75 Any of 0 to 1000 nM.

A detectable decrease in the hydrolysis of the β-secretase site of the peptide in the presence of membrane aspartate 2 can be tested in a cell model or an animal model (or additionally causes a role for membrane aspartic protease 2) Compounds that are capable of selectively causing a detectable decrease in the amount or production of beta-amyloid (Aβ). For example, an isosteric inhibitor of membrane aspartic acid protease 2 has been tested to reduce the ability of Aβ production in cultured cells (see U.S. Patent Application Publication No. 20040121947, International Application No. PCT/US02/34324 No. WO 03/039454) and International Application No. PCT/US06/13342 (Publication No. WO 06/110668), the contents of each of which are hereby incorporated by reference. Briefly, inhibitors can be added to cells that are stably transfected with a nucleic acid construct encoding human APP and, if desired, a nucleic acid construct encoding human membrane aspartate 2 (eg, human embryonic kidney (HEK293)) A culture of cells, HeLa cells, Chinese hamster egg cells or neuroblastoma strain SK-N-BE (2). Immunoprecipitation of Aβ followed by SDS-gel electrophoresis allows detection and quantification of Aβ production in the presence and absence of inhibitors.

In addition to cell culture, an animal model can be used to test the ability of the inhibitor of membrane aspartic protease 2 to reduce A[beta] production. For example, an inhibitor can be administered orally or intravenously to an animal, such as a rat. Plasma can then be collected and assayed for A[beta] content by capture ELISA (BioSource International, Camarillo, CA).

In some embodiments, the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X Or any of its variations, Example 2 and/or any of the compounds of Table 1 can reduce cellular A[beta] production. In some embodiments, the compound capable of reducing cell Aβ generation, its IC ₅₀ (e.g. using the Aβ inhibition of analysis described herein) of less than about 10 μM, 5 μM, 1 μM , or less than about 750,500,400,300, Any of 200, 100, 50, 25, 10, 5, 2 or 1 nM, or about 1 to 5 nM, 1 to 10 nM, 1 to 100 nM, 1 to 300 nM, 1 to 500 nM, 1 to 1000 nM, 100 to 500 nM, 200 to 500 nM, 300 to 500 nM, 100 to 750 nM, 200 to 750 nM, 300 to 750 nM, 400 to 750 nM, 500 to 750 nM, 100 to 1000 nM, Any of 250 to 1000 nM, 500 to 1000 nM, or 750 to 1000 nM. In some embodiments, the compound capable of reducing cell Aβ generation, its IC ₅₀ (e.g. using the Aβ inhibition of analysis described herein) of less than 1 μM, between 1 μM and 5 μM, or greater than 5 μM.

The presence of an inhibitor in an organ of an animal model or in a cell compartment can be determined using a fluorescent label associated with the inhibitor and observed 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 each of which is hereby incorporated by reference in its entirety.

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 tissue. The amount of beta-amyloid or the reduction in beta-amyloid production can be measured using standard techniques such as western blotting and ELISA assays.

Further examples for the analysis of the membrane aspartate protease 2-[beta]-secretase inhibitors are set forth in the Examples section below. Other methods for analyzing the activity of membrane aspartic protease 2, membrane aspartic protease 1, cathepsin D and CYP3A4 and the activity of agents which reduce the activity of such enzymes are known in the art. The choice of an appropriate analytical method is well within the capabilities of those skilled in the art, especially in light of the teachings provided herein.

IV. Formulations

In another aspect, a formulation (eg, a pharmaceutical formulation) comprising a membrane aspartate 2[beta]-secretase inhibitor compound (eg, formula (I), (II), (III), (IIIa) is provided , (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), ( VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1, and a carrier, such as pharmaceutically acceptable Carrier. Such formulations may include optical isomers, diastereomers or pharmaceutically acceptable salts of the inhibitors disclosed herein. The membrane aspartate 2[beta]-secretase inhibitor included in the formulation can be covalently linked to the carrier moiety. Alternatively, the membrane aspartate 2[beta]-secretase inhibitor included in the formulation is not covalently linked to the carrier moiety.

Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, and carbohydrates such as lactose, amylose or starch, fatty acid esters. , hydroxymethyl cellulose and polyvinylpyrrolidine. The preparations may be sterilized and, if necessary, mixed with auxiliaries, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and/or aromatic substances and An analog that does not adversely react with the compound to be used.

The compounds described herein can be administered alone or co-administered to an individual. Co-injection is intended to include the simultaneous or sequential administration of individual compounds or combinations of compounds (more than one compound). Thus, if desired, the formulation may also be combined with other active ingredients for treating a given condition (e.g., reducing metabolic degradation).

The β-secretase inhibitors described herein can be prepared (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2) , (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), X) or any variation thereof, any of the compounds of Example 2 and/or Table 1) and administered in a variety of oral, parenteral and topical dosage forms. Thus, a compound herein can be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal). The compounds described herein can also be administered by inhalation (e.g., intranasally). Additionally, the compounds herein can be administered transdermally. The compounds herein may also be administered topically (e.g., by eye, such as topical eye drops or ointments). It is also envisioned that the inhibitor compounds described herein can be administered using a variety of routes of administration (e.g., intramuscular, oral, transdermal). Accordingly, pharmaceutical formulations are also provided which comprise a pharmaceutically acceptable carrier or excipient and one or more inhibitor compounds described herein (eg, formula (I), (II), (III), (IIIa) ), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1.

For the preparation of pharmaceutical formulations from the compounds described herein, the pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, lozenges, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which can also act as a diluent, a flavoring agent, a binder, a preservative, a tablet disintegrating agent or an encapsulating material.

In the powder, the carrier is a finely divided solid which is a mixture with the finely divided active component. In lozenges, the active component is mixed in a suitable ratio with a carrier having the necessary binding properties and compressed into the desired shape and size.

Powders and lozenges preferably comprise 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, low melting wax, Cocoa butter and its analogues. The term "formulation" is intended to include the active compound and the formulation of the encapsulating material as a carrier to provide an active ingredient (with the carrier which is associated with the active ingredient) with or without the carrier. Capsules. Similarly, it includes a sachet and an ingot. Tablets, powders, capsules, pills, cachets, and buccal tablets may be suitable for use in solid dosage forms for oral administration.

With regard to the preparation of suppositories, a low melting wax such as a mixture of a fatty acid glyceride and cocoa butter is first melted and the active component is uniformly dispersed therein, such as by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool, and solidified.

Liquid form preparations include solutions, suspensions and emulsions such as water or water/propylene glycol solutions. For parenteral injection, the liquid preparation can be formulated with a polyethylene glycol aqueous solution in a solution state.

Mixtures which are especially suitable for the compounds herein are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants (including suppositories) when parenteral applications are desired. In particular, carriers for parenteral administration include aqueous solutions of dextrose, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. . Ampoules are suitable unit doses. The compounds herein can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use herein are well known to those skilled in the art and are described, for example, in Pharmaceutical Sciences (17th ed., Mack Pub. Co., Easton, PA) and WO 96/05309, both of which teach The manner of reference is incorporated herein.

Transdermal formulations (e.g., for glaucoma treatment) include, but are not limited to, formulations using physiological saline, including other carriers, stabilizers, and the like, which are known to those skilled in the art, as appropriate.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents, if desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents ) prepared in water.

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 ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a package preparation which contains discrete quantities of preparations such as a package, a capsule, and a vial or a powder in an ampule. The unit dosage form can also be a capsule, lozenge, sachet, or buccal preparation itself, or it can be a suitable number of such compositions in the form of a package.

Unit dosage forms comprising the formulations described herein are also provided. These unit dosage forms can be stored in a suitable package in single or multiple unit doses and can be further sterilized and sealed. For example, a pharmaceutical formulation (eg, a pharmaceutical formulation in a dosage or unit dosage form) can include (i) an inhibitor (eg, formula (I), (II), (III), (IIIa), (IV), IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa) And (VII), (VIII), (IX), (X) or any of its variations, any of the compounds of Example 2 and/or Table 1, and (ii) a pharmaceutically acceptable carrier. In some embodiments, the formulation also includes one or more additional 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: from about 5 to about 50 mg, from about 20 to about 50 mg, from about 50 to about 100 mg, from about 100 to about 125 mg, From about 125 to about 150 mg, from about 150 to about 175 mg, from about 175 to about 200 mg, from about 200 to about 225 mg, from about 225 to about 250 mg, from about 250 to about 300 mg, from about 300 to about 350 mg, about 350 to about 400 mg, from about 400 to about 450 mg, or from about 450 to about 500 mg. In some embodiments, the amount of the compound in the formulation (eg, a dosage or unit dosage form comprising Formula I, II, III, or any variation thereof, any of the compounds of Example 2 and/or Table 1) is from about 5 mg to about 500. The range of mg, such as from about 30 mg to about 300 mg or from about 50 mg to about 200 mg of the compound.

Some compounds may have limited solubility in water and thus may require a surfactant or other suitable 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 familiar with the technology Other agents known to those. These cosolvents are typically employed in amounts between about 0.01% and about 2% by weight.

It may be desirable to have a viscosity greater than that of a simple aqueous solution to reduce variability in the dispensing formulation, to reduce physical separation of the components of the suspension or emulsion of the formulation, and/or to otherwise modify the formulation. Such viscosity constituting agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, sulfated cartilage. And its salts, hyaluronic acid and its salts, combinations of the above, and other agents known to those skilled in the art. Such agents are typically employed in amounts between about 0.01% and about 2% by weight. Determination of the acceptable amount of any of the above adjuvants is readily determined by those skilled in the art.

The formulation may additionally include components that provide sustained release and/or comfort. These components include high molecular weight, anionic mumuimetic polymers, curdlan and finely powdered pharmaceutical carriers. Such components are discussed in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire content of these patents is hereby incorporated by reference in its entirety for all purposes.

A. Effective dose

The pharmaceutical formulation comprises a formulation comprising an effective amount of an active ingredient (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1, that is, the amount is effective to achieve its intended purpose. The actual amount effective for a particular application will depend on the condition being treated. For example, when administered in a method of treating Alzheimer's disease, the compositions will contain the active ingredient in an amount effective to achieve the desired result (eg, decreased beta-secretase activity or decreased beta-amyloid) produce). 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 disclosure detailed herein.

The dose and frequency of administration to a mammal (single or multiple doses) may vary depending on various factors, including diseases that result in increased membrane aspartyl protease 2 activity or increased beta-amyloid accumulation, and whether the mammal suffers from another Disease and its route of administration; the size, age, sex, health status, weight, body mass index and diet of the recipient; the nature and extent of the symptoms of the disease (eg Alzheimer's disease), and the type of treatment, Complications or other health related problems caused by the disease being treated. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein. The adjustment and processing of the determined dose (e.g., frequency and duration) is well within the capabilities of those skilled in the art.

For any of the compounds described herein, an effective amount can be determined initially from cell culture assays. The target concentration will be the concentration of the active compound capable of reducing the activity of the membrane aspartate 2, as measured using methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined by automated animal models. For example, dosages for humans can be formulated to achieve concentrations that have been found to be effective in animals. The human dose can be adjusted by monitoring membrane aspartate 2 inhibition and adjusting the dose up or down as described above. Adjusting the dosage according to the above methods and other methods (methods well known in the art) to achieve maximum efficacy in humans is well within the capabilities of the average skilled person, especially in view of the teachings provided herein.

The dosage will vary depending on the individual requirements and the compound used. The dosage administered to the individual should be sufficient to effect a beneficial therapeutic response over time in the individual. The size of the dose will also be determined by the existence, nature and extent of any adverse side effects. The determination of the appropriate dose for a particular situation is within the skill of the practitioner. Treatment generally begins with a smaller dose that is less than the optimal dose of the compound. Subsequently, the dose is increased in small increments until an optimal effect is achieved under certain circumstances. In one embodiment, the dosage ranges from 0.001% to 10% w/v. In another embodiment, the dosage range is from 0.1% to 5% w/v.

Other examples of dosages that can be used are effective amounts ranging from about 0.1 μg/kg to about 300 mg/kg, or from about 1.0 μg to about 40 mg per kilogram of body weight, or about 1.0 per kilogram of body weight. Between μg and about 20 mg, or about 1.0 μg to about 10 mg per kg of body weight, or about 10.0 μg to about 10 mg per kg of body weight, or about 100 μg to about 10 mg per kg of body weight, or Within about 1.0 mg to about 10 mg per kg of body weight, or about 10 mg to about 100 mg per kg of body weight, or about 50 mg to about 150 mg per kg of body weight, or about 100 mg per kg of body weight to Within about 200 mg, or about 150 mg to about 250 mg per kg of body weight, or about 200 mg to about 300 mg per kg of body weight, or about 250 mg to about 300 mg per kg of body weight. Other doses that can be used are about 0.01 mg per kilogram of body weight, about 0.1 mg per kilogram of body weight, about 1 mg per kilogram of body weight, about 10 mg per kilogram of body weight, about 20 mg per kilogram of body weight, about 30 mg per kilogram of body weight, per kilogram. Weight about 40 mg, about 50 mg per kg body weight, about 75 mg per kg body weight, about 100 mg per kg body weight, about 125 mg per kg body weight, about 150 mg per kg body weight, about 175 mg per kg body weight, per kg body weight About 200 mg, about 225 mg per kilogram of body weight, about 250 mg per kilogram of body weight, about 275 mg per kilogram of body weight or about 300 mg per kilogram of body weight. The compounds herein can be administered in a single daily dose, or the total daily dose can be administered in two, three or four doses per day.

Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and is fully effective in treating the clinical symptoms exhibited by a particular individual. This plan should include careful selection of the active compounds by consideration of factors such as compound potency, relative bioavailability, weight of the individual, the presence and severity of adverse side effects, preferred mode of administration, and toxicity profile of the selected agent.

B. Set

Also provided are kits for administering the compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa) -2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX) And (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1, formulations, and dosage forms thereof.

In certain embodiments, the kits can include a dose of at least one formulation as disclosed herein. The kit may further comprise suitable packaging and/or instructions for use of the formulation. The kit can also include components that convey its formulation.

A kit can include one or more compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2) ), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variants, any of the compounds of Example 2 and/or Table 1, in combination with other agents. In some variations, the agent can be one or more antipsychotic drugs. Such agents may be provided in individual form or in admixture with the compounds described herein with the proviso that the combination does not reduce the effectiveness of the agents or compounds described herein and is compatible with the route of administration. Similarly, a kit can include other agents for adjunctive therapy or other agents known to those skilled in the art to be effective in treating or preventing the conditions described herein.

The kit may optionally include appropriate instructions for the preparation and administration of the composition, the side effects of the composition, and any other relevant information. These instructions may be in any suitable format including, but not limited to, printed matter, videotapes, computer readable disks, optical discs or instructions based on the Internet Directive.

In another aspect, a kit for treating an individual suffering from or susceptible to a condition described herein, comprising a first container comprising a dose of a formulation as disclosed herein and using Instructions. The container can be any of the containers known in the art and is suitable for storing and delivering intravenous formulations. In certain embodiments, the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, and the like for preparing a composition for administration to the individual.

A kit comprising a sufficient amount of an inhibitor (including a formulation thereof) as disclosed herein to provide a long-term effective treatment to an individual can also be provided, such as 1-3 days, 1-5 days, 1 week, 2 weeks, 3 Week, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or longer.

The kit may also include multiple doses of the compound and instructions for use and is packaged in quantities sufficient for storage and use in a pharmacy, such as a hospital pharmacy and a compound pharmacy.

A kit can include a compound as described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa) packaged in unit dosage form or in multiple use. -1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1. The kit can also include unit dosage forms of multiple units. In certain embodiments, the compounds described herein are provided in unit dosage form. In other embodiments, the composition can be provided in multiple dosage forms (eg, blister packs, etc.).

C. Toxicity

The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index and can be the ratio between LD ₅₀ (amount of compound that is lethal in 50% of the population) and ED ₅₀ (amount of compound that is effective in 50% of the population) Said. Compounds exhibiting a high therapeutic index are preferred. Therapeutic index data obtained from cell culture assays and/or animal studies can be used to formulate dosage ranges for use in humans. The dosage of such compounds include the preferred plasma concentration range that have little or no toxicity to the ED _50. The dosage may vary within this range depending on the dosage form employed and the route of administration employed. See, for example, Fingl et al, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 1, page 1, 1975. The precise formulation, route of administration, and dosage can be selected by the individual physician in view of the condition of the individual and the particular method in which the compound is employed.

V. Method for reducing the activity of membrane aspartic protease 2β-secretase

In another aspect, a beta-secretase inhibitor compound herein can be used in a method to separately beta-secretase relative to the amount of membrane aspartate protease 2 activity in the absence of a beta-secretase inhibitor, respectively. Hydrolysis of site and accumulation of β-amyloid, decrease membrane aspartyl protease 2 activity, reduce hydrolysis of membrane-aspartic protease 2-dependent β-secretase site, and/or reduce beta-starch The accumulation of protein.

In an exemplary embodiment, a method of reducing membrane aspartic protease 2 activity is provided. The method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor compound herein. Membrane aspartic acid protease 2 can be contacted under any suitable environment (eg, in vitro, in vivo). Membrane aspartate 2 activity is reduced relative to the amount of activity in the absence of a beta-secretase inhibitor.

In another exemplary embodiment, there is provided an inhibitor (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1) as described herein. , (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII) , (IX), (X) or any variation thereof, any of the compounds of Example 2 and/or Table 1), which selectively mediated (e.g., reduces) membrane aspartyl protease 2 activity. Selectively reducing the activity of membrane aspartic protease 2 means not only reducing the activity of membrane aspartic protease 2 in the absence of the inhibitor, but also by targeting another enzyme (such as a peptide hydrolase, such as cathepsin). D, the decrease in activity caused by the action of the inhibitor of membrane aspartic acid protease 1) and/or cytochrome P450 3A4 is greater than that. For example, as described above, a decrease in the activity of an enzyme can suppress the expression of a constant (K _i ). When the inhibitor selectively reduces the activity of membrane aspartate 2, the K _i of the reaction between the inhibitor compound described herein and membrane aspartate 2 is less than the inhibitor compound and another peptide hydrolase herein. And / or K _i of the reaction between cytochrome P450 3A4.

In some embodiments, the inhibitor compound (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V) ), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or The K _i of the reaction between any of its variants, Example 2 and/or any of the compounds of Table 1 and membrane aspartic acid protease 2 is less than the inhibitor compound and another peptide hydrolase (eg, cathepsin D, membrane aspartate) K _i of the reaction between the amino acid proteases 1). In some related embodiments, the inhibitor selectively reduces the activity of membrane aspartic protease 2 compared to membrane aspartate 1 . In other related embodiments, the inhibitor selectively reduces the activity of membrane aspartic protease 2 compared to cathepsin D. In some embodiments, the inhibitor compound (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V) ), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variations, example 2, and / or any compound of table 1) and the membrane aspartic proteinase K of the reaction between _I 2 _I is less than K of the reaction between the inhibitor compound P450 3A4 cytochrome. In an exemplary embodiment, the K _i of the reaction between the inhibitor compound herein and the membrane aspartate 2 is the reaction between the inhibitor compound herein and another peptide hydrolase and/or cytochrome P450 3A4. At least 1/2 of K _i . In another exemplary embodiment, the K _i of the reaction between the inhibitor compound herein and the membrane aspartate 2 is the reaction between the inhibitor compound herein and another peptide hydrolase and/or cytochrome P450 3A4. At least 1/3, 1/5, 1/7, 1/10, 1/25, 1/50, 1/75, 1/100, 1/300, 1/200, 1/500, 1 of K _i /750, 1/1000, 1/2000, 1/5000 or 1/10000.

Therefore, a method of selectively reducing the activity of membrane aspartic protease 2 is provided. Such methods include subjecting membrane aspartic acid protease 2 to a beta-secretase inhibitor compound (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa- 1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), Contact VIII), (IX), (X) or any of its variations, Example 2 and/or any of the compounds of Table 1. In a related embodiment, the method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor in the presence of membrane aspartate protease 1. In an alternative related embodiment, the method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor in the presence of cathepsin D. In another related embodiment, the method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor in the presence of cathepsin D and membrane aspartate protease 1. In another embodiment, the method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor in the presence of cytochrome P450 3A4. In yet another related embodiment, the method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor in the presence of cathepsin D, membrane aspartate 1 and cytochrome P450 3A4.

In some embodiments, the activity of membrane aspartic protease 2 β-secretase can be determined by measuring the hydrolysis of the β-secretase site of the β-secretase receptor. Thus, a method for reducing the hydrolysis of a β-secretase site of a β-secretase receptor is described by using a membrane aspartic protease 2 and a β-secretase inhibitor compound (eg, formula (I), (II) ), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variations, any of the compounds of Example 2 and/or Table 1 get on. In some embodiments, the hydrolysis of the β-secretase site is reduced relative to the amount of hydrolysis in the absence of the inhibitor. In other embodiments, the hydrolysis is selectively reduced as compared to hydrolysis by membrane aspartic acid protease 1 and/or cathepsin D. Accordingly, a method for selectively reducing hydrolysis of a β-secretase site of a β-amyloid precursor protein in a sample relative to membrane aspartic acid protease 1 and/or cathepsin D is provided. The method comprises contacting membrane aspartic protease 2 with a beta-secretase inhibitor compound.

In another embodiment, there is provided a method of reducing the amount of beta-amyloid in a sample by subjecting membrane aspartic acid protease 2 to an inhibitor compound (eg, formula (I), (II), (III) , (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), ( Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any of its variations, any of the compounds of Example 2 and/or Table 1 are contacted. The amount of β-amyloid in the sample is reduced relative to the amount of β-amyloid in the sample in the absence of the inhibitor. Therefore, thereby reducing the accumulation of β-amyloid.

Membrane aspartic acid protease 2 can be contacted in any suitable environment or in any suitable sample. For example, membrane aspartate 2 can be contacted in vitro, in cells, or in a mammal. Generally, an in vitro solution (e.g., an aqueous solution) is selected such that the component does not substantially interfere with the enzymatic activity of membrane aspartic protease 2. In some embodiments, the in vitro solution comprises a biological sample, such as a mammalian sample. Exemplary mammalian samples include plasma or serum samples and tissue samples or extracts, such as brain biopsy tissue. Any suitable cell or cell sample can be selected to contact membrane aspartate 2 with the inhibitor therein. As described previously, the cells may contain endogenous membrane aspartic acid protease 2 or recombinant membrane aspartic acid protease 2 (see U.S. Patent Application Publication No. 20040112947, the disclosure of which is incorporated herein by reference) International Application No. PCT/US02/34324 (Publication No. WO 03/039454)). Exemplary cells include human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster egg cells, or neuroblastoma cell line SK-N-BE (2) (ATCC No. CRL-2271), HeLa cells, 293 cells. In an exemplary embodiment, a compound of the invention is administered to a mammal (eg, mouse, rat, or human) to inhibit hydrolysis of the beta-secretase site of the beta-amyloid precursor protein.

VI. Methods of treating Alzheimer's disease

In another aspect, the β-secretase inhibitor compound is useful for the treatment of β-secretase activity, hydrolysis of β-secretase sites of β-amyloid precursor protein, and/or accumulation of β-amyloid. And/or a disease or condition mediated by it. The disease or condition of a mammal is typically treated. In an exemplary embodiment, the condition is Alzheimer's disease.

Accordingly, in some embodiments, a method of treating Alzheimer's disease in a mammal comprising administering to the mammal in need thereof an effective amount of a beta-secretase inhibitor (eg, formula (I), II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd) , (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variant thereof, any of the compounds of Example 2 and/or Table 1) step. 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 mammal treated with the inhibitor can be a human primate, a non-human primate or a non-human mammal (e.g., a rodent, a dog). In one embodiment, a compound of the invention that reduces beta-secretase activity (inhibition of membrane aspartic protease 1 and membrane aspartate 2 activity) is administered to a mammal. In another embodiment, a compound that selectively reduces membrane aspartic protease 2 activity is administered to a mammal. In a related embodiment, the compound has little or no effect on reducing membrane aspartate protease activity. Accordingly, there is also provided 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 beta-secretase inhibitor compound. In an exemplary embodiment, the beta-secretase inhibitor compound is part of a pharmaceutical formulation, as described above.

The inhibitor compounds herein are useful for treating a disease or condition associated with beta-secretase activity (eg, membrane aspartate 2 activity) in an individual that stops, reverses, or reduces the disease or condition (especially Az Progress in Hermès disease. In some embodiments, the individual has one or more symptoms of a disease or condition associated with beta-secretase activity. In some embodiments, the individual has been diagnosed with a disease or condition associated with beta-secretase activity. In addition to compounds that reduce membrane aspartate 2 activity, compounds that selectively reduce membrane aspartic protease 2 activity are useful in the treatment of diseases or conditions or biological processes associated with membrane aspartate 2 activity. A disease or condition or biological process that is not associated with membrane aspartic protease 2 activity and another peptide hydrolase such as cathepsin D or membrane aspartate protease 1.

For example, both membrane aspartate 1 and membrane aspartate 2 cleave amyloid precursor protein (APP) at the β-secretase site to form β-amyloid (also referred to herein as Aβ). Or β-amyloid). Therefore, both membrane aspartic acid protease 1 and membrane aspartate protease 2 have β-secretase activity (Hussain, I. et al., J. Biol Chem. 276: 23322-23328 (2001)). However, the β-secretase activity of membrane aspartic acid protease 1 was significantly less than the β-secretase activity of membrane aspartate 2 (Hussain, I. et al., J. Biol. Chem. 276: 23322-23328 ( 2001)). Membrane aspartate 2 is localized in the brain and pancreas and other tissues (Lin, X. et al., Proc. Natl Acad Sci. USA 97: 1456-1460 (2000)) and membrane aspartate 1 is preferred. Located in the placenta (Lin, X. et al, Proc. Natl. Acad Sci. USA 97: 1456-1460 (2000)). Alzheimer's disease is associated with accumulation of Aβ in the brain due to cleavage of APP by β-secretase (also referred to herein as membrane aspartate 2, ASP2 and BACE). Therefore, a method of selectively inhibiting membrane aspartic protease 2 activity relative to membrane aspartic acid protease 1 activity can be used in the treatment of membrane aspartyl protease 2 related diseases such as Alzheimer's disease. More important. Selective inhibition of membrane aspartic protease 2 activity renders the compounds herein drug candidates suitable for the treatment of Alzheimer's disease.

VII. Methods of treating glaucoma

In another aspect, the beta-secretase inhibitor compounds herein can be used to treat diseases associated with loss of vision (eg, glaucoma). In some embodiments, a method of treating glaucoma (eg, angle-closure glaucoma and open-angle glaucoma) in a subject is provided, comprising administering to the individual in need thereof an effective amount of a beta-secretase inhibitor herein (eg, I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc) , (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, Example 2 and/or Table 1. The step of any compound). In an exemplary embodiment, the beta-secretase inhibitor compound is part of a pharmaceutical formulation, as described above.

In some aspects, the inhibitor compounds herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-I), (IVa-2), V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) Or any of its variations, any of the compounds of Example 2 and/or Table 1), can be used to treat a disease or condition associated with beta-secretase activity, which can stop, reverse or reduce glaucoma (eg, angle-closure glaucoma and Progress in open angle glaucoma. In some embodiments, the inhibitor compounds herein can be used to stop, reverse or reduce the loss of retinal ganglion cells (RGC). In other embodiments, the compounds herein (eg, Formula I, II, III, or any variation thereof, Example 2 and/or any of the compounds of Table 1) are used to improve or reduce intraocular pressure (POP).

Compounds described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va ), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof , any of the compounds of Example 2 and/or Table 1) can be used to treat glaucoma by one of several known routes of administration including, but not limited to, oral (eg, in the form of a lozenge or capsule), Parenteral (eg, injected into the anterior chamber, intravenous, intramuscular, or subcutaneous) or topical (eg, topical eye drops or ointments). The compounds herein can also be formulated for sustained release during glaucoma treatment.

Using the compounds herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof, examples 2 and/or any of the compounds of Table 1) Other embodiments of treating glaucoma are described by modifying one or more of the following documents: 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 contents of these applications are incorporated herein by reference in their entirety.

A. Method of administering a β-secretase inhibitor to the CNS

Inhibitor compounds herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa), (IVa-1), (IVa-2), (V), (Va ), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), (VII), (VIII), (IX), (X) or any variation thereof The compound of Example 2 and/or any of the compounds of Table 1 can be administered to the CNS via an invasive or non-invasive method. Non-invasive methods of administration include methods that do not require the use of mechanical or physical means to disrupt the integrity of the blood-brain barrier. Generally, non-invasive methods include the use of immunoliposomes, blood-brain barrier disruption (BBBD) or olfactory pathways.

An immunoliposome is a liposome containing an antibody or antibody fragment that binds to a receptor or transporter expressed on brain capillary endothelial cells attached to the surface of a liposome. Exemplary immunoliposome combination polymer (eg, PEGylation) techniques and chimeric amine techniques. For example, a beta-secretase inhibitor can be packaged in a monolayer of liposome containing a PEG ²⁰⁰⁰ derivative having a reactive group at one end to attach to a complementary reactive group of the antibody or fragment thereof. Complementary reactive groups are well known in the art and include, for example, amines and activated carboxylic acids, thiols and maleimide and the like (Ambikanandan et al, J. Pharm Pharmacent 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); Patent No. 6,372,250, the entire contents of each of which is hereby incorporated by reference in its entirety in its entirety in its entirety.

Blood-brain barrier disruption is a transient loss of the integrity of the tight junction between endothelial cells containing the blood-brain barrier. Typically, the compound is administered via systemic or inter-arterial injection in conjunction with transient blood-brain barrier disruption (BBBD). Exemplary agents suitable for inducing BBBD include solvents such as dimethyl hydrazine (DMSO); ethanol (EtOH); metals (eg, aluminum); X-irradiation; induction of pathological conditions (eg, hypertension, hypercapnia, hypoxia) Or ischemic); anti-neoplastic agents (eg VP-16, cisplatin, hydroxyurea, fluorouracil and etoposide); or simultaneous systemic administration of the convulsant drug metrazol And the anticonvulsant 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)); carotid infusion of bradykinin, histamine or 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)); hyaluronic acid enzyme (US Patent Application Publication No. 20030215432) number, Kreil et al., Protein Sci, 4 (9): . 1666-1669 (1995)); inert osmotic pressure between the carotid artery injection solution, such as mannitol or A Primary sugar (Neuwelt, EA et al., Neuwelt EA (eds), Implications of the Blood Brain Barrier and its Manipulation:. Clinical Aspects Volume 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)).

The olfactory pathway is administered by intranasal delivery of the compound to the olfactory nerve at one-third of the nasal cavity. After intranasal delivery, the compound is transported back along the sensory olfactory neurons, producing significant concentrations in the cerebrospinal fluid (CSF) and olfactory bulbs (Thorne et al, Brain Res, 692(1-2): 278-282 (1995); Thorne Et al., Clin Pharmacokinet 40: 907-946 (2001); Illum, Drug Discov Today 7: 1184-1189 (2002); U.S. Patent No. 6,180,603; U.S. Patent No. 6,313,093; and U.S. Patent Application Publication No. 20030215398.

Invasive methods of administration include methods that physically destroy the blood-brain barrier, either mechanically or physically, to introduce a compound into the CSF or directly into the parenchyma of the brain. Generally, invasive methods of administration can include injection or surgical implantation of a compound.

In the injection method, the needle is used to physically destroy the BBB and the compound is delivered directly to the CSF. Exemplary injection methods include intraventricular, intrathecal or intralumbar routes of administration and may also include infusion of a compound via a reservoir outside 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)).

In surgical implantation methods, the compound is placed directly into the parenchyma of the brain. An exemplary surgical implantation method can include incorporating a compound into a polyanhydride wafer placed directly in the brain interstitial (Brem et al, Sci Med 3(4): 1-11 (1996); Brem et al, J Control Release 74: 63-67 (2001)).

VIII. Crystalline complex

In another aspect, a crystalline complex comprising a membrane aspartic protease 2 protein and a beta-secretase inhibitor herein is provided. Membrane aspartic protease 2 proteins suitable for forming co-crystals with electron isosteric compounds (eg, membrane aspartic protease 2 protein fragments, transmembrane proteins, etc.) have been previously discussed in detail (see US Patent Application Publication No. No. 20040121947 and International Application No. PCT/US02/34324 (Publication No. WO 03/039454)). These membrane aspartic protease 2 proteins are equally suitable for use with the beta-secretase inhibitors described herein (eg, formula (I), (II), (III), (IIIa), (IV), (IVa). , (IVa-1), (IVa-2), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VI), (VIa), ( VII), (VIII), (IX), (X) or any of its variations, any of the compounds of Example 2 and/or Table 1) form a crystalline complex.

The crystallization complex can be formed using the techniques described in U.S. Patent Application Publication No. 20040112947 and International Application No. PCT/US02/34324 (Publication No. WO 03/039454). Briefly, a nucleic acid construct encoding a membrane aspartic protease 2 protein is produced, and the protein is in a host cell such as a mammalian host cell (eg, HeLa cells, 293 cells) or a bacterial host cell (eg, E. coli). Performance, followed by purification of the protein and crystallization with the compounds herein. The diffraction resolution limit of the crystalline protein can be determined, for example, by x-ray diffraction or neutron diffraction techniques.

In an exemplary embodiment, the x-ray diffraction resolution limit of the crystalline protein can be no greater than about 4.0 angstroms. The x-ray diffraction resolution limit of the crystalline protein may also be no 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 x-ray diffraction resolution limit of the crystalline protein can also be no greater than about 2 angstroms. The diffraction resolution limit of the crystalline protein can be determined using standard x-ray diffraction techniques.

The terms and expressions used herein are used as descriptive terms and not as a limiting term, and do not intend to use the terms and expressions that exclude the features and the equivalents thereof. . In addition, any one or more of the features of any of the embodiments described herein can be combined with any one or more of the features of any other embodiments described herein without departing from the scope of the invention. For example, the features of the beta-secretase inhibitors described herein are equally applicable to methods of treating disease conditions and/or pharmaceutical formulations described herein. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety herein in their entirety

IX. Example Example 1: Preparation of selected β-secretase inhibitors and precursor compounds

The synthesis of the β-secretase inhibitor and the precursor compound is related to the following patent: WO 2006/110668, filed on April 10, 2006, entitled "Compounds Which Inhibit Beta-Secretase Activity and Methods of Use Thereof", The content is hereby incorporated by reference in its entirety in its entirety, in its entirety, in its entirety, in its entirety, in the s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s U.S. Provisional Patent Application Serial No. 60/952,198, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety, in its 83-86 and paragraphs 161-354.

The following synthetic precursor compounds are suitable for use in the methods of preparing the compounds provided herein. Using the guidance provided (e.g., in the exemplary synthesis of Scheme 1), those skilled in the art will immediately recognize that exemplary synthesis of the following precursor compounds can be modified using known techniques and teachings provided herein to achieve various inhibitions. A compound (such as the compound of Example 2). Some of the starting materials and some of the precursor compounds not described are commercially available and are commercially available, for example, from Sigma-Aldrich, Alfa Aesar or Ryan Scientific.

The NMR spectra were collected on a commercial NMR spectrometer such as a Varian Mercury Model VX-300 NMR spectrometer or other commercially available NMR spectrometer. 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. Additionally, the characterization of some of the compounds was performed using standard LCMS instruments.

Solvents for the synthesis of inhibitor compounds are commercially available from commercial sources including, but not limited to, Aldrich, VWR and EMD. Typically, the solvent is at the ACS reagent grade or better and is used without further purification.

Example 1.1: Synthetic amine building block. Example 1.1.1: (4-Methylthiazol-2-yl)methylamine

A solution of methylthiazole (1.0 g, 10.1 mmol) in tetrahydrofuran (THF) was treated with n-BuLi (1.6 M, 7.56 mL) at -78 °C for 30 min, and dimethylformamide (DMF) was added dropwise. mL, 18.2 mmol). The resulting reaction mixture was allowed to warm to room temperature. After the disappearance of the starting material (according to TLC), the reaction mixture was again cooled to 0 ° C and lithium aluminum hydride (LAH) (0.69 g, 18.5 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour, with aqueous ₄ Cl NH The reaction was quenched, diluted with ethyl acetate (EtOAc). The organic solution was separated, extracted twice with EtOAc, washed with Na ₂ SO ₄ dried and concentrated. The residue was purified by flash chromatography eluting EtOAc ¹ H-NMR: (300 MHz, CDCl ₃ ), δ: 6.89 (s, 1 H); 4.95 (s, 2 H); 2.48 (s, 3 H).

Methylthiazole methanol (0.57 g, 4.4 mmol) was treated with methanesulfonium chloride (0.42 mL, 5.4 mmol) and triethylethylamine in dichloromethane. The resulting mixture was stirred for 20 minutes, followed by ₄ Cl NH quenched with aq. Evaporation of the solvent from the organic layer and flash chromatography of the residue to give the corresponding methanesulfonate as an oil. This methanesulfonate (0.25 g, 1.2 mmol) was then dissolved in DMF and sodium azide (0.62 g, 9.6 mmol) was added. The mixture was heated to reflux for 2 hours, then cooled and washed with aqueous NH ₄ Cl. The solvent is evaporated from the organic layer to give the corresponding azide. The azide (0.14 g, 0.91 mmol) was dissolved in ethyl acetate. Pd(OH) ₂ (0.07 g) was added, and the suspension was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through celite. The solvent was evaporated and the residue was crystallised eluted elut elut elut ¹ H-NMR: (300 MHz, CDCl ₃ ), δ: 6.74 (m, 1 H); 4.09 (m, 2 H); 2.37 (s, 3 H).

NaBH ₄ (0.75 g, 19.9 mmol, 1.3 eq.) was added to stirred 4-methylthiazole-2-carbaldehyde (Aldrich, 1.7 ml, 2.0 g, 15.3 mmol, 1) at 0 °C using an alternative synthetic route. Equivalent) in a solution of 30 ml of anhydrous MeOH. After 45 minutes, the solvent was removed in vacuo. The residue was diluted (3 times) with EtOAc and extracted with saturated aqueous NH ₄ Cl. With brine (1 time) and washed the organics were dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo. Purification by flash chromatography gave (4-methylthiazol-2-yl)methanol as a quantitative yield.

Diphenylphosphonium azide (DPPA) (1.2 equivalents) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) (1.2 equivalents) were added under Ar to A stirred solution of (4-methylthiazol-2-yl)methanol (1 eq.) in 7 mL dry EtOAc. After stirring overnight, the solvent was removed in vacuo. Purification by flash chromatography gave 2-(azidomethyl)-4-methylthiazole.

2-(Azidomethyl)-4-methylthiazole was dissolved in 5 ml of MeOH. Was added Pd (OH) ₂ (20 wt% on carbon) and the mixture vigorously stirred overnight under H _2. The mixture was filtered through celite and the filter cake was rinsed with MeOH. The solvent was removed in vacuo to give (4-methylthiazol-2-yl)methylamine.

Example 1.1.2

Ti(O ⁱ PR) ₄ (1.3 eq.) was added to MeNH ₂ (2.0 M MeOH solution, 3 eq.) with stirring at EtOAc. After 15 minutes, an aldehyde (Aldrich, 1 equivalent) was added and the solution was stirred for 2-3 hours. NaBH ₄ (1.4 eq.) was added portion wise and the mixture was stirred at EtOAc EtOAc. The MeOH was removed via rotary evaporation. The residue was diluted with water / CH ₂ Cl ₂ and a white precipitate formed. The mixture was filtered through celite and the layers were separated. With CH ₂ Cl ₂ (3 times) and the aqueous layer was extracted over Na ₂ SO ₄ the combined organics were dried. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by column chromatography gave the product (80-85%).

Example 1.1.3

Add NaOH (860 mg, 21.5 mmol) and hydroxylamine hydrochloride to a stirred solution of N-Boc-2-aminoacetonitrile (3.0 g, 19.21 mmol) in a 4:1 mixture of EtOH and water (25 mL) Salt (1.44 g, 20.7 mmol) and the reaction was stirred 30 h. All solvents were evaporated under reduced pressure. The solid was dissolved in water and the aqueous layer was extracted with EtOAc. Over ₂ SO ₄ organic layers were dried of Na and concentrated to give 1.8 g (Z) -2- amino-2- (hydroxyimino) ethyl carbamic acid tert-butyl ester.

To a stirred solution of (Z)-2-amino-2-(hydroxyimino)ethylcarbamic acid tert-butyl ester (945 mg, 5 mmol) and EtOAc (2.0 mL, 20.0 mmol) A solution of NaOEt in EtOH (13 mL, 50.0 mmol) was added to the solution in EtOAc. The reaction mixture was cooled and all solvents were evaporated under reduced pressure. The residue was dissolved in water and aqueous was extracted with EtOAc. Over Na ₂ SO ₄ the combined organic layers were dried and concentrated to give 1.0 g (5- methyl-1,2,4-oxadiazol-3-yl) methyl carbamic acid tert-butyl ester.

Conversion of (5-methyl-1,2,4-oxadiazol-3-yl)methylcarbamic acid tert-butyl ester to (5) using a standard deprotection scheme for the Boc group using TFA -Methyl-1,2,4-oxadiazol-3-yl)methylamine.

Example 1.1.4: N-Methyl-1-(pyrazin-2-yl)methylamine

The 1.4.1 (3.0 g, 32 mmol) in CHCl ₃ (100 mL) was heated to reflux in the 4 portions was added and the solid cyanuric acid trichloroisocyanuric (3.11 g, 13.4 mmol) over 1 hour and The reactants were refluxed overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The crude 1.4.2 (3.0 g) was taken to the next step without purification.

Pure 1.4.2 was added to a solution of MeNH ₂ (25 mL, 40% aqueous) and stirred for 2 h. Excess steam is removed on a rotary MeNH _2, extracted with chloroform, dried and concentrated to give N- methyl-l- (pyrazin-2-yl) methanamine (1.8 g).

Example 1.1.5: N-Methyl-1-(2-methylthiazol-4-yl)methylamine

To a solution of thioacetamide (5.0 g, 70 mmol) in EtOAc (EtOAc) (EtOAc) Evaporate the solvent. The residue was dissolved in water and adjusted by addition of solid NaHCO ₃ to pH ~ 8. The mixture was extracted with ether, dried and concentrated. Crude 1.5.1 (6.0 g) The next step can be started without purification.

Pure 1.5.1 was added to a solution of MeNH ₂ (25 mL, 40% aqueous) and stirred for 2 h. Excess MeNH ₂ was removed on a rotating vapor, extracted with chloroform and dried. To the residue was acidified and extracted with CHCl ₃ pH ~ 1. Solid NaHCO ₃ was added to adjust the aqueous layer to pH ~ 8 and extracted with CHCl _3, to give N- methyl-1- (2-methyl-thiazol-4-yl) methanamine (2.5 g).

Example 1.1.6: N-Methyl-1-(2-methyloxazol-4-yl)methylamine

Add NaHCO ₃ (7.2 g, 85.0 mmol) to a solution of acetamide (5.0 g, 85.0 mmol) and 1,3-dichloroacetone (10.7 g, 85.0 mmol) in acetone (100 mL) Ear) and MgSO ₄ (13.65 g, 113 mmol) and reflux for 60 hours. The reaction mixture was filtered through diatomaceous earth and concentrated, and silica gel for chromatography (80% ether / 20% pentane) to give 20% 1.6.1.

Add a solution of 1.6.1 (2.56 g, 17.2 mmol) in 1,2-dichloroethane (10 mL) to sulfoxide (1.5 mL, 20.6 mmol) at 0 °C In a solution of 1,2-dichloroethane (40 mL). The solution was heated at 70 ° C for 15-20 minutes, cooled to room temperature and concentrated. The residue was dissolved in water and neutralized with solid NaHCO ₃ to reach pH ~ 8 and extracted with ether, dried, and concentrated to give crude 88% 1.6.2, which was used without purification.

Pure 1.6.2 was added to a solution of MeNH ₂ (25 mL, 40% aqueous) and stirred for 2 h. Remove excess MeNH ₂ in the rotational vapor extracted with chloroform, dried and concentrated to give quantitative yield of N- methyl-1- (2-methyl-4-yl) methanamine.

Example 1.1.7: (R)-(1-(4-methylthiazol-2-yl)ethyl)carbamic acid tert-butyl ester

To a solution of 1.7.1 (1.38 g, 7.34 mmol) in 1,2-DME (35 mL) was added Lawesson's reagent (1.55 g, 3.82 mmol) and stirred for 4 hours. All solvent was evaporated, and extracted with diethyl ether (2 × 200 mL) with 100 mL of saturated NaHCO ₃ diluted. ₂ SO ₄ organic layers were dried over anhydrous Na and the concentrated. The residue was subjected to silica gel chromatography (35% ethyl acetate / 75% hexane) to afford 1.5 g 1.7.2 .

Boc-D-alanine-thioguanamine (1.5 g, 7.35 mmol), chloroacetone (0.65 mL, 8.18 mmol) and calcium carbonate (1.0 g, 10.22 mmol) in ethanol (25 mL) The mixture of the ears was refluxed for 4 hours. The reaction was cooled to rt and treated with 20 mL quenched with saturated aqueous NaHCO _3. Ethanol was evaporated under reduced pressure and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was subjected to silica gel chromatography (20% ethyl acetate / 80% hexane) to give 600 mg of (R)-(1-(4-methylthiazol-2-yl)ethyl)carbamic acid ester.

Example 1.1.8: N-Methyl-1-(5-methylthiazol-2-yl)methylamine

Add 5-methylthiazole 1.8.1 (2.0 g, 20.2 mmol) to a solution of BuLi (1.6 M in hexanes, 12.6 mL, 20.2 mmol) in 25 mL of diethyl ether at -78 °C. The solution in diethyl ether (6 mL) was stirred at -78 °C for 1.5 h. A solution of DMF (2.33 mL, 30.3 mmol) elute Some ice was added to the reaction mixture and 4 N HCl was added slowly. This material was dissolved in a sep. funnel, 30 mL diethyl ether was added and mixture was shaken. Discard the organic layer. With solid NaHCO ₃ to 7.5 and the aqueous layer extracted twice with diethyl ether pH ~. ₂ SO ₄ and dried over Na ether layer was concentrated and the crude product was 1.8.2 (1.6 g) was used without purification in the next step to proceed.

Ti(O ⁱ Pr) ₄ (1.3 eq.) was added to MeNH ₂ (2.0 M MeOH solution, 3 eq. After 5 minutes, the aldehyde 1.8.2 (1 equivalent) was added and the solution was stirred for 1-2 hours. The reaction was cooled to 0 ℃ and add NaBH ₄ (1.3 equiv). The solution was stirred at 0 ° C to room temperature overnight. After quenching the reaction with water, the mixture was filtered through Celite to remove a white precipitate. The MeOH was removed in vacuo. The residue was diluted with EtOAc. Washed with water (3 times), it was washed with brine (1X) and was dried over Na ₂ SO _4. The inorganic material was filtered off and the solvent was removed in vacuo to give a crude material. Purification by column chromatography gave the pure product N-methyl-l-(5-methylthiazol-2-yl)methylamine in 80% yield.

Example 1.1.9: Methyl ((4-methyloxazol-2-yl)methyl)carbamic acid tert-butyl ester

Add Et ₃ N (4.65 mL, 33.59 mmol) to a solution of L-hamic acid methyl ester hydrochloride (4.76 g, 30.54 mmol) in CH ₂ Cl ₂ (150 mL) at 0 ° C. Ear), Boc-D-glycine (5.35 g, 30.54 mmol) and DCC (6.92 g, 33.59 mmol). The reaction was allowed to warm to rt and stirred overnight. All solvents were evaporated and the residue was triturated with ethyl acetate and filtered. The filtrate was concentrated and performed at low pressure silica gel chromatography (80% ethyl acetate / 30% chloroform) to give 7.5 g 1.9.1.

The at -20 ℃ Deoxo-flour (5.51 mL, 29.89 mmol) was added dropwise to 1.9.1 (7.5 g, 27.17 mmol) in CH ₂ Cl ₂ (200 mL) in the solution. The solution was stirred for 30 min and added dropwise BrCCl ₃ (9.65 mL, 97.8 mmol). The reaction was stirred at 2-3 ℃ was 8 hours, quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was concentrated and silica gel chromatography (30% ethyl acetate / 70% hexane) to afford 2.95 g 1.9.2.

Add LiBH ₄ (17.2 mL, 2.0 M in THF, 34.5 mmol), EtOH (3.4) to a solution of 1.9.2 (2.95 g, 11.5 mmol) in THF (25 mL). mL, 57.5 millimoles). The reaction was allowed to warm to rt and stirred for 3 h. Ethyl acetate (11 mL) was added dropwise and stirred for 30 min. The reaction was cooled to 0 &lt;0&gt;C and 17 mL 1N HCl was added dropwise and diluted with 30 mL water. Followed by extraction with ethyl acetate, dried over Na ₂ SO _4, concentrated and silica gel chromatography (3% MeOH / 97% chloroform) to give 1.54 g 1.9.3.

I ₂ (3.43 g, 13.51 mmol) was added to a solution of TPP (3.54 g, 13.51 mmol) in CH ₂ Cl ₂ (30 mL) and stirred for 10 min. Was added imidazole (920 mg, 13.51 mmol) and stirred for 10 minutes, followed by 1.9.3 (1.54 g, 6.75 mmol) in CH ₂ Cl ₂ (40 mL) in the solution. After 2 hours, washed successively with saturated aqueous NaHCO _3, Na ₂ S ₂ O ₃ solution the reaction mixture was washed, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (25% ethyl acetate / 75% hexane) to afford 1.81 g 1.9.4.

To 1.9.4 (1.81 g, 5.34 mmol) in the at HMPA (30 mL) was added NaCNBH ₃ (1.34 g, 21.36 mmol). The reaction was stirred for 4 h and poured into ice cold water and extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, concentrated and silica gel chromatography (10% ethyl acetate / 90% hexane) to afford 580 mg 1.9.5.

To a stirred solution of 1.9.5 (380 mg, 1.78 mmol) in THF (8 mL), EtOAc (EtOAc) (EtOAc) The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. Dried with Na ₂ S ₂ O _3, the organic layer was washed with brine and over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 175 mg of the product methyl((4-methyloxazol-2-yl)methyl)carbamic acid as the butyl ester.

Example 1.1.10: 1-(2,5-Dimethyloxazol-4-yl)-N-methylmethylamine

Ti(O ⁱ PR) ₄ (1.08 mL, 3.69 mmol) was added to MeNH ₂ (4.3 mL, 2.0 M MeOH solution, 8.5 mmol) with stirring at 0 °C. After 15 minutes, aldehyde (360 mg, 2.83 mmol) was added and the reaction was stirred for 2-3 h. Was added portionwise NaBH ₄ (139 mg, 3.69 mmol), and stirred at 0 ℃ reaction to rt overnight. The solvent was removed via rotary evaporation. The residue was diluted with water / CH ₂ Cl ₂ . A white precipitate formed and was removed by filtration through celite. Separate the layers. With CH ₂ Cl ₂ (3 times) and the aqueous layer was extracted over Na ₂ SO ₄ the combined organics were dried. The inorganics were filtered off and the solvent was removed via rotary evaporation to afford 300 mg of 1-(2,5-dimethyloxazol-4-yl)-N-methylamine.

Example 1.1.11: (3-Methyl-1,2,4-oxadiazol-5-yl)methylamine

Add NaOH (4.26 g, 107 mmol) and hydroxylamine hydrochloride (7.1 g, 0.1 mmol) to a solution of EtOAc (5 mL, EtOAc) The reaction was refluxed for 24 hours. It was then concentrated under reduced pressure. The white solid was dissolved in 150 mL absolute EtOH and filtered to remove inorganic salts. The filtrate was concentrated to give a crude white solid which crystallised from isopropyl alcohol to afford 3.2 g 1.11.1 .

To the stirred molecular sieve (3 Add 1.11.1 (900 mg, 10.0 mmol) to a suspension in dry THF (200 mL) and stir for 15 min. NaH (1.3 g, 32.0 mmol) was added and the reaction was stirred for 45 min. Methylglycine (1.89 g, 10 mmol) was then added and the reaction was taken and evaporated, filtered and evaporated. The residue was dissolved in CH ₂ Cl _2, washed with water, dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (40% EtOAcEtOAcEtOAc)

The 1.11.2 was converted to (3-methyl-1,2,4-oxadiazol-5-yl)methylamine using a standard deprotection scheme for the Boc group using TFA.

Example 1.1.12

To a solution of 4-methylthiazole-2- aldehyde (3.217 g, 25.296 mmol) in THF (100 mL) was added &lt;RTI ID=0.0&gt;&gt; . Followed by _{NaB (OAc) 3 H (10.73} g, 50.593 mmol) was slowly added portion-wise to the reaction, the resulting mixture was stirred for 16 hours, diluted with EtOAc and washed with aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution, separated, dried (Sodium sulfate) and EtOAc (EtOAc)

Example 1.1.13

Example 1.1.4 was synthesized using the same procedure as in Example 1.1.2. 2-Aminoethanol was purchased from Aldrich.

Example 1.1.14: Synthesis of N-((4-methylthiazol-2-yl)methyl)ethylamine

Ti(O ⁱ PR) ₄ (commercial source: sigma-aldrich) (2.9 g, 10.22 mmol) was added to EtNH ₂ (commercial source: sigma-aldrich) (2.0 M MeOH solution, 12 ml, with stirring under Ar). 23.6 mmol). After 5 minutes, aldehyde, 4-methylthiazole-2-carbaldehyde (1.0 g, 7.86 mmol) (commercial source: sigma-aldrich) was added, and the solution was stirred for 2 hours. The reaction was cooled to 0 ℃ and add _{NaBH 4 (418 mg, 11.0 mmol} ). The solution was stirred at 0 ° C to room temperature overnight. After quenching the reaction with water, the mixture was filtered through Celite to remove a white precipitate. The MeOH was then removed in vacuo. The residue was diluted with EtOAc. Washed with water (3 times), it was washed with brine (1X) and was dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo to give a crude material. Purification by column chromatography gave 50% yield of pure N-((4-methylthiazol-2-yl)methyl)ethylamine.

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

Ti(O ⁱ PR) ₄ (commercial source: sigma-aldrich) (2.95 g, 10.4 mmol) was added to MeNH ₂ (commercial source: sigma-aldrich) (2.0 M MeOH solution, 12 ml, with stirring under Ar). 23.7 mmol). After 5 minutes, aldehyde, 3-fluoropyridinecarboxaldehyde (1.0 g, 7.99 mmol) (commercial source: sigma-aldrich) was added, and the solution was stirred for 2 hours. The reaction was cooled to 0 ℃ and add _{NaBH 4 (395 mg, 10.4 mmol} ). The solution was stirred at 0 ° C to room temperature overnight. After quenching the reaction with water, the mixture was filtered through Celite to remove a white precipitate. The MeOH was then removed in vacuo. The residue was diluted with EtOAc. Washed with water (3 times), it was washed with brine (1X) and was dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo to give a crude material. Purification by column chromatography gave 67% yield of pure 1-(3-fluoropyridin-2-yl)-N-methylmethylamine.

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

Add 3-bromo-1 to thioguanamine, 2-amino-2-thioketoethyl pivalate (3.0 g, 17.02 mmol) (commercial source: Acros organics) in ethanol (10 ml). 1,1-Trifluoropropan-2-one (3.23 g, 17.02 mmol) (commercial source: Apollo scientific) and heated at 60 ° C for 24 hours. The reaction mixture was then cooled, DBU (2.59 g, 17.02 mmol) was then evaporated and The volatiles were then removed in vacuo and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried, evaporated and purified by column to afford (4-(trifluoromethyl)thiazol-2-yl)methanol.

To a solution of (4-(trifluoromethyl)thiazol-2-yl)methanol (245 mg, 1.34 mmol) in DCM (10 mL). The reaction was allowed to reach room temperature and stirred for 3 hours. Saturated sodium bicarbonate, baking soda mixture was then added and stirred for 10 minutes. The reaction mixture was then further diluted with DCM and the product was extracted with DCM. The volatiles were removed in vacuo and the obtained aldehyde, 4-(trifluoromethyl)thiazole-2-carbaldehyde, was taken to the next step without further purification.

Ti(O ⁱ PR) ₄ (commercial source: sigma-aldrich) (495 g, 1.74 mmol) was added to MeNH ₂ (commercial source: sigma-aldrich) (2.0 M MeOH solution, 2 ml, with stirring under Ar). 4.02 mmol). After 5 minutes, the aldehyde, 4-(trifluoromethyl)thiazole-2-carbaldehyde (245 mg, 1.34 mmol) was added, and the solution was stirred for 2 hr. The reaction was cooled to 0 ℃ and add _{NaBH 4 (66 mg, 1.742 mmol} ). The solution was stirred at 0 ° C to room temperature overnight. After quenching the reaction with water, the mixture was filtered through Celite to remove a white precipitate. The MeOH was then removed in vacuo. The residue was diluted with EtOAc. Washed with water (3 times), it was washed with brine (1X) and was dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo to give a crude material. Purification by column chromatography gave pure N-methyl-l-(4-(trifluoromethyl)thiazol-2-yl)methylamine as a 37% yield.

Example 1.2: Synthesis of a cyclic amine building block. Example 1.2.1: (R)-4-Methyl-2-(pyrrolidin-2-yl)thiazole

Add to a solution of commercially available (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (Synthetech, 9.97 g, 40.0 mmol) in 1,4-dioxane (60 mL) Pyridine (2 mL), di-tert-butyl dicarbonate ((Boc) ₂ O) (11.35 mL, 52 mmol) and NH ₄ HCO ₃ (3.98 g, 50.4 mmol) were stirred for 12 hours. All the solvent was evaporated, diluted with EtOAc and washed with water, 5% H ₂ SO ₄ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. Quantitative yield of (R)-2-aminopyridylpyrrolidine-1-carboxylic acid benzyl ester was used in the next step without further purification.

To (R)-2-Aminopyridylpyrrole-1-carboxylic acid benzyl ester (9.97 g, 40.0 mmol) to 1,2-dimethoxyethane (1,2-DME or DME) ( Lawson's reagent (8.9 g, 0.55 mmol) was added to the solution in 2000 mL) and stirred for 4 hours. All solvent was evaporated, with 100 mL of saturated NaHCO ₃ diluted and extracted with ether (2 × 200 mL). ₂ SO ₄ organic layers were dried over anhydrous Na and the concentrated. The crude (R)-2-thiocarbamomidyrrolidine-1-carboxylate phenyl ester was taken to the next step without further purification.

To a solution of (R)-2-thiocarbamomidyrrolidine-1-carboxylic acid benzyl ester (about 40 mmol) in EtOH (120 mL) was added chloroacetone (4.7 mL, 60 mmol) And heated at 75 ° C for 6 hours. The reaction was cooled to room temperature and poured into 100 mL of saturated aqueous NaHCO ₃ solution. Ethanol was evaporated under reduced pressure and aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was subjected to silica gel chromatography (35% ethyl acetate / 80% hexanes). After three steps, yielded 86% yield of (R)-2-(4-methylthiazol-2-yl)pyrrolidine Benzene-1-carboxylate.

An AcOH solution of HBr (60 mL) was added to (R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (pure) at room temperature. After 1 hour, ether (150 mL) was slowly added with vigorous stirring. Stirring was continued for 10 minutes and allowed to settle for 5-10 minutes. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colorless. The semi-solid was dissolved in water (50 mL) and treated with 1 N LiOH and reaches P ^H ~ 8 (3 × 100 mL) and extracted with _{5% MeOH / 95% CHCl 3} , to give 4.0 g (R) -4- methyl - 2-(pyrrolidin-2-yl)thiazole.

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

Add Et ₃ N (4.88 mL, 35.2) to a solution of L-hamic acid methyl ester hydrochloride (Aldrich, 5.0 g, 32.0 mmol) in CH ₂ Cl ₂ (150 mL) at 0 ° C. Millol), Cbz-D-proline (8.01 g, 32.0 mmol) and N,N'-dicyclohexylcarbodiimide (DCC) (7.26 g, 35.2 mmol). The reaction was allowed to warm to rt and stirred overnight. All solvents were evaporated and the residue was triturated with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (70% ethyl acetate / 30% chloroform) to give 8.5 g of (R)-2-((S)-3-hydroxy-1-methoxy-1-oxoxy Phenyl-2-propanylpyridinylpyrrolidine-1-carboxylate.

Deoxo-flour (4.5 mL, 24.16 mmol) was added dropwise to (R)-2-((S)-3-hydroxy-1-methoxy-1-oxo-propanol at -20 °C. acyl-2-yl carbamoyl) -pyrrolidine-l-carboxylic acid benzyl ester (8.5 g, 22.0 mmol) in CH ₂ Cl ₂ (150 mL) in the solution. The solution was stirred for 30 minutes and BrCCl ₃ (7.8 mL, 79.0 mmol), DBU (11.8 mL, 79 mmol) was then added dropwise. At 2-3 ℃ reaction was stirred 10 hours, quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was concentrated and subjected to silica gel chromatography (10% ethyl acetate / 90% chloroform) to afford 6.95(R)-2-(1-(phenylmethoxycarbonyl)pyrrolidin-2-yl)oxazole-4- Methyl formate.

Methyl (R)-2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4-carboxylate (6.95 g, 21.1 mmol) in THF (50 mL) LiBH ₄ (32 mL, 2.0 M in THF, 63.2 mmol) was added to the solution. The reaction was allowed to warm to rt and stirred for 3 h. Ethyl acetate (25 mL) was added dropwise and stirred for 30 min. The reaction was cooled to 0 &lt;0&gt;C and 50 mL 1N HCl was added dropwise and diluted with 100 mL water. Followed by extraction with ethyl acetate, dried over Na ₂ SO _4, concentrated and silica gel chromatography (3% MeOH / 97% chloroform) to give 4.1 g (R) -2- (4- ( hydroxymethyl) oxazole - 2-Benzylpyrimidine-1-carboxylic acid benzyl ester.

To a solution of (R)-2-(4-(hydroxymethyl)oxazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.1 g, 3.64 mmol) in HMPA (18 mL) Methyl iodide iodide (3.29 g, 7.28 mmol) was added and stirred for 30 minutes. NaCNBH ₃ was then added and the reaction was heated for 3 hours at 50 ℃, poured into 100 mL of ice-cold water and extracted with ether (2 × 100 mL). The organic layer was dried over Na ₂ SO _4, concentrated and silica gel chromatography (50% ethyl acetate / 50% hexane) to afford 180 mg (R) -2- (4- methyl-oxazol-2-yl) pyrrole Phenyl-1-carboxylate.

An AcOH solution of HBr (60 mL) was added to (R)-2-(4-methyloxazol-2-yl)pyrrolidine-1-carboxylate (pure) at room temperature. After 1 hour, ether (20 mL) was slowly added with vigorous stirring. Stirring was continued for 10 minutes and allowed to settle for 5-10 minutes. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colorless. The semi-solid was dissolved in water (50 mL) and taken to pH -8 with 1 N LiOH and extracted with 5% MeOH / 95% CHCl ₃ (3 x 100 mL) to give &lt; - (pyrrolidin-2-yl)oxazole.

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

Deoxofluor (commercial source: sigma-aldrich) was added to methylene chloride (DCM) (50 ml) containing alcohol 2.3.1 (5.0 g, 20.38 mmol) at -78 °C. The reaction mixture was then brought to room temperature (rt) and stirred at room temperature for 12 h. The reaction mixture was then quenched with saturated aqueous sodium carbonate at 0 ° C and warmed to room temperature. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with water and brine and dried. The crude residue was subjected to column chromatography to give 3.05 g of ester 2.3.2 .

To a solution of the ester 2.3.2 (3.05, 12.33 mmol) MeOH (20 ml), THF (20 ml) After 2 hours, the volatiles were removed in vacuo. The pH of the aqueous layer of concentrated HCl was adjusted to about 3 and the mixture was extracted with MeOH / CHCl ₃ (1:9). The combined organic layers were washed with brine, dried and concentrated to give 2.8 g of acid 2.3.3.

Pyridine (commercial source: sigma-aldrich) (1 ml), (Boc) ₂ O (commercial source: sigma-) was added sequentially to dioxane (20 ml) containing acid 2.3.3 (2.07 g, 8.87 mmol). Aldrich) (2.52 g, 11.53 mmol), sodium bicarbonate (882 mg, 11.2 mmol). The reaction mixture was stirred at room temperature overnight, then the volatiles were removed in vacuo. The reaction mixture was then partitioned between chloroform and water. The organic layer was dried and evaporated to give a quantitative yield of decylamine 2.3.4 .

Lawson's reagent (commercial source: sigma-aldrich) (1.98 g, 4.90 mmol) was added to DME (commercial source: sigma-aldrich) (30 ml) containing guanamine 2.3.4 (2.07 g, 8.91 mmol) and The reaction mixture was stirred at room temperature overnight. The volatiles were then removed in vacuo and the reaction mixture was partitioned between diethyl ether and water. The ether layer was concentrated and subjected to column purification to obtain 1.74 g thioxo Amides 2.3.5.

Calcium carbonate (2.06 g, 20.55 mmol), chloroacetone (commercial source: sigma-aldrich) (955 mg, was added sequentially to ethanol (20 ml) containing thioguanamine 2.3.5 (1.7 g, 6.85 mmol). 10.27 mmol). After heating at 70 ° C for 5 hours, the volatiles were removed in vacuo. The reaction mixture was filtered and partitioned between water and diethyl ether. The organic layer was dried and evaporated. 4 N HCl/dioxane (commercial source: sigma-aldrich) (4 ml) was added to the residue and stirred at room temperature for 3 hr. The volatiles were then removed in vacuo and the reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. The organic layer was dried, evaporated and purified by column to afford 900 mg proline 2.3.6.

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

Add triethylamine to a solution of ice cold 4-(R)-hydroxy-2-(R)-hydroxymethylpyrrolidine-carboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) 16.2 mL, 163.73 mmol) and sulfur trioxide-pyridine complex (12.73 g, 81.87 mmol). The mixture was stirred for 30 minutes, warmed to EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Purification by flash chromatography gave the ketone (7.5 g). ¹ H NMR (300 MHz, CDCl ₃ ), δ: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871 (s, 1 H), 3.749 (s, 3 H), 3.03-2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H).

To a solution of 4-oxooxypyrrolidine-N-1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.5 g, 35.76 mmol) in dichloromethane (80 mL) Deoxo-Fluor (17 mL, 1.07 mol) was added. The mixture was stirred and warmed to EtOAc EtOAc (EtOAc)EtOAc. The mixture was warmed to room temperature, dried (MgSO4) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 4.568-4.422 (m, 1 H), 3.894-3.725 (m, 2 H), 3.376 (s, 3 H), 2.78-2.601 (m, 1 H) , 2.553-2.385 (m, 1 H), 1.470, 1.422 (s, 9 H).

A solution of sodium hydroxide (60 mL of 1 M solution, 15 mL of water, 32 mmol) was added to EtOAc (EtOAc) After 3 hours, the volatiles were removed in vacuo. The aqueous layer was adjusted to about pH = 3 with a 3 M HCl solution and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

Pyridine (commercial source: Sigma-Aldrich) (1.25 ml), (Boc) ₂ O (commercial source: Sigma-Aldrich) was added sequentially to dioxane (50 ml) containing crude acid (5.55 g, 22.08 mmol). (6.75 g, 30.92 mmol), ammonium hydrogencarbonate (2.36 g, 29.82 mmol). The resulting reaction mixture was stirred at room temperature overnight then the volatiles were removed in vacuo. The reaction mixture was then taken up in ethyl acetate and washed with dilute aqueous HCI (1 M), sodium hydrogen carbonate and brine. The organic layer was dried <RTI ID=0.0></RTI> and evaporated to give EtOAc (EtOAc)

Lawson's reagent (commercial source: Sigma-Aldrich) (5.41 g, 13.37 mmol) was added to decylamine (5.6 g, 22.28 mmol) in DME (commercial source: Sigma-Aldrich) (100 ml) at room temperature The reaction mixture was stirred overnight. The volatiles were then removed in vacuo and the reaction mixture was partitioned between diethyl ether and water. The ether layer was concentrated and purified by column to yield 4.6 g of thiosamine.

Chloroacetone (commercial source: sigma-aldrich) (2.3 g, 25.81 mmol) was added to thioguanamine (4.6 g, 17.21 mmol) in ethanol (50 ml). After heating at 75 ° C for 5 hours, the volatiles were removed in vacuo. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen sulfate. The organic layer was dried and evaporated. 4 N HCl/dioxane (commercial source: Sigma-Aldrich) (10 ml) was added to the residue and stirred at room temperature for 3 hr. The volatiles were then removed in vacuo and the reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. The organic layer was dried and evaporated to give 1.2 g of desired product. ¹ H NMR (300 MHz, CDCl ₃ ), 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).

Example 1.2.5: (R)-2-(piperidin-2-yl)-4-methylthiazole

The methylthiazole-piperidine ligand 2.5.9 was prepared according to the same procedure as for the preparation of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole , commercially available as R- N- Boc-2. - piperidine 2.5.7 (Aldrich) formic acid as starting material, 2.5.8 was obtained, and the protecting group was removed using standard TFA conditions to give 2.5.9 .

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

2-(5-Methylfuran-2-yl)pyrrolidine was purchased from ACB Blocks.

Example 1.2.7: (R)-4-Methyl-2-(pyrrolidin-2-yl)thiazole

Add pyridine (2 mL), (Boc) ₂ O (11.35 mL, 52 mmol) to a solution of 2.7.1 (9.97 g, 40.0 mmol) in 1,4-dioxane (60 mL) And NH ₄ HCO ₃ (3.98 g, 50.4 mmol) and stirred for 12 hours. All the solvent was evaporated, diluted with EtOAc and washed with water, 5% H ₂ SO ₄ and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The crude yield of 2.7.2 is quantitative. This material was not purified.

Lawson's reagent (8.9 g, 0.55 mmol) was added to a solution of 2.7.2 (9.97 g, 40.0 mmol) in 1,2-DME (2000 mL) and stirred for 4 hours. All solvent was evaporated, and extracted with diethyl ether (2 × 200 mL) with 100 mL of saturated NaHCO ₃ diluted. ₂ SO ₄ organic layers were dried over anhydrous Na and the concentrated. The coarse 2.7.3 continues to the next step.

Chloroacetone (4.7 mL, 60 mmol) was added to a solution of 2.7.3 (ca. 40 mmol) in EtOH (120 mL) and heated at 75 °C for 6 hours. The reaction was cooled to room temperature and poured into 100 mL of saturated aqueous NaHCO ₃ solution. Ethanol was evaporated under reduced pressure and aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was subjected to silica gel chromatography (35% ethyl acetate / 80% hexane). After three steps, 86% 2.7.4 .

The HBr AcOH solution (60 mL.) was added to 2.7.4 (pure) at room temperature. After 1 hour, ether (150 mL) was slowly added with vigorous stirring. Stirring was continued for 10 minutes and allowed to settle for 5-10 minutes. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colorless. The semi-solid was dissolved in water (50 mL) and extracted with 1 N LiOH to pH~8 and extracted with 5% MeOH/95% CHCl ₃ (3×100 mL) to give 4.0 g of (R)-4-methyl-2- (pyrrolidin-2-yl)thiazole.

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

2-((2R,4S)-4-Fluoropyridin-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)oxazole

To a solution of commercially available D-seramine hydrochloride 2.9.1 (3.0 g, 24.8 mmol) in H ₂ O (8 mL) at room temperature, 37% formaldehyde solution (817 mg, 27.3 m) Mohr) and stirred for 24 hours. Then add NH ₂ OH.HCl (172 mg, 2.48 mmol), NaOH (50 mL, 2 N, 100 mmol), acetone (50 mL) and (Boc) ₂ O (6.27 mL, 27.28 mmol) ) and stirred for 12 hours. The reaction mixture was extracted with diethyl ether. The aqueous layer was acidified to pH ~ 3.5 with 1 N HCl then extracted with 5% MeOH / 95% CHCl ₃ (3 x 100 mL). Dried over anhydrous sodium sulfate the organic extracts were combined and concentrated to give 2.49 g of crude 2.9.2.

2.9.2 was converted to (R)-4-(4-methylthiazol-2-yl)oxazole by the procedure described in Example 1.2.7.

Example 1.2.10

( 2R )-2-(4-cyclopropyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester: stirred ( 2R )-2- at room temperature 2-Bromo-1-cyclopropylethanone (315 mg, 1.74) was added to a solution of thiolmethionylpyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.868 mmol) in EtOH (8 ml). Methyl) and CaCO ₃ (261 mg, 2.61 mmol) and the mixture was stirred at 80 ° C for 5 min. The volatiles were evaporated to give the crude material was purified by column chromatography (hexane solution of EtOAc = 0-66%) to give a colorless oil of (2 R) -2- (4- cyclopropyl -1 , 3-thiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 90% yield). MS (ESI) m / z: 295 [M+H] ⁺ .

4-cyclopropyl-2-[(2 R )-pyrrolidin-2-yl]-1,3-thiazole: (2 R )-2-(4-cyclopropyl-1,3 at room temperature a solution of thiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 0.781 mmol) and TFA (1 ml) in CH ₂ Cl ₂ (2 ml). material, to give a crude material, which was dissolved in CHCl _3. Washed with saturated aqueous NaHCO ₃ the mixture, dried over MgSO ₄ and evaporated to give crude free form of 4-cyclopropyl -2 - [(2R) - pyrrolidin-2-yl] -1,3-thiazole (120 Mg, 79% yield) which was used in the next reaction without further purification. MS (ESI) m / z: 195 [M + H] +.

Example 1.2.11

( 2R )-2-(4-ethyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester: in a manner similar to the case of Example 1.2.10 , from ( 2R )- The desired compound was synthesized from 2-butylamine-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.955 mmol). (228 mg, 85% yield) MS (ESI) m / z : 283 [M + H] +.

4-ethyl-2-[( 2R )-pyrrolidin-2-yl]-1,3-thiazole: in a similar manner to Example 1.2.10 , from ( 2R )-2-(4-ethyl -1,3-1,3-thiazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (228 mg, 0.807 mmol). (103 mg, 70% yield) MS (ESI) m / z : 183 [M + H] +.

Example 1.2.12

( 2R )-2-[4-(Chloromethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester: in a manner similar to Example 1.2.10 , by (2 R )-2-Thiocarbamimidyryrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.868 mmol). (262 mg,> 99% yield) MS (ESI) m / z : 303 [M + H] +.

Example 1.2.13

( 2R )-2-[4-(Methoxymethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester: stirred at room temperature (2 R a solution of tert-butyl 2-[4-(chloromethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxylate (262 mg, 0.865 mmol) in MeOH (5 mL) K ₂ CO ₃ (598 mg, 4.33 mmol) was added and the mixture was stirred at 70 ° C for 3 hours. Complete consumption of the starting molecule in 3 h and the volatiles evaporated to give the crude material was purified by column chromatography (hexane solution of EtOAc = 0-66%), to give (2 R) -2- [4- ( Methoxymethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 25% yield). MS (ESI) m/z: 299 [M+H] ⁺ .

4-(methoxymethyl)-2-[(2 R )-pyrrolidin-2-yl]-1,3-thiazole trifluoroacetate (1:1): stirred at room temperature ( 2 R )-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 0.219 mmol) in CH ₂ Cl ₂ ( TFA (1 ml) was added to the solution in 2 ml) and the mixture was allowed to stand at room temperature for 2 hours. The volatiles were evaporated to give crude 4-(methoxymethyl)-2-[( 2R )-pyrrolidin-2-yl]-1,3-thiazole trifluoroacetate (1:1) without Further purification was used for the next reaction. MS (ESI) m / z: 195 [M+H] ⁺ .

Example 1.3: Synthesis of isophthalate building blocks. Example 1.3.1

To a stirred solution of dimethyl 5-aminoisophthalate (Aldrich, 2.09 g, 10 mmol) in dichloromethane (30 mL Methanesulfonium chloride (0.86 mL, 11 mmol) was added at 0 ° C and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and ethyl acetate (50 mL). The resulting white precipitate was filtered and washed with EtOAc afforded EtOAc (EtOAc)

Add dimethyl 5-(methylsulfonylamino) isophthalate sequentially to a suspension of stirred NaH (0.24 g, 10 mmol, 60% oil dispersion) in 10 mL DMF at room temperature (1.435 g, 5 mmol), methyl iodide (0.62 mL, 10 mmol). After 5 hours, the H ₂ O (25 mL) The reaction was quenched. The reaction mixture was then extracted with EtOAc, washed further with H ₂ O to remove the excess of DMF, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product thus obtained was washed with hexane to give dimethyl 5-(N-methylmethanesulfonylamino)isophthalate as a white solid in a yield of 91% (1.37 g).

The 5- (N- methyl-methanesulfonamide acyl group) isophthalate (0.842 g, 2.8 mmol) was dissolved in THF: MeOH (1: 1) (8 mL) and H ₂ O (3 mL) in. 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 NaHCO ₃ (10 mL) was added to the reaction mixture and extracted with toluene (to remove the <10% of unreacted starting material). The aqueous solution was acidified, extracted and dried over anhydrous Na ₂ SO ₄ diluted with EtOAc and HCl (10%). The solvent was evaporated and dried <RTI ID=0.0> It is used immediately after purification.

Example 1.3.2

The starting material (1.0 g, 4.78 mmol, 1 eq.) Was cooled in dry CH ₂ Cl ₂ (10 ml) in the to -78 ℃. Tf ₂ O (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. With saturated aqueous NaHCO ₃ The reaction was quenched and diluted with EtOAc. Separate the layers. The organic layer was washed with water (3×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.8979 g (2.63 mmol, 55%) 3.2.10 .

A solution of stirred 3.2.10 (0.6013 g, 1.76 mmol, 1 eq.) in anhydrous DMF (5 mL) The resulting solution was protected from light and cooled to 0 °C. NaH (60% oil dispersion, 0.1057 g, 2.64 mmol, 1.5 eq.) was added and the mixture was stirred at <RTIgt; / H ₂ O and the resulting mixture was diluted with saturated aqueous NaHCO ₃ and the reaction was quenched with EtOAc. Separate the layers. The organic layer was washed with water (3×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.5693 g (1.60 mmol, 91%) 3.2.11 .

Example 1.3.3

2-Tributylstannylpyrazine (1 g, 2.71 mmol), Pd (2 g) was added to toluene (10 ml) containing dimethyl 5-bromoisophthalate (Matrix Scientific, 617 mg, 2.26 mmol). PPh ₃ ) ₄ (102 mg, 0.09 mmol). The reaction mixture was then refluxed for 22 hours. The reaction mixture was then filtered through celite and the volatiles were removed in vacuo. Column chromatography (50% ethyl acetate / 50% hexanes) afforded 455 mg of y.

Example 1.3.4

2,5-Dimethoxytetrahydrofuran (0.74 ml, 0.76 g, 5.74 mmol, 1.2 eq.) was added to the stirred dimethyl 5-aminoisophthalate (Aldrich, 1.0 g, 4.78 mmol). , 1 equivalent) in a suspension of 7 ml of acetic acid. The mixture was heated to reflux overnight at 135 °C. After 45 minutes, the reaction was cooled to room rt and solvent was evaporated in vacuo. The residue was stirred overnight in saturated aqueous NaHCO ₃ / EtOAc in. Separate the layers. Dried, water (twice), the organic layer was washed with brine (1 time) ₃ solution (once) and saturated NaHCO over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo. Purification by flash chromatography gave 1.00 g (4.6 mmol, 80% yield) of dimethyl 5-(1H-pyrrol-1-yl)isophthalate.

Example 1.3.5

CH ₂ O (aqueous solution, 37%) (3.2 ml, 3.49 g, 43.0 mmol, 6 eq.) was added to the stirred dimethyl 5-aminoisophthalate (1.5 g, 7.17 mmol, 1 eq.) in CH ₃ CN (50 ml) in a solution. After 15 minutes, was added _{NaBH 3 CN (1.09 g, 16.49} mmol, 2.3 equiv). The reaction was adjusted to pH ~ 7 with HOAc. Stir at 0 ° C to room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NaHCO _3. Separate the layers. The organic layer was washed with water (3×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed in vacuo. Purification by flash chromatography gave 1.62 g (6.83 mmol, 95% yield) of dimethyl 5-(dimethylamino)isophthalate.

Example 1.3.6

Stirring diester (1.00 g, 4.78 mmol, 1 eq) in 6 ml EtOH and glyoxal trimer in _{‧2H 2 O (1.004 g, 4.78} mmol, 1 eq.) Overnight. NH ₄ Cl (0.5114 g, 9.56 mmol, 2 eq.) was added. After 15 minutes, 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 hour, the reaction was allowed to cool to room temperature. After H ₃ PO ₄ (85%, 0.65 ml, 1.1 g, 9.56 mmol, 2 eq.) was added dropwise, the reaction was heated to reflux at 95 °C. After 6 hours, the reaction was cooled to rt and solvent was evaporated in vacuo. The residue was stirred in a mixture of CHCl ₃ and filtered through cotton to remove any insoluble material. Purification via flash chromatography gave 0.7329 g (2.

Example 1.3.7

A solution of (NH ₄ ) ₂ Ce(NO ₃ ) ₆ (7.6 g, 12.6 mmol, 2 eq.) in water (16 ml) was added dropwise to a stirred diester (1.6 g, 6.3 mmol, 1 eq) In a solution in HOAc (16 ml). The reaction was heated to 70 °C. After 90 minutes, the reaction was allowed to cool to room temperature. The reaction was diluted with water and extracted with EtOAc EtOAc. Dried organic layer was washed with saturated aqueous NaHCO ₃ (4 times), brine (1 time) and over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo to afford &lt;RTI ID=0.0&gt;&gt;

NH ₃ (2.0 M MeOH solution, 4.8 ml, 9.6 mmol, 8 eq.) was added to a diester (0.300 g, 1.2 mmol, 1 eq.) and glyoxal trimer ‧2H under ar. ₂ O (0.252 g, 1.2 mmol, 1 eq.) in a flask. The reaction was stirred at 0 ° C to room temperature overnight. The solvent was removed in vacuo. The residue was stirred in EtOAc and filtered thru a cotton to remove any insoluble material. Purification via flash chromatography gave 0.1293 g (0.45 mmol, 37% yield).

Example 1.3.8

And added K ₂ CO ₃ solution (15 mL) of (483 mg, 2.5 mmol) in DME (15 mL) in MeOH and stirred over the aldehyde (529 mg, 2.1 mmol) p-toluene sulfonic acyl isocyanide to. The resulting mixture was heated to reflux for 4 hours and cooled to room temperature. The solvent was removed and the residue was dissolved in EtOAc and H ₂ O in. The layers were separated and aqueous was extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 9 (103 mg, 19%) . _{^{1 H NMR (CDCl 3) δ}} 8.63 (s, 1H), 8.49 (s, 2H), 8.00 (s, 1H), 7.54 (s, 1H), 4.00 (s, 6H).

Example 1.3.9

The drop of Et ₃ N (catalytic) to a stirred solution of 4-chlorobutyric acid (0.029 ml, 0.35 g, 2.87 mmol, 1.2 equiv) in _{SOCl 2 (2 ml, 3.27 g} , 27.5 mmol, 11.5 equiv) was The mixture was heated to 80 °C. After 1.5 hours, the reaction was cooled to room temperature and solvent was removed in vacuo. The flask was evacuated and backfilled with Ar (3 times). The residue was dissolved in 2 ml of anhydrous CH ₂ Cl ₂ in. The resulting solution was added dropwise to a stirred solution of 5-amino dimethyl terephthalate in 8 ml of anhydrous CH ₂ Cl ₂ in the suspension. After 1 hour, add _{Et 3 N (1 ml, 0.73} g, 7.17 mmol, 3 equiv). After 2 h, the solvent was removed in vacuo and EtOAcqqqqq Water, and dried with saturated aqueous NaHCO ₃ (2), (3). The organic layer was washed with brine (1 time) over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed in vacuo. Purification by flash chromatography gave 0.6353 g (2.0 mmol, 85% yield) of &lt;RTI ID=0.0&gt;

A solution of dimethyl 5-(4-chlorobutylamido)isophthalate (0.635 g, 2.02 mmol, 1 eq.) dissolved in 5 ml of anhydrous DMF at 0 ° C was added dropwise to the solution. A stirred NaH (60% oil dispersion, 0.101 g, 2.53 mmol, 1.25 eq.) in 2 ml of dry DMF. The reaction was stirred at 0 ° C to room temperature overnight. After stirring overnight, the reaction was heated to 100 ° C for 19 hours. After cooling to room temperature, the reaction was poured into ice water to quench. The mixture was extracted with EtOAc (1×). The organic layer was washed with water (4 times), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed in vacuo. Purification by flash chromatography gave 0.3487 g (1. <RTI ID=0.0></RTI></RTI><RTIgt;

Example 1.3.10

A mixture of 5.0 g (32.2 mmol) of citrazinic acid (Aldrich), 3.9 g (35.6 mmol) of Me ₄ NCl and 9 mL of POCl ₃ was stirred in a CaCl ₂ drying tube while gradually heating to 130 ° C for about 16 hours. Add MeOH (100 mL) was cooled in an ice bath; After 1 h, addition of solid NaHCO ₃ to pH = 8. Water was added and the aqueous layer was extracted with EtOAc (2×). With brine (100 mL) The combined extracts were washed, dried over Na ₂ SO ₄ dried, filtered, and concentrated. Purification by flash chromatography (10% EtOAc / hexanes) afforded 4. <RTIgt;

To a stirring of at 0 ℃ (7.33 mmol) was added methyl ester (21.7 mmol) NaBH ₄ in MeOH and 5 mL THF solution of 25 mL. After 2 hours, the ice bath was removed and stirring was continued while warming to room temperature and continued for another 15 minutes. Add 1.06 g of NaBH ₄ . After a further 15 minutes, the solution was concentrated and EtOAc was added. The pH was adjusted to 7 with 1 N HCl and the layers were separated. With EtOAc (2 times) and the aqueous layer was extracted and washed with brine (50 mL) The combined extracts were washed, dried over Na ₂ SO _4, filtered and concentrated. Purification by flash gel chromatography gave crude alcohol.

The mixture of the crude alcohol in 7 mL of (CH ₃ ) ₂ NH (40 wt% H ₂ O solution) was stirred at room temperature for 45 min. The temperature was increased to 50 ° C and the solution was stirred at 50 ° C for about 24 hours. Ethyl acetate and H ₂ O (15 mL), and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine and aq. ₂ SO ₄ dried over Na The extracts were filtered and concentrated. Purification by flash gel chromatography (40% EtOAc / hexane) afforded &lt;RTI ID=0.0&gt;&gt;

To a stirred solution of N,N-dimethylaminopyridine in 7 mL of pyridine was added 1.2 mL of Ac ₂ O. After stirring the solution for 12 hours, the solution was concentrated and a saturated NaHCO ₃ solution was added to pH = 7. The aqueous layer and washed with H ₂ O (15 mL) and the organic layer was washed with brine (15 mL) and extracted with EtOAc,, dried over Na ₂ SO _4, filtered and concentrated. Purification by flash gel chromatography (15% EtOAc / hexanes) elute

To a solution of 1.17 g (5.10 mmol) of 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(PPh ₃ ) ₄ . The mixture was stirred at 80 ° C and Pd(PPh ₃ ) ₄ : 486 mg (50 minutes), 708 mg (3 hours), 657 mg (6 hours) were further added at various time intervals over a period of 10 hours. The temperature was increased to 100 ° C and stirring was continued for about 11 hours. Ethyl acetate was added and 50 mL 10% NH ₄ OH solution. The aqueous layer was extracted with EtOAc and brine was washed with brine. The aqueous layer (brine) was extracted with EtOAc, and the combined and dried over ₂ SO ₄ of Na extracts were filtered and concentrated. Purification by flash chromatography (30% EtOAc / hexanes)

To a stirred solution of 364 mg (1.66 mmol) in acetic acid was added _{365 mg (2.64 mmol) K 2} CO 3 7 mL MeOH was in. After 1 h, the mixture was filtered with EtOAc EtOAc. EtOAc was added and then H ₂ O (30 mL); the aqueous layer was extracted with EtOAc (4 times). With brine (50 mL) The combined extracts were washed, dried over Na ₂ SO ₄ dried, filtered, and concentrated. Purification by flash chromatography (50% EtOAc / EtOAc) elute

A mixture of 440 mg of cyanide in 3 mL of concentrated H ₂ SO ₄ and 1.8 mL of H ₂ O was stirred at 135 ° C for 12 hours. The temperature was lowered to 95 ° C, 6 mL of MeOH was added, and the solution was stirred at 95 ° C for 1 hour. The solution was added to ice H ₂ O and EtOAc in the. Solid NaHCO ₃ and saturated NaHCO ₃ solution were added to pH = 8. The aqueous layer was extracted with EtOAc (2×). With brine (40 mL) The combined extracts were washed, dried over Na ₂ SO _4, filtered, and concentrated to afford the methyl ester, which was used without further purification.

A mixture of 250 mg (1.19 mmol) of alcohol and 1.12 g (12.8 mmol) of MnO ₂ in 10 mL of CH ₂ Cl ₂ was stirred at 50 °C. Additional MnO ₂ was added to the mixture at various time intervals over the 75 minute period: 674 mg (15 minutes), 788 mg (15 minutes), 924 mg (10 minutes), 675 mg (15 minutes), 690 mg (15 minutes). The mixture was filtered through celite with EtOAc and EtOAc. The acid was used in the next reaction without further purification.

Example 1.3.11

KMNO ₄ (19.15 g, 121.2 mmol, 6.6 eq.), anisole (Aldrich, 2.6 ml, 2.5 g, 18.36 mmol, 1 eq.) was added sequentially to stirred KOH (3.30 g, 58.74 mmol, 3.2 eq) In a solution of 98 ml of water. The reaction was heated to 80 °C. After 3 hours, the reaction was allowed to cool to room temperature. The mixture was filtered through diatomaceous earth. Adjust the solution to pH with concentrated HCl 7 and again filter the mixture via diatomaceous earth. The solution was adjusted to pH = 2-3 with cone. HCl and extracted with EtOAc (2). With brine (1 time) and washed the organics were dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation to afford &lt;RTI ID=0.0&gt;&gt;

SOCl ₂ (1.85 ml, 3.03 g, 25.5 mmol, 10 eq.) was added dropwise at 0 ° C under stirring to a solution of diacid (0.500 g, 2.55 mmol, 1 eq.) in 10 mL anhydrous MeOH. in. The reaction was stirred at 0 ° C to room temperature overnight. The solvent was removed via rotary evaporation and the residue was taken in EtOAc. Water, brine and dried with saturated aqueous NaHCO ₃ (2), (3) (1) The solution was washed with Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation to afford &lt;RTI ID=0.0&gt;&gt;

BBr ₃ (1.0 M CH ₂ Cl ₂ solution, 7.53 ml, 7.53 mmol, 2.5 eq.) was added dropwise to EtOAc (0.6 785 g, 3.01 mmol, 1 eq. In a solution of CH ₂ Cl ₂ (4 ml). After 30 minutes, the reaction was allowed to warm to room temperature. After 2 h the reaction was quenched with EtOAc EtOAc EtOAc. The solvent was removed via rotary evaporation and the residue was taken in EtOAc. Water, and dried with saturated aqueous NaHCO ₃ (2), (3). The organic layer was washed with brine (1 time) over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification via flash chromatography gave 0.4045 g (1.

Add benzyl bromide (0.34 ml, 0.49 g, 2.89 mmol, 1.5 eq.) to a stirred phenol (0.4045 g, 1.92 mmol, 1 eq.) and K ₂ CO ₃ (0.5317 g, 3.85 mmol, 2) Equivalent) in suspension in anhydrous DMF (2 ml). After 48 hours, the reaction was diluted with Et ₂ O. Washed with water (4 times), brine (1) the mixture was washed and dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification via flash chromatography gave 0.5207 g ( 1.73 mmol, 90% yield).

Example 1.3.12

Add 2-cyano-phenylzinc bromide to a solution of dimethyl 5- iodoisophthalate 3.12.12 (commercial source: Matrix Scientific) (2 g, 6.25 mmol) in 15 mL THF (commercial source) : sigma-aldrich) (15 mL, 7.5 mmol, 0.5 M THF) and hydrazine (triphenylphosphine) palladium (commercial source: sigma-aldrich) (71 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 2 hours . The precipitated solid was filtered, and the filtrate was diluted with MeOH and filtered to give a second crop of a total of 1.2 g of dimethyl 5-(2-cyanophenyl)isophthalate 3.12.13 .

Example 1.3.13

To the bromine compound 3.13.14 (2.1 g, 8.0 mmol) (commercial source: Matrix Scientific), 1-methyl-4-pyrazole Acid pinacol ester (2.0 g, 9.61 mmol) (commercial source: sigma-aldrich) and K ₂ CO ₃ (3.32 g, 24.0 g, 24.0 mmol) (commercial source: sigma-aldrich) in 40 ml of dioxane and Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (653 mg, 0.80 mmol) was added to a mixture of 16 ml of water (commercial source: sigma- Aldrich). The reaction mixture was heated at 80 ° C for 6 hours, then concentrated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut

Example 1.3.14

Add 2-pyridine to iodine-containing compound (commercial source: Matrix Scientific) 3.14.16 (800 mg, 2.5 mmol) in THF (20 ml) Acid N-phenyldiethanolamine (commercial source: Aldrich) (1.8 g, 6.6 mmol), K ₂ CO ₃ (912 mg, 6.6 mmol), triphenylphosphine (173 mg, 0.66 mmol), followed by the addition of Pd ( OAc) ₂ and cuprous iodide (251 mg, 1.32 mmol). After refluxing for 24 hours, the reaction mixture was filtered through a pad of Celite. The residual solvent was evaporated on a rotary evaporator under reduced pressure and the crude material was dissolved in ethyl acetate. The insoluble material was filtered off and the residue was evaporated to dryness eluting elut elut elut elut elut

Example 1.3.15

Add 1-hydroxybenzotriazole (HOBT) (1.83 g, 13.54 mmol) and 1-ethyl-3-[3-di) to DCM (30 ml) containing acid 3.19.18 (3.0 g, 11.28 mmol) Methylaminopropyl]carbodiimide (EDCI or EDC) (3.03 g, 15.79 mmol). After stirring at room temperature for 1 hour, the reaction mixture was cooled and acetonitrile (commercial source: Sigma-Aldrich) (834 mg, 11.28 mmol), DIPEA (0.5 ml) was sequentially added. After stirring at room temperature for 16 hours, DCM was removed in vacuo. EtOAc and saturated aqueous sodium bicarbonate were added sequentially to the crude material. A white precipitate formed. The precipitate was filtered, washed with water and dried well to give EtOAc 3.15 .

POCl ₃ (commercial source: Sigma-Aldrich) (40 ml) was added to hydrazine (1.3 g, 4.03 mmol) and heated at 100 ° C for 5 hours. The reaction mixture was then cooled, POCl ₃ is removed in vacuo. The crude material was dissolved in ethyl acetate, washed with water, NaHCO ₃ solution, brine and dried. Column chromatography of the crude residue gave 600 mg of oxadiazole 3.15.20 .

Example 1.3.16

To a solution of oxazole 3.16.21 (226 mg, 3.28 mmol) in THF (10 ml) was added n-BuLi (2.4 ml, 3.79 mmol). After 0.5 hours, ZnCl ₂ (21 ml, 10.33 mmol) was added. After stirring at -78 ° C for 0.5 hours, and then at 0 ° C for 1 hour, iodine-isophthalic acid 3.16.22 (1 g, 3.12 mmol), Pd(PPh ₃ ) ₄ (191 mg, 0.16 mmol) were added sequentially. ). The reaction mixture was then refluxed for 2.5 hours. The reaction mixture was cooled, diluted with water and evaporated with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the volatiles were removed on a rotary evaporator under reduced pressure. The crude residue was chromatographed to give a di-ester, 3.26 .

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 NaHCO _3. The mixture was extracted with EtOAc (2×). Adjust the water layer to pH with concentrated HCl 3, and extracted with EtOAc (3 times). Appropriate organics were combined, washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation to afford & lt

Example 1.3.17

Add pyridine 3- to 1,4-dioxane (10 ml) containing iodine compound 3.17.25 (commercial source: Matrix scientific) Acid, sodium carbonate (2 M aqueous solution) and Pd(PPh ₃ ) ₄ were heated at 90 ° C for 4 hours. The reaction mixture was then diluted with ether, washed with water and brine and dried. The volatiles were removed in vacuo <RTI ID=0.0>: </RTI><RTIID=0.0>

Example 1.3.18

The ester was synthesized in a similar manner to Example 1.3.16.

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

The 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 [1,1'-biphenyl]-3,5-dicarboxylic acid diethyl ester

Stir Na ₂ CO ₃ (776 mg, 7.32 mmol), Pd(OAc) ₂ (4.5 mg, 0.02 mmol), aryl halide, diethyl 5-bromoisophthalate (1 gm, 3.66) at 35 °C Methyl), phenyl A mixture of acid (670 mg, 5.49 mmol), distilled water (14 ml) and acetone (12 ml). Thereafter, the reaction solution was extracted four times with diethyl ether (4 × 20 ml). The combined organic phases were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude diester [1,1 '-biphenyl]-3,5-dicarboxylic acid diethyl ester was taken to the next step without further purification.

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

Stir 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (commercial source: sigma-aldrich) (3.5 ml, 27.49 mmol), cuprous iodide (business) at 70 ° C under argon atmosphere Source: sigma-aldrich) (2.74 g, 14.37 mmol) and a mixture of the iodine compound 5-iodoisophthalate (commercial source: Matrix Scientific) (4.0 g, 12.5 mmol) in DMF (25 ml) hour. The reaction was then allowed to cool to room temperature. Diluted with DCM, and the solution was washed with water, dried over Na ₂ SO ₄ and concentrated to give a syrup. Purification by column chromatography (10% ethyl acetate / 90% hexane) afforded 1.5 g of y.

Example 1.3.21: Synthesis of dimethyl 5-(N-methylaminesulfonyl)isophthalate

Add sulfite chloride (20 ml), a few drops of DMF to the diester, sodium 3,5-bis(methoxycarbonyl)benzene sulfinate (5 g, 17.12 mmol) (commercial source: sigma-aldrich). . The reaction mixture was heated at 80 ° C for 20 hours. The volatiles are then removed under vacuum. The crude material was washed with water and brine, dried and then purified and purified to give 5 g of 5-(chlorosulfonyl)isophthalate.

To a solution of sulfonium chloride (1.0 g, 3.47 mmol) in THF (10 ml) was added methyleneamine (2.0 M, 6 ml, 12.25 mmol). The volatiles were then removed, the reaction mixture was diluted with ethyl acetate, washed with 1 N HCI, brine and dried. The crude residue was purified by column chromatography to yield &lt;RTI ID=0.0&gt;&gt;

Example 1.3.22

3-Chloro-6-methoxyisonicotinic acid tert-butyl ester: Stirred 2-chloro-6-methoxyisonicotinic acid (20 g, 106.6 mmol) and Boc ₂ O at room temperature (53.5 g, 245.2 mmol), EtOAc (EtOAc m. Complete consumption of the starting molecule and the mixture was diluted with EtOAc and H ₂ O. The organic phase was separated and aqueous was extracted with EtOAc (3times). And the organic layer was washed with H ₂ O (3 times) The combined washed with brine, dried over MgSO ₄ and evaporated to give a crude product, simply by column chromatography (hexane solution of EtOAc _{= 10%, SiO 2 50 g} ) was purified 2-Chloro-6-methoxyisonicotinic acid tert-butyl ester (22.2 g, 85% yield) was obtained as a white solid. MS (ESI) m / z: 244[M+H] ⁺ .

6-methoxypyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: Stirred 2-chloro-6-methoxyisonicotinic acid tert-butyl ester at room temperature ( 22.2 g, solution (240 ml) in 90.9 mmol) and _{Et 3 N (41.2 ml, 296} mmol) in MeOH (240 ml) and DMSO was added _{Pd (OAc) 2 (2.20 g} , 9.82 mmol) and dppf (5.44 g, 9.82 mmol). CO was bubbled into the mixture for 10 minutes and the mixture was stirred at 80 ° C under a CO atmosphere (balloon) overnight, at which time the starting molecule was consumed completely. The mixture was filtered through a pad of celite and the filtrate was evaporated to some extent (to remove MeOH). With EtOAc and H ₂ O was diluted DMSO solution of the residue. The organic layer was separated and aqueous was extracted with EtOAc (3times). And the organic layer was washed with H ₂ O (3 times) The combined washed with brine, dried over MgSO ₄ and evaporated to give crude material, simply by column chromatography (hexane solution of EtOAc = 10 to 20%, SiO ₂ 100 g Purification gave 6-methoxypyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (22.4 g, 92% yield). MS (ESI) m / z: 268.1 [M+H] ⁺ .

Example 1.3.23

6-Sideoxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-methoxypyridine-2,4- to a stirred at room temperature Add NaI (25.2 g, 168 mmol) and TMSCl (21.3 ml, 168 mmol) in a solution of 4-tributyl ester 2-methyl ester (15.0 g, 56.1 mmol) in MeCN (150 ml) The mixture was stirred under an Ar atmosphere at a temperature of 18 hours. The mixture was quenched with saturated aqueous NaHCO _3. The organic layer was separated and aqueous was extracted with EtOAc (3times). With saturated aqueous NaHCO ₃ and brine and the organic layers were combined, dried over MgSO ₄ and evaporated to give the crude material was purified by column chromatography simply (= hexanes EtOAc solution of 20 to 100%), to give a white solid 6-Phenoxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (22.2 g, 85% yield). MS (ESI) m / z: 254 [M+H] ⁺ .

Example 1.3.24

6-(methoxycarbonyl)-2-oxooxy-1,2-dihydropyridine-4-carboxylic acid: 6-methoxypyridine-2,4-dicarboxylic acid 4-distilled at room temperature Add NaI (8.41 g, 56.1 mmol) and TMSCl (7.10 ml, 56.1 mmol) in a solution of tributyl ester 2-methyl ester (5.0 g, 18.7 mmol) in MeCN (50 ml) and at the same temperature in Ar atmosphere The mixture was stirred for 12 hours. To the stirred mixture was added H ₂ O (0.66 ml) at room temperature and the mixture was stirred at 60 ° C for 30 min. The mixture was cooled to rt and treated with H ₂ O (100 ml) and quenched. The precipitated solid was collected and washed with EtOAc (EtOAc) (EtOAc) Formic acid (3.68 g, >99% yield). MS (ESI) m / z: 198 [M+H] ⁺ .

Example 1.3.25

6-{[(Trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-side oxy group to be stirred at 0 ° C 1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (2.0 g, 7.90 mmol) and i- Pr ₂ NEt (2.02 ml, 11.8 mmol) in CH ₂ Cl ₂ ( Tf ₂ O (1.59 ml, 9.48 mmol) was added dropwise to the solution in 80 ml) and the mixture was stirred at the same temperature for 1 hour. With complete consumption of the starting molecule and quenched with saturated aqueous NaHCO _3. The organic layer was separated and the aqueous layer was extracted with CHCl ₃ (3 times). With saturated aqueous NaHCO ₃ and brine and the organic layers were combined, dried over MgSO ₄ and evaporated to give the crude material was purified by column chromatography (hexane solution of EtOAc = 0-20%), to give a white solid of 6 -{[(Trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (2.68 g, 88% yield). MS (ESI) m / z: 386 [M+H] ⁺ .

Example 1.3.26

6-Cyclopropylpyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-{[(trifluoromethyl)sulfonyl]oxy}pyridine stirred at room temperature -2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (200 mg, 0.519 mmol) and cyclopropyl Add Pd ₂ (dba) ₃ (mg, 0.052 mmol), SPhos (85 mg, 0.21 mmol) and K ₃ PO ₄ (331 mg, 1.56) to a solution of the acid (89 mg, 1.04 mmol) in toluene (2.0 ml). (mmol) and the mixture was stirred at 100 ° C for 1 hour. The starting molecule was completely consumed and evaporated to give a purple residue. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc - Methyl ester (36 mg, 25% yield). MS (ESI) m / z: 278 [M+H] ⁺ .

Example 1.3.27

6-(2-Cyanophenyl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: in a similar manner to Example 1.3.26 , from 6-{[(trifluoromethyl) Sulfhydryl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (200 mg, 0.519 mmol). (35 mg, 20% yield) MS (ESI) m / z : 339 [M + H] +.

Example 1.3.28

6-(1,3-oxazol-2-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 1,3-oxazole (0.5 M THF solution ) at -78 °C A solution of 15.6 ml, 7.79 mmol) was placed under reduced pressure for 30 minutes to remove O ₂ dissolved in THF. To the stirred oxazole/THF solution, n-BuLi (1.65 M hexane solution, 2.83 ml, 4.67 mmol) was added at -78 ° C and the mixture was stirred at the same temperature for 30 minutes. ZnCl ₂ (1.0 M in THF, 4.67 ml, 4.67 mmol) was added to the mixture at the same temperature and the mixture was warmed at room temperature. To this stirred solution was added 6-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (300 mg, 0.779 mmol) And Pd(PPh ₃ ) ₄ (180 mg, 0.156 mmol) and the mixture was heated at 85 ° C for 1 min. The starting molecule was completely consumed and was quenched with EtOAc EtOAc (EtOAc) , 3-oxazol-2-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (87 mg, 37% yield). MS (ESI) m/z: 355 [M+H] ⁺ .

Example 1.3.29

6-[Methyl(methylsulfonyl)amino]pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-{[(trifluoromethyl) stirred at room temperature Sulfo]yloxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (300 mg, 0.779 mmol), CH ₃ SO ₂ NHCH ₃ (170 mg, 1.56 mmol) and K ₃ Add Pd ₂ (dba) ₃ (143 mg, 0.156 mmol) and Xantphos (270 mg, 0.467 mmol) to a solution of PO ₄ (496 mg, 2.34 mmol) in dioxane (3 ml) and stir at 100 ° C The mixture was 1 hour. The volatiles were evaporated and the mixture was purified eluting with EtOAc EtOAc EtOAc 4-Dibutyl phthalate 2-methyl ester (234 mg, 87% yield). MS (ESI) m / z: 345 [M+H] ⁺ .

Example 1.3.30

6-(2-Sideoxypyrrolidin-1-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-{[(trifluoromethyl)sulfonyl]oxy Pyrrolidin-2-one (44 mg) was added sequentially to a solution of 4-pyridyl-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (100 mg, 0.26 mmol) in toluene (3 ml). 0.52 mmol), Cs ₂ CO ₃ (127 mg, 0.39 mmol), xantphos (54 mg, 0.093 mmol), Pd ₂ (dba) ₃ (14 mg, 0.016 mmol). After refluxing for 1.5 hours, the reaction mixture was purified eluting elut elut elut elut elut elut elut eluting -yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester. MS (ESI) m / z: 321 [M+H] ⁺ .

Example 1.3.31

6-(2-Sideoxy-1,3-oxazolidin-3-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: in a similar manner to Example 1.3.30 , The desired compound was synthesized from 6-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-t-butyl ester 2-methyl ester (62 mg, 74% yield). MS (ESI) m / z: 323 [M+H] ⁺ .

Example 1.3.32

6-(2-Methyl-5-oxooxypyrrolidin-1-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: in a manner similar to Example 1.3.30 , 6-{[(Trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester The desired compound (72 mg, 83% yield). MS (ESI) m / z: 335 [M+H] ⁺ .

Example 1.3.33

6-(2-Sideoxypiperidin-1-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: in a manner similar to Example 1.3.30 , from 6-{[( Trifluoromethyl)sulfonyl]oxy}pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester The desired compound was synthesized (258 mg, 99% yield). MS (ESI) m / z: 335 [M+H] ⁺ .

Example 1.3.34

6-(pyrrolidin-1-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-{[(trifluoromethyl)sulfonyl]oxy} to the stirred Pyrrolidine (0.5 mL) was added to a solution of pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (119 mg, 0.309 mmol) in dioxane (1 mL). After stirring for 30 minutes, the reaction mixture was evaporated mjjjjjjjjjjjjjjj Pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester. (63 mg, 67% yield) MS (APCI/ESI) M/Z: 307[M+H] ⁺ .

Example 1.3.35

1-methyl-6-o-oxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-sideoxy-1,6-dihydropyridine Add methyl iodide (0.15 mL, 2.37 mmol) and potassium carbonate (218 mg) to a solution of 4-tert-butyl 2-methyl benzoate (200 mg, 0.791 mmol) in DMF (4 mL) , 1.58 mmol). After stirring for 14 hours, the reaction mixture was concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc 4-Dibutyl 4-carboxylate 2-methyl ester. (146 mg, 69% yield) MS (ESI) M / Z : 268 [M + H] +.

Example 1.3.36

6-(Difluoromethoxy)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester: 6-sided oxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4 Add a solution of tert-butyl ester 2-methyl ester (55 mg, 0.217) in MeCN (1 mL) with difluoro(fluorosulfonyl)acetic acid (0.027 mL, 0.26 mmol) and potassium carbonate (35 mg, 0.33) Mm). After stirring for 14 hours, the mixture was filtered with EtOAc (EtOAc)EtOAc.EtOAc.

Example 1.4: Synthesis of m-xylyleneamine intermediate. Example 1.4.1

20% Pd(OH) _{2 /} C (0.04 g, 40 wt%) was added to a solution of stirred acid (0.1006 g, 0.24 mmol) in MeOH. The mixture was stirred overnight under H ₂ (balloon double). The mixture was filtered through celite and solvent was evaporated from rotary evaporated to afford &lt;RTI ID=0.0&gt;&gt;

Example 1.4.2

Added to monomethyl terephthalate (0.294 mmol, 1.0 eq.) In 2 ml of SOCl ₂ in between the suspension stirred Et ₃ N (1 drop, catalytic) under Ar. The mixture was heated to reflux at 90 ° C for 2 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was taken up in an ar atmosphere and dissolved in 2 mL anhydrous CH ₂ Cl ₂ . Under Ar was dissolved in 1 ml of the resulting solution of anhydrous CH ₂ Cl ₂ solution was treated with an amine (0.294 mmol, 1.0 equiv). After stirring at room temperature for 30 minutes, ET ₃ N (0.294 mmol, 1 eq.) The reaction was treated. Was stirred at room temperature for 30 minutes, the reaction was poured into a separatory funnel, and dried ₃ with saturated NaHC03 (1 time), water (3 times), brine (twice), dried over Na ₂ SO _4. The inorganics were removed via filtration and the solvent was removed in vacuo to afford crude material in 93% yield.

Example 1.4.3

Add triethyl bromide to a solution of ice cold 4-(R)-hydroxy-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (9.81 g, 40.93 mmol) in DMSO (50 mL) Amine (16.2 mL, 163.73 mmol) and sulfur trioxide-pyridine complex (12.73 g, 81.87 mmol). The mixture was stirred for 30 minutes, warmed to EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Purification by flash chromatography gave the ketone (7.5 g). ¹ H NMR (300 MHz, CDCl ₃ ), δ: 4.818-4.673 (m, 1 H), 3.903 (s, 1 H), 3.871 (s, 1 H), 3.749 (s, 3 H), 3.03-2.862 (m, 1 H), 2.605-2.542 (m, 1 H), 1.468, 1.445 (s, 9 H).

To a solution of 4-oxooxypyrrolidine-N-1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.5 g, 35.76 mmol) in dichloromethane (80 mL) Deoxo-Fluor (17 mL, 1.07 mol) was added. The mixture was stirred and warmed to EtOAc EtOAc (EtOAc)EtOAc. The mixture was warmed to room temperature, dried (MgSO4) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 4.568-4.422 (m, 1 H), 3.894-3.725 (m, 2 H), 3.376 (s, 3 H), 2.78-2.601 (m, 1 H) , 2.553-2.385 (m, 1 H), 1.470, 1.422 (s, 9 H).

A solution of sodium hydroxide (60 mL of 1 M solution, 15 mL of water, 32 mmol) was added to EtOAc (EtOAc) After 3 hours, the volatiles were removed in vacuo. The aqueous layer was adjusted to about pH = 3 with a 3 M HCl solution and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

Pyridine (commercial source: sigma-aldrich) (1.25 ml), (Boc) ₂ O (commercial source: sigma-aldrich) was added sequentially to dioxane (50 ml) containing crude acid (5.55 g, 22.08 mmol). (6.75 g, 30.92 mmol), ammonium hydrogencarbonate (2.36 g, 29.82 mmol). The resulting reaction mixture was stirred at room temperature overnight then the volatiles were removed in vacuo. The reaction mixture was then taken up in ethyl acetate and washed with dilute aqueous HCI (1 M), sodium hydrogen carbonate and brine. The organic layer was dried <RTI ID=0.0></RTI> and evaporated to give EtOAc (EtOAc)

Lawson's reagent (commercial source: sigma-aldrich) (5.41 g, 13.37 mmol) was added to decylamine (5.6 g, 22.28 mmol) in DME (commercial source: sigma-aldrich) (100 ml) at room temperature The reaction mixture was stirred overnight. The volatiles were then removed in vacuo and the reaction mixture was partitioned between diethyl ether and water. The ether layer was concentrated and purified by column to yield 4.6 g of thiosamine.

Chloroacetone (commercial source: sigma-aldrich) (2.3 g, 25.81 mmol) was added to thioguanamine (4.6 g, 17.21 mmol) in ethanol (50 ml). After heating at 75 ° C for 5 hours, the volatiles were removed in vacuo. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen sulfate. The organic layer was dried and evaporated. 4 N HCl/dioxane (commercial source: sigma-aldrich) (10 ml) was added to the residue and stirred at room temperature for 3 hours. The volatiles were then removed in vacuo and the reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. The organic layer was dried and evaporated to give 1.2 g of desired product. ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.818 (s, 1H), 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).

To a solution of the stirred monobasic acid (726.2 mg, 2.94 mmol), amine (600 mg, 2.94 mmol) in DCM was added triethylamine (1.64 mL, excess), Py-BOP (1.68 g, 3.23 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with chloroform. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product thus obtained was purified by silica gel flash column chromatography to give the corresponding decylamine (700 mg). ¹ H NMR (300 MHz, CDCl ₃ ), δ: 8.817 (s, 1 H), 8.414 (s, 1 H), 8.286 (s, 1 H), 7.78 (s, 1 H), 7.306 (m, 1) H), 6.789 (s, 1 H), 5.918 (m, 1 H), 4.159 (m, 1 H), 3.978 (s, 3 H), 3.78 (m, 1 H), 3.175 (m, 1 H) , 2.948 (m, 1 H), 2.467 (s, 3H).

The ester (700 mg, 1.62 mmol) was dissolved in THF: MeOH (1: 1) (15:15 mL) and H ₂ O (3 mL) in. Solid NaOH (194 mg, 4.845 mmol) was added and stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. A saturated NaHCO ₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The reaction with dilute HCl (10%) was acidified aqueous mixture was extracted with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried under reduced pressure to give a crude acid which was used directly in the next reaction.

Example 1.4.4

Dimethyl 5-(N-methylmethane-5-ylsulfonylamino)isophthalate: dimethyl 5-aminoisophthalate (2.09 g, 10 mmol) at room temperature Pyridine (2.43 mL, 30 mmol) was added to a solution in dichloromethane (30 mL). Methanesulfonium chloride (0.86 mL, 11 mmol) was added at 0 ° C and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and ethyl acetate (50 mL). The resulting white precipitate was filtered and washed with EtOAc afforded EtOAc EtOAc See Stachel et al, J. Med. Chem. 2004, 47, 6447-6450.

The above sulfonamide (1.435 g, 5 mmol) and methyl iodide (0.62) were added sequentially to a suspension of stirred NaH (0.24 g, 10 mmol, 60% oil dispersion) in 10 mL DMF at room temperature. mL, 10 mmol). After 5 hours, the H ₂ O (25 mL) The reaction was quenched. The reaction mixture was then extracted with EtOAc, washed further with H ₂ O to remove the excess of DMF, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product thus obtained was washed with hexane to give a diester as a white solid (yield: 91%).

3-(Methoxycarbonyl)-5-(N-methylmethyl-5-ylsulfonylamino)benzoic acid: The diester (0.842 g, 2.8 mmol) was dissolved in THF:MeOH (1:1) In mL) and H ₂ O (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 NaHCO ₃ (10 mL) was added to the reaction mixture and extracted with toluene (to remove the <10% of unreacted starting material). The aqueous solution was acidified and extracted with dilute HC1 (10%) with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried <RTI ID=0.0>

To a solution of the stirred monobasic acid (0.393 g, 1.37 mmol), amine (185 mg, 1.3 mmol) in DCM was added triethylamine (1 mL, excess), Py-BOP (784 mg, 1.507 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was then added and the reaction mixture was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product thus obtained was purified by silica gel flash chromatography (2% EtOAcEtOAcEtOAc) elute 15 mL) and H ₂ O (2 mL). Solid NaOH (146 mg, 3.645 mmol) was added and stirred at 50 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. A saturated NaHCO ₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The reaction with dilute HCl (10%) was acidified aqueous mixture was extracted with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried under reduced pressure to give crude acid 2 which was used directly in the next reaction.

Example 1.4.5

According to the general procedure, amine 4.5.27 was coupled with 4.5.28 using HOBT and EDCI and the ester thus obtained was saponified to give the acid 4.5.29 .

Example 1.4.6

EDCI ‧ HCl (0.372 g, 1.9 mmol, 1.3 eq.) and HOBT ‧ H ₂ O (0.202 g, 1.5 mmol, 1.0 eq.) were added to the stirred acid 4.6.30 (0.37 g, 1.5 mmol, 1 eq.) in 8 ml dry CH ₂ Cl ₂ in a solution. With 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 of anhydrous CH ₂ Cl ₂ solution was treated in the resulting solution. The reaction was stirred at 0 ° C to room temperature overnight. The solvent was removed via rotary evaporation. The residue was quenched with EtOAc (EtOAc) The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.8308 g (2.5 mmol, 65% yield) 4.6.32 .

To a solution of 4.6.32 (0.38 g, 2.5 mmol, 1 eq.) in THF (3 mL). After stirring for 2 hours, the medium was adjusted to pH with 1 N HCl. 3 and extracted with 10% MeOH / 90% EtOAc (2). The organics were combined and dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation, to give 0.28 g (76% yield) of the product 4.6.33.

Similar to 4.6.33 , acids 4.6.34 and 4.6.35 were synthesized using the appropriate commercially available isophthalic acid diester as the starting material.

Example 1.4.7

3-methoxycarbonyl-5-hydroxy-methylbenzoic acid: The diester (4.12 g, 16.33 mmol) was dissolved in THF: MeOH (1: 1) (80 mL) and H ₂ O (15.52 mL) in. Solid NaOH (0.62 g, 15.52 mmol) was added and stirred at 0 ° C and slowly warmed to room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Saturated NaHCO ₃ (10 mL) was added to the reaction mixture and extracted with toluene (to remove the <10% of unreacted starting material). The aqueous solution was acidified and extracted with dilute HCl (10%) with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried <RTI ID=0.0>

Add diisopropylethylamine (6.7 mL, excess), HOBt (1.3 g, 9.64 mmol) to a solution of the amine (1.62 g, 9.64 mmol) and acid (2.23 g, 10.6 mmol) in DCM (100 mL) And EDCI (2.4 g, 12.53 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogen sulfate and evaporated. The aqueous layer was extracted again with chloroform. The combined organic layers were concentrated to give a crystal crystal crystal crystal crystal crystal ¹ H NMR (300 MHz, CDCl ₃ ), 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).

Anhydrous (2.1 g, 5.83 mmol) of anhydrous DCM (60 mL) was slowly added to trifluoro[bis(2-methoxyethyl)amino]sulfide and stirred at the same temperature at -78 °C. After 2 hours, the temperature was raised to room temperature overnight. Carefully with saturated aqueous NaHCO ₃ was quenched reaction was extracted three times with chloroform. Dried over anhydrous Na ₂ SO ₄ dried the combined organic solvent was removed in vacuo and purified by silica gel chromatography on the residue to give a fluoride (1.6 g, 76%). ¹ H NMR (CDCl ₃ ) δ 8.211-7.784 (m, 2.7 H), 7.420 (s, 0.3 H), 6.78 (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).

The ester (1.53 g, 4.22 mmol) was dissolved in THF: MeOH (1: 1) (20:20 mL) and H ₂ O (6.5 mL) in. Solid NaOH (507 mg, 12.66 mmol) was added and stirred at 50 ° C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The reaction with dilute HCl (10%) was acidified aqueous mixture was extracted with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried <RTI ID=0.0>

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

Synthesis of 2'-cyano-5-(2-(5-methylfuran-2-yl)pyrrolidin-1-carbonyl)-[1,1'-biphenyl according to an experimental procedure similar to that in Example 1.4.6 ]-3-carboxylic acid.

Example 1.4.9: 3-(Methyl((3-methyl-1,2,4-oxadiazol-5-yl)methyl)aminecarboxamido)benzoic acid

3-(Methyl((3-methyl-1,2,4-oxadiazol-5-yl)methyl)aminecarboxamido)benzoic acid was synthesized according to a procedure similar to the procedure of Example 1.4.6.

Example 1.4.10

This compound was synthesized according to an experimental procedure similar to that in Example 1.4.7.

Example 1.4.11

This compound was synthesized according to an experimental procedure similar to that in Example 1.4.6.

Example 1.4.12

This compound was synthesized according to an experimental procedure similar to that in Example 1.4.6.

Example 1.4.13

This compound was synthesized according to an experimental procedure similar to that in Example 1.4.6.

Example 1.4.14

DMP Oxidation: Dess-Martin periodinane (790.8 mg, 1.864 mmol) was added to a solution of the alcohol (560 mg, 1.554 mmol) in DCM (60 mL). After stirring for 2 hours, the mixture was poured in a mixture of 1 M Na ₂ S ₂ O ₃ solution (30 mL) and saturated aqueous NaHCO ₃ (30 mL) of, and the extracted three times with DCM. The combined organic layers were concentrated in vacuo and purified title crystall ¹ H NMR (CDCl ₃ ) 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).

To a solution of aldehyde (530 mg, 1.47 mmol) in CH ₂ Cl ₂ (50 mL) was slowly added at a solution of &quot;bis(2-methoxyethyl)amino] sulphur (0.46 mL) , 2.49 mmol), followed by the addition of a few drops of ethanol, and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was allowed to warm to room temperature and stirred overnight. The solution was slowly poured into saturated NaHCO _3, extracted three times with dichloromethane, dried (Na ₂ SO _4), filtered and evaporated in vacuo. Flash chromatography on silica gel gave the pure product (442 mg). ¹ H NMR (CDCl ₃ ) 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).

To a solution of the aldehyde (740 mg, 2.065 mmol) in THF (40 mL), EtOAc (EtOAc m. The resulting mixture was allowed to warm to room temperature and stirred overnight. The solution was slowly poured into saturated aqueous NH ₄ Cl, extracted three times with EtOAc, washed with brine, dried (Na ₂ SO _4), filtered and evaporated in vacuo. Flash chromatography on silica gel gave the pure product (720 mg).

The second alcohol is fluorinated with Deoxo-Fluro to give the product ( 4.14.1 ).

The second alcohol is oxidized with DMP to give the product ( 4.14.2 ).

The ketone is fluorinated with Deoxo-Fluro to give the product ( 4.14.3 ).

Example 1.4.15

Treatment of the ketone (240 mg) with N,N-dimethylformamide dimethyl acetal (5 mL, excess) at 100 ° C for 17 hours afforded crude product (170 mg), then at 90 ° C Hydroxylamine hydrochloride (81.3 mg, 1.17 mmol) in ethanol (10 mL) was taken overnight to afford crude material. Flash chromatography on silica gel gave the pure product (50 mg). The intermediate was treated with hydrazine to give the pyrazole product.

Example 1.4.16

The aldehyde (610 mg, 1.702 mmol) in methanol (5 mL) was treated with hydroxyamine hydrochloride (130 mg, 1.872 mmol) and sodium acetate (237.3 mg, 2.8934 mmol) at room temperature overnight. The solvent is removed in vacuo, diluted with EtOAc, washed with saturated NH ₄ Cl, saturated aqueous NaHCO _3, washed with brine, dried (Na ₂ SO _4), filtered and evaporated in vacuo to give the crude product, followed by at room temperature Treatment with THF (6.5 mL) containing trimethyldecyl acetylene (1 mL) and bleach (6.5 mL) overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO _3, saturated aqueous NH ₄ Cl, washed with brine, dried (Na ₂ SO _4), filtered and evaporated in vacuo. Flash chromatography on silica gel gave the pure product (325 mg).

A general hydrolysis procedure is carried out to obtain the corresponding acid while removing the decyl group.

Example 1.4.17

EDCI HCl (0.3946 g, 2.1 mmol, 1.1 eq.) and HOBT ‧ H ₂ O (0.2789 g, 2.1 mmol, 1.1 eq.) were added to the stirred acid (Aldrich, 0.500 g, 1.9) at 0 °C. mmol, 1 equiv) in dry CH ₂ Cl ₂ (10 ml) in a solution. After 1 hour, the resulting solution was treated sequentially with EtOAc (0.30 <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI><RTIgt; 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 / layers are separated between H ₂ O. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave a quantitative yield of the diester.

The solution of the diester (0.8097 g, 1.9 mmol, 1 eq.) in 2:1 THF / MeOH (5 ml) was cooled to 0. 1 N 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 NaHCO _3, and the volatiles were removed via rotary evaporation. And the resulting mixture was diluted with water (2x) and extracted with CH ₂ Cl _2. Adjust the water layer to pH with HCl 2 and extracted with EtOAc (2 times). The EtOAc was dried over Na ₂ SO _4. The inorganics were filtered off and the volatiles were removed via rotary evaporation to afford &lt;RTI ID=0.0&gt;&gt;

Example 1.4.18

A solution of the alcohol (0.0955 g, 0.24 mmol, 1 eq.) in anhydrous DCM (4 mL) was cooled to -78. The cooled solution was treated with Deoxo-Fluor (53 μl, 0.06 g, 0.29 mmol, 1.2 eq.). The reaction was stirred at -78 °C to room temperature overnight. The layers were separated and the aqueous was diluted with saturated NaHCO ₃ the reactants. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography gave 0.0204 g (0.051 mmol, 21%). Saponification was carried out in a manner similar to that in Example 1.4.4.

Example 1.4.19

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

Example 1.4.20

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

Example 1.4.21

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

Example 1.4.22

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

Example 1.4.23

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

Example 1.4.24

The ester is synthesized in a manner similar to 1.4.2 using the appropriate starting materials. Saponification was carried out in a manner similar to that in Example 1.4.4.

Example 1.4.25: Synthesis of (R)-5-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-3-carboxylic acid

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

Example 1.4.26: Synthesis of (R)-3-iodo-5-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

Example 1.4.27: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-5-(trifluoromethyl)benzoic acid

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

Example 1.4.28: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-5-nitrobenzoic acid

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

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

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

Example 1.4.30: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-5-(pyrazin-2-yl)benzoic acid

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

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

The ester was formed in a manner similar to that described in Example 1.4.6, followed by saponification of the resulting ester.

Example 1.4.32

Methyl 6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate: 6- The pendant oxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (6.4 g, 25.3 mmol) was dissolved in SOCl ₂ (55 ml) and a catalytic amount of DMF was added. (5 drops). The mixture was stirred at 80 ° C for 36 hours. Further DMF (30 drops) was added and the mixture was stirred at 80 ° C for 24 hours. The SOCl ₂ was evaporated to give a residue which was azeotroped with toluene. The residue obtained was dissolved in CH ₂ Cl ₂ (64 ml) and Et ₃ N (7.05 ml, 50.5 mmol) and 4-methyl-2-[(2R)-pyrrolidine-2 was added at room temperature. -yl]-1,3-thiazole (5.02 g, 29.8 mmol). The mixture was stirred at the same temperature for 2 hours. The reaction was quenched with 1 M aqueous HCl and organic layer was separated. With CHCl _{3 (3} times) and the aqueous layer was extracted with aqueous and the combined organic layers were washed with brine, saturated NaHCO _3, dried over MgSO ₄ and evaporated to give the crude material by column chromatography (hexane solution of EtOAc = 30 to 100 Purification to give 6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl as a pale yellow oil } pyridine-2-carboxylate (8.67 g, 94% yield), MS (ESI) m / z: 366 [m + H] +.

Example 1.4.33

3-(cyclopropyl((4-methylthiazol-2-yl)methyl)aminemethanyl)-5-(oxazol-2-yl)benzoic acid: according to an experimental procedure similar to Example 1.4.2 To synthesize the desired compound.

Example 1.4.34

The ester was synthesized in a manner similar to that of Example 1.4.6 using the appropriate starting materials. Saponification was carried out in a manner similar to that in Example 1.4.4 .

Example 1.4.35

The ester was synthesized in a manner similar to that of Example 1.4.6 using the appropriate starting materials. Saponification was carried out in a manner similar to that in Example 1.4.4 .

Example 1.5: Synthesis of an anthracene intermediate. Example 1.5.1

So that the acid stirred under Ar (Aldrich, 0.5 g, 4.3 mmol, 1 eq.) In dry suspension was cooled CH ₂ Cl ₂ (15 ml) to the 0 ℃. (, 0.66 g, 6.5 mmol, 1.5 equiv. 0.9 ml) The reaction was treated with Et ₃ N. After 5 minutes, was added dropwise _{(Boc) 2 O (1.3 ml} , 1.2 g, 5.6 mmol, 1.3 equiv). After 3 hours, the reaction was quenched by addition of aqueous citric acid (5%, 15 mL). The layers and the organic layer over Na ₂ SO ₄ dried isolated. The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.7386 g (3.4 mmol, 80%).

Under Ar with stirring the acid (0.7386 g, 3.4 mmol, 1 equiv) in dry CH ₂ Cl ₂ (10 ml) in the solution was cooled to 0 ℃. The solution was treated with HOBT ‧ H ₂ O (0.5559 g, 4.1 mmol, 1.2 eq.). After 1 hour, add anhydrous _{N 2 H 4 (0.43 ml,} 0.44 g, 13.2 mmol, 4 equiv) was added DIPEA 10 minutes (2.3 ml, 1.7 g, 13.2 mmol, 4 equiv). The reaction was stirred at 0 ° C to room temperature overnight. The reaction was quenched with water and diluted with saturated aqueous NaHCO _3. Separate the layers. The aqueous layer was extracted with CH ₂ Cl ₂ (3 times). Dried over Na ₂ SO ₄ the combined organics. The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.5616 g (2.4 mmol, 72%).

Example 1.5.2

(, 10.75 mmol 3.0 g) in CH ₃ CN was added the solution of EDC (3.5 g, 18.28 mmol) was added to 5.2.36. After 5 minutes, anhydrous hydrazine was added and stirred at room temperature overnight. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue extracted with EtOAc. The organic extracts were washed with brine, dried, concentrated and purified by silica gel (3% MeOH / 97% CHCl 3), to obtain 1.42 g (45%) 5.2.37.

Example 1.5.3: (R)-(3-(4-Fluorophenyl)-1-indenyl-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester

(10 mmol 2.97 g) in CH ₃ CN was added the solution of EDC (3.25 g, 17 mmol) was added to 5.3.1. After 5 minutes, anhydrous hydrazine (0.79 mL, 25 mmol) was added and stirred at room temperature overnight. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue extracted with EtOAc. The organic extracts were washed with brine, dried, concentrated and purified by silica gel (3% MeOH / 97% CHCl 3), to obtain 2.15 g (R) - (3- (4- fluorophenyl) -1-hydrazino-2 Tert-butyl methyl-1-acetoxypropan-2-yl)carbamate.

Example 1.5.4.

In a manner similar to Example 1.5.1, hydrazine was synthesized using the appropriate starting material (Peptech).

Example 1.5.5: Synthesis of (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-5-(pyrazin-2-yl)benzamide

To the acid, (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)-5-(pyrazin-2-yl)benzoic acid (300 mg, 0.76 mmol HOBT (103 mg, 0.76 mmol), EDCI (146 mg, 0.76 mmol) was added to DCM (5 ml) and stirred at room temperature for 2 hr. The resulting solution was then added to aqueous hydrazine (114 mg, 2.28 mmol) in DCM at -30 °C. The reaction mixture was stirred at room temperature for 48 hours, then worked up and purified by column to give (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl. -5-(Pyrazin-2-yl)benzimidazole.

Example 1.6: Synthesis of advanced intermediates. Example 1.6.1

Under Ar with stirring the acid (0.1106 g, 0.33 mmol, 1 equiv) in dry CH ₂ Cl ₂ (5 ml) in the solution was cooled to 0 ℃. The solution was treated with HOBT ‧ H ₂ O (0.0497 g, 0.37 mmol, 1.1 eq.). After 30 min, EDCI HCl (0.0703 g, 0.37 mmol, 1.1 eq.). After 1 hour, add anhydrous _{N 2 H 4 (0.042 ml,} 0.043 g, 1.34 mmol, 4 equiv) and after 10 minutes was added DIPEA (0.12 ml, 0.087 g, 0.67 mmol, 2 eq). The reaction was stirred at 0 ° C to room temperature overnight. After stirring overnight, the reaction was quenched with water and volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc and water and layers were separated. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.1223 g (0.36 mmol, 108%).

Under Ar with stirring the acid (0.0935 g, 0.335 mmol, 1 eq.) Was cooled in dry CH ₂ Cl ₂ (3 ml) in the to 0 ℃. The solution was treated with HOBT ‧ H ₂ O (0.0542 g, 0.40 mmol, 1.2 eq.) and EtOAc EtOAc (0.0 EtOAc, After 1 hour, the crude acyl hydrazide (0.1223 g, 0.36 mmol, about 1 eq) in dry CH ₂ Cl _{2 (2} ml) was treated in the reactants. After 5 minutes, DIPEA (0.22 mL, 0.17 g, 1.28 mmol, 4 eq.). The reaction was quenched with water and the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc and water and layers were separated. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.1507 g (0.25 mmol, 75%).

Example 1.6.2

A solution of the starting material (0.0641 g, 0.11 mmol, 1 eq.) in anhydrous DMF (2 mL). MeI (0.017 ml, 0.039 g, 0.27 mmol, 2.5 eq.) was added and the reaction was protected from light. NaH (60% oil dispersion, 0.0065 g, 0.16 mmol, 1.5 eq.) was added and the mixture was stirred at <RTIgt; The reaction was quenched with EtOAc (EtOAc) The organic layer was washed with water (3×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.0608 g (0.10 mmol, 92%).

Example 1.6.3: (R)-3-(5-(2-((t-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 2-yl)-5-(oxazol-2-yl)benzoic acid

Including use containing HOBT, EDCI and DIPEA of CH ₂ Cl ₂ standard coupling procedures to make a coupling 6.3.1 and 6.3.2, and stirred overnight to produce a yield of 81% 6.3.3.

Borghis reagent (3.6 g, 15.43 mmol) was added to a solution of 6.3.3 (3.51 g, 6.72 mmol) in dichloroethane (25 mL) and refluxed for 5 h. The reaction mixture was then allowed to cool to room temperature, diluted with CH ₂ Cl ₂ and washed successively with saturated aqueous NaHCO ₃ and brine, dried, concentrated and purified by silica gel (1% MeOH / 99% CHCl 3), to obtain 3.1 g 6.3.4 .

The standard hydrolysis conditions were carried out using a THF containing 1 N LiOH to hydrolyze 6.3.4 for 1 hour followed by acid treatment to obtain a quantitative yield of (R)-3-(5-(2-((t-butoxycarbonyl)) Amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid.

Example 1.6.4: (R)-3-(5-(2-((T-Butoxycarbonyl))amino)-1-(4-fluorophenyl)propan-2-yl)-1,3,4 -oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid

Synthesis of (R)-3-(5-(2-((t-butoxycarbonyl))amino)-1-(4-fluorophenyl)propan-2-yl using the same procedure as in Example 1.6.3 )-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)benzoic acid.

Example 1.6.5: (R)-3-(5-(2-((t-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 2-yl)-5-(pyrazin-2-yl)benzoic acid

Synthesis of (R)-3-(5-(2-((t-butoxycarbonyl))amino)-1-phenylpropan-2-yl)-1,3 using the same procedure as in Example 1.6.3 , 4-oxadiazol-2-yl)-5-(pyrazin-2-yl)benzoic acid.

Example 1.6.6: (R)-3-(5-(2-(t-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazole -2-yl)-5-(pyridin-2-yl)benzoic acid

Synthesis of (R)-3-(5-(2-((t-butoxycarbonyl))amino)-1-phenylpropan-2-yl)-1,3 using the same procedure as in Example 1.6.3 , 4-oxadiazol-2-yl)-5-(pyridin-2-yl)benzoic acid.

Example 1.6.7: (R)-3-(5-(2-(t-Butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 2-yl)-4-chlorobenzoic acid

To 5-bromo-2-chlorobenzoic acid (2 g, 8.49 mmol) and (R)-(1-indolyl-2-methyl-1-oxo-3-phenylpropan-2-yl)amine Add THBT (1.301 g, 8.49 mmol), EDC (1.954 g, 10.19 mmol) and DIPEA (4.45) to a solution of tributyl carboxylic acid (2.74 g, 9.34 mmol) in CH ₂ Cl ₂ (vol.: 50 ml). Ml, 25.5 mmol) and stirred overnight. The reaction mixture was diluted with: (50 ml volume) and washed with 0.1 M HCl, saturated NaHCO ₃ and saturated NaCl CH ₂ Cl _2. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. The residue was purified on a combi-flash 0-30% EtOAc / 70% hexane to afford 2.5 g of (R)-(1-(2-(5-bromo-2- chlorobenzyl) decyl) -Methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester ( 6.7.1 ).

To (R)-(1-(2-(5-bromo-2-chlorobenzylidenyl)indolyl)-2-methyl-1-oxo-3-phenylpropan-2-yl)amine Bordeaux reagent (3.44 g, 14.44 mmol) was added to a solution of tributyl carboxylic acid (2.95 g, 5.78 mmol) in DCE (vol.: 75 ml) and refluxed for 4 h. The reaction was cooled to rt, diluted with CH ₂ Cl ₂ (50 mL) and washed with saturated NaHCO ₃ and saturated NaCl. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. The residue was purified on a combi-flash 0-30% EtOAc / 70% hexane to afford 2. <RTIgt; Tert-butyl 2-oxazol-2-yl)-1-phenylpropan-2-yl)carbamate ( 6.7.2 ).

Purification of (R)-(2-(5-(5-bromo-2-chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2- in a vial with carbon monoxide a solution of tert-butyl carbamic acid (492.793 mg, 1.000 mmol) in Et ₃ N (volume: 8 mL) and MeOH (1.214 mL, 30.0 mmol) (with both solvents degassed) and Palladium(II) acetate (22.45 mg, 0.100 mmol) (Aldrich batch # 83697 MJV) and XANTPHOS (116 mg, 0.200 mmol) (Aldrich batch # MKBF8281V) were added and refluxed for 2 hours and 15 minutes. TLC showed approximately 95% conversion. The reaction was filtered through a pad of tampon and concentrated. The residue was purified on a combi-flash 0-40% EtOAc / 60% hexane to afford 370 mg of (R)-3-(5-(2-((t-butoxycarbonyl)amino)-1-phenyl Methyl propan-2-yl)-1,3,4-oxadiazol-2-yl)-4-chlorobenzoate ( 6.7.3 ).

To (R)-3-(5-(2-((t-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) To a solution of methyl -4-chlorobenzoate (370 mg, 0.784 mmol) in EtOAc (EtOAc:EtOAc) TLC showed approximately 60% conversion. Stirring was continued for another 2 hours. 1 N HCl was added dropwise to bring it to pH ~4. The mixture was diluted with EtOAc and washed with brine, dried and concentrated to give &lt -1,3,4-oxadiazol-2-yl)-4-chlorobenzoic acid.

Example 1.6.8

The ester (216 mg) was treated with hydrazine (0.3 mL, excess) in ethanol under microwave conditions (140 ° C, 28 min) to afford product (170 mg) in toluene under microwave conditions (170 ° C, 15 min) Treatment with triethyl orthoformate (2 mL) gave crude (90 mg).

The hydrazine-containing product (170 mg) in DCM (10 mL) was cooled with EtOAc (EtOAc:EtOAc) The solvent is removed in vacuo to give the crude product was diluted with EtOAc, washed with saturated aqueous NH ₄ Cl, saturated aqueous NaHCO _3, washed with brine, dried (Na ₂ SO _4), filtered and evaporated in vacuo. Flash chromatography on silica gel gave the pure product (100 mg).

Example 1.6.9

Iodide (150 mg, 0.2147 mmol) was treated with Cu ₂ O (8.25 mg, 0.0577 mmol) and CsCO ₃ (125.3 mg, 0.385 mmol) in DMF (4 mL) under microwave conditions (140 ° C, 70 min) Pyrazole (13.2 mg, 0.1923 mmol) gave the product (30 mg). ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.298 (m, 1 H), 8.19 (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) , 2.46 (m, 3 H), 2.130 (m, 2 H), 1.794 (m, 2 H), 1.668 (s, 3 H).

Example 1.6.10

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

Example 1.6.11

A solution of the starting material (0.4 g, 1.4 mmol, 1 eq.) in MeOH was purified with EtOAc. Rh (5% / alumina, 0.4 g, 100% by weight) was added. The mixture was hydrogenated via a Parr shaker at 55 psi and 50 °C for 60 hours. After cooling to room temperature, the mixture was filtered through celite. The volatiles were removed via rotary evaporation to afford 0.3502 g (88%).

Example 1.6.12: Synthesis ((R)-2-(5-(3-(1-methyl-1H-imidazol-2-yl)-5-((R)-2-(4-methylthiazole)- 2-butyl)pyrrolidine-1-carbonyl)phenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl)carbamic acid tert-butyl ester

HOBT (261 mg, 1.93 mmol), EDCI (433 mg, 2.26 mmol) was added to the acid (400 mg, 1.61 mmol) of DCM (10 ml) and stirred at room temperature for 2 hr. To the resulting solution was then added hydrazine (612 mg, 2.09 mmol). The reaction mixture was stirred at room temperature for 16 hours, then worked up and purified by column column to afford &lt

Borges reagent (861 mg, 3.6 mmol) (commercial source: Alfa-Aesar) was added to hydrazine (630 mg, 1.2 mmol) of 1,2-DCE and the reaction mixture was heated at 60 °C for 5 hours. The reaction mixture was then cooled, diluted with EtOAc EtOAc EtOAc. Column chromatography of the crude residue gave the product in 75% yield.

The resulting ester was converted to the acid using an aqueous sodium hydroxide solution in a manner similar to that described in Example 1.4.6.

HOBT (51 mg, 0.42 mmol), EDCI (94 mg, 0.49 mmol) was added to EtOAc (EtOAc) The amine, (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole (59 mg, 0.35 mmol) and DIPEA (0.1 ml) were then added to the reaction mixture and stirred overnight and then worked up Column column purification was carried out to obtain a Boc compound in 30% yield.

Example 1.6.13

2-cyclopropyl-6-(methoxycarbonyl)isonicotinic acid: 6-cyclopropylpyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (236 mg, 0.85 mmol) In a container with TFA (4.9 ml) added. The mixture was stirred at room temperature for 1 hour and the volatile material was evaporated to give crude 2- <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;

Methyl 6-cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate: Stirring 2-cyclopropyl-6-(methoxycarbonyl)isonicotinic acid (188 mg, 0.85 mmol), 4-methyl-2-[(2R)-pyrrolidin-2- at room temperature yl] -1,3-thiazole (172 mg, 1.02 mmol) and added to CH ₂ Cl ₂ (5 ml) in a solution of _{Et 3 N (0.118 ml, 0.85} mmol) EDCI-HCl (196 mg, 1.02 mmol) HOBt (138 mg, 1.02 mmol) was added and the mixture was stirred overnight at the same temperature. The mixture was quenched with H ₂ O and the organic layer was separated. Aqueous HCl and the organic layer was CHCl _{3 (3} times) and the aqueous layer was extracted with saturated aqueous NaHCO ₃ (2 times), 1 N merger washed with brine, dried over MgSO ₄ and evaporated to give the crude material by column chromatography ( Purification of EtOAc in hexanes = 0 to 66% afforded 6-cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazole-2 as a yellow oil. Methyl-pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (245 mg, 78% yield). MS (ESI) m / z: 372 [M+H] ⁺ .

6-Cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine: Stirring 6-cyclopropyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine at room temperature NH ₂ NH ₂ -H ₂ O (0.32 ml, 6.60 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; Chedi continue the reaction and diluted with H ₂ O / EtOAc. The organic phase was separated and aqueous was extracted with EtOAc (3times). And the organic layer was washed with H ₂ O (3 times) The combined washed with brine, dried over MgSO ₄ and evaporated to give a colorless oil of the crude 6-cyclopropyl -4 - {[(2 R) -2- (4 -Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine, which was used in the next reaction without further purification.

[(2 R )-1-{2-[(6-Cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: at room temperature To a stirred 6-cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2- Formazan (245 mg, 0.66 mmol) and N- (t-butoxycarbonyl)-α-methyl-D-phenylalanine (221 mg, 0.79 mmol) in CH ₂ Cl ₂ (5 mL) EDCI-HCl (152 mg, 0.79 mmol) and HOBt (107 mg, 0.79 mmol) were added and the mixture was stirred overnight at the same temperature. The mixture was quenched with H ₂ O and the organic layer was separated. With aqueous 1 M HCl and the organic layer was CHCl _{3 (3} times) and the aqueous layer was extracted with saturated aqueous NaHCO ₃ (2 times), the combined was washed with brine, dried over MgSO ₄ and evaporated to give crude [(2 R) -1- {2-[(6-Cyclopropyl-4-{[(2 R )-2-(4-mefhyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2- Benzyl)carbonyl]mercapto}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester, which was used in the next reaction without further purification. MS (ESI) m / z: 633[M+H] ⁺ .

Example 1.6.14

2-(2-Cyanophenyl)-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1): in a manner analogous to Example 1.6.13 , from 6-(2-cyano Phenyl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (95 mg, 0.281 mmol). MS (ESI) m / z: 283 [M+H] ⁺ .

6-(2-Cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2 Methyl formate: in a manner similar to the case of Example 1.6.13 , from 2-(2-cyanophenyl)-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) (111 mg , 0.281 mmol) of the desired compound. (121 mg,> 99% yield) MS (ESI) m / z : 433 [M + H] +.

6-(2-Cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2 - formazan: in a manner similar to the case of Example 1.6.13 , from 6-(2-cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazole- The desired compound was synthesized from methyl 2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (121 mg, 0.281 mmol). MS (ESI) m / z: 437 [M+H] ⁺ .

[(2 R )-1-(2-{[6-(2-Cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl) Pyrrolidin-1-yl]carbonyl}pyridin-2-yl]carbonyl}mercapto)-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester : in a manner similar to the case of Example 1.6.13 , from 6-(2-cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl) The desired compound was synthesized from pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine (121 mg, 0.281 mmol). MS (ESI) m / z: 694[M+H] ⁺ .

Example 1.6.15

2-(methoxycarbonyl)-6-(1,3-oxazol-2-yl)isonicotinic acid trifluoroacetate (1:1): in a manner similar to Example 1.6.13 , from 6-( The desired compound was synthesized from 1,3-oxazol-2-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (92 mg, 0.302 mmol). MS (ESI) m / z: 283 [M+H] ⁺ .

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

4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl) Pyridine-2-carboxamidine. In a manner similar to the case of Example 1.6.13, from 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( The desired compound was synthesized from methyl 1,3-oxazol-2-yl)pyridine-2-carboxylate (114 mg, 0.286 mmol). MS (ESI) m / z: 437 [M+H] ⁺ .

[(2 R )-2-methyl-1-(2-{[4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1- Carbonyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl]aminocarboxylic acid Third butyl ester: in a similar manner to Example 1.6.13, from 4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] The desired compound was synthesized from carbonyl}-6-(1,3-oxazol-2-yl)pyridine-2-carboxamidine (110 mg, 0.251 mmol). MS (ESI) m / z: 660[M+H] ⁺ .

Example 1.6.16

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

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

N- [6-(indolylcarbonyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2 -yl] -N -methylmethanesulfonamide: in a manner similar to the case of Example 1.6.13, from 6-[methyl(methylsulfonyl)amino]-4-{[(2 R )-2- Methyl (4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (171 mg, 0.390 mmol). (156 mg, 91% yield) MS (ESI) m / z : 439 [M + H] +.

[( 2R )-2-methyl-1-{2-[(6-[methyl(methylsulfonyl)amino]-4-{[(2 R )-2-(4-methyl-) 1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-1-oxo-3-phenylpropan-2-yl]aminocarboxylic acid Third butyl ester: in a manner similar to the case of Example 1.6.13, from N- [6-(fluorenylcarbonyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazole- The desired compound was synthesized from 2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl] -N -methylmethanesulfonamide (156 mg, 0.356 mmol). MS (ESI) m / z: 671 [M+H] ⁺ .

Example 1.6.17

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

Methyl 6-methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate: in a manner analogous to the example 1.6.13, from 2-methoxy-6- (methoxycarbonyl) isonicotinic acid trifluoroacetic acid salt (1: 1) (370 mg , 1.14 mmol) to synthesize the desired compound. (170 mg, 41% yield) MS (ESI) m / z : 362 [M + H] +.

6-Methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine: In a manner analogous to Example 1.6.13 , from 6-methoxy-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] The desired compound was synthesized from methyl carbonyl}pyridine-2-carboxylate (170 mg, 0.470 mmol). MS (ESI) m/z: 372[M+H] ⁺ .

[(2 R )-1-{2-[(6-methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]carbonyl}pyridin-2-yl)carbonyl]indolyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar to the example The manner of 1.6.13 , from 6-methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine 2-Procarbazine (170 mg, 0.470 mmol) was synthesized as the desired compound.

Example 1.6.18

2-(methoxycarbonyl)-6-[methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1:1): 6-[methyl(methylsulfonyl)amine Pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (234 mg, 0.679 mmol) was placed in a container to which was added TFA (4 ml). The mixture was stirred at room temperature for 1 hour and the volatiles were evaporated to give crude 2-(methoxycarbonyl)-6-[methyl(methylsulfonyl)amino]isonicotinic acid trifluoroacetate (1:1 ), which was used in the next reaction without further purification. MS (ESI) m / z: 289[M+H] ⁺ .

4-[(2-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl} fluorenyl)carbonyl]-6-[methyl (Methanesulfonyl)amino]pyridine-2-carboxylic acid methyl ester: 2-(methoxycarbonyl)-6-[methyl(methylsulfonyl)amino]isonicotinine to be stirred at room temperature Add [(2 R )- to a solution of the acid trifluoroacetate (1:1) (93 mg, 0.23 mmol) and i- Pr ₂ NEt (0.087 ml, 0.51 mmol) in CH ₂ Cl ₂ (5 ml) Tributyl butyl 1-nonyl-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamate (81 mg, 0.28 mmol) and HATU (105 mg, 0.28 mmol) The mixture was stirred at the same temperature overnight. The mixture was quenched with H ₂ O and the organic layer was separated. CHCl _{3 (3} times) aqueous layer was extracted and treated with aqueous KHSO ₄ (pH ₄₎ the organic layer, NaHCO ₃ solution and merger brine, dried over MgSO ₄ dried and evaporated to give crude 4 - [(2 - {( 2 R -2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropenyl}indenyl)carbonyl]-6-[methyl(methylsulfonyl)amino]pyridine Methyl-2-carboxylate was used in the next reaction without further purification.

4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl) Methyl-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylate: 4-[(2-{( 2R )-2-[(Tertidinoxycarbonyl)amino]- Methyl 2-methyl-3-phenylpropenyl}indenyl)carbonyl]-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylate (130 mg, 0.23 mmol) and Bogey The reagent (164 mg, 0.69 mmol) was placed in a vessel for microwave reaction. The container was sealed and irradiated with microwave at 120 ° C for 20 minutes. The volatiles were evaporated to give the crude material was purified by column chromatography (hexane-EtOAc = solution of 20 to 100%), to give a pale yellow oil of 4- (5 - {(2 R ) -2- [ (Third-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino group Pyridine-2-carboxylic acid methyl ester (99 mg, 79% yield, 3 steps). MS (ESI) m / z: 546[M+H] ⁺ .

Example 1.6.19

{( 2R )-2-[5-(6-[methyl(methylsulfonyl)amino]-4-{[(2 R )-2-(4-methyl-1,3-thiazole- 2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Butyl ester: in a similar manner to Example 1.6.18 , from [( 2R )-2-methyl-1-{2-[(6-[methyl(methylsulfonyl)amino]-4-{ [(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-1-yloxy The desired compound was synthesized from tributyl -3-phenylpropan-2-yl]carbamate (248 mg, 0.354 mmol). (117 mg, 48% yield) MS (ESI) m / z : 682 [M + H] +.

Example 1.6.20

4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl) -6-Sideoxy-1,6-dihydropyridine-2-carboxylic acid: in a similar manner to Example 1.7.56 , from 4-(5-{( 2R )-2-[(T-butoxycarbonyl) Amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-oxooxy-1,6-dihydropyridine-2-carboxylic acid methyl ester (406 mg, 0.893 mmol) of the desired compound.

{(2 R )-2-[5-(6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2 -trioxy-1,2-dihydropyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester : in a manner analogous to Example 1.7.56 , from 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1, The desired compound was synthesized from 3,4-oxadiazol-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (393 mg, 0.892 mmol). (268 mg, 51% yield, 2 steps) MS (ESI) m / z : 591 [M + H] +.

Example 1.6.21

6-Chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylic acid: at room temperature To a stirred 6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylic acid A solution of the ester (3.21 g, 8.77 mmol) in EtOAc. With 6 M HCl aq (4.38 ml) and the mixture was quenched volatiles were evaporated to give crude 6-chloro -4 - {[(2 R) -2- (4- methyl-1,3-thiazol-2-yl Pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylic acid, which was used in the next reaction without further purification.

[(2 R) -1- {2 - [(6- chloro -4 - {[(2 R) -2- (4- methyl-1,3-thiazol-2-yl) pyrrole-1 Benzyl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: at room temperature Stirred 6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylic acid (3.09) g, 8.77 mmol) and [(2 R )-1-fluorenyl-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (2.70 g, 9.21 added mmol) in CH ₂ Cl ₂ (50 ml) in a solution of HATU (3.50 g, 9.21 mmol) and _{i -Pr 2 NEt (1.58 ml,} 9.21 mmol) and the mixture was stirred overnight at the same temperature. The mixture was quenched with aqueous citric acid (pH 3) and the organic layer was separated. , Dried, and the organic layer was CHCl _{3 (3} times) and the aqueous layer was extracted with aqueous citric acid solution (pH 3) with saturated NaHCO ₃ brine merger over MgSO ₄ and evaporated to give the crude material by column chromatography (NH- silicon dioxide, EtOAc in hexane 20 to 100% of =, followed by a solution of ₃ = 0-20%) of MeOH purified CHCl, to give a yellow oil of [(2R) -1- {2 - [(6- Chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-2 -Methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (3.84 g, 70% yield). MS (ESI) m / z: 627[M+H] ⁺ .

{(2 R ) -2-[5-(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Benzyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester: [( 2R )-1 -{2-[(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2- Benzyl)carbonyl]mercapto}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (3.84 g, 6.12 mmol) and Burgess reagent (4.38 g, 18.4 mmol) was placed in a vessel for microwave reaction. The container was sealed and irradiated with microwave at 120 ° C for 20 minutes. Evaporation of the volatile material afforded crude material eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadi T-butyl ester of oxazol-2-yl]-1-phenylpropan-2-yl}carbamate (2.55 g, 68% yield). MS (ESI) m / z: 609 [M+H] ⁺ .

Example 1.6.22

2-methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1): 6-methoxypyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-A The ester (400 mg, 1.49 mmol) was placed in a container and TFA (4 ml) was added at room temperature. The mixture was stirred at the same temperature for 1 hour and the volatile material was evaporated to give crude 2-methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) as a white solid. After further purification, it was used in the next reaction.

4-[(2-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropenyl}indolyl)carbonyl]-6-methoxy Methyl pyridine-2-carboxylate: stirred to 2-methoxy-6-(methoxycarbonyl)isonicotinic acid trifluoroacetate (1:1) (486 mg, 1.49 mmol) at room temperature Add HATU (597 mg, 1.57 mmol) and [(2 R )-1-indenyl-2-methyl group to a solution of i- Pr ₂ NEt (0.52 ml, 3.06 mmol) in CH ₂ Cl ₂ (10 ml) -1-Phenoxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (460 mg, 1.57 mmol) and the mixture was stirred at the same temperature overnight. The mixture was quenched with H ₂ O and the organic layer was separated. (Twice) and the organic layer was CHCl _{3 (3} times) and the aqueous layer was extracted with saturated aqueous NaHCO ₃ of brine, dried over MgSO ₄ and evaporated to give crude 4 - [(2 - {( 2 R) -2 -[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl}indenyl)carbonyl]-6-methoxypyridine-2-carboxylic acid methyl ester without further purification That is for the next reaction. MS (ESI) m/z: 495[M+H] ⁺ .

4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl) Methyl-6-methoxypyridine-2-carboxylate: 4-[(2-{( 2R )-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenyl) Methyl propyl] fluorenyl)carbonyl]-6-methoxypyridine-2-carboxylate (727 mg, 1.49 mmol) and Bourges reagent (1.07 g, 4.48 mmol) were placed in a container for microwave reaction. . The container was sealed and irradiated with microwave at 120 ° C for 20 minutes. The volatiles were evaporated to give crude material, simply by column chromatography (hexane solution of EtOAc _{= 33%, 2 10 g SiO} ) to give a pale yellow oil containing some by-product and the 4- (5 -{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-A Methyl oxypyridine-2-carboxylate. MS (ESI) m / z: 469[M+H] ⁺ .

Example 1.6.23

4-(5-{(2 R )-2-[(tatabutoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole trifluoromethanesulfonate -2-yl)-6-{[(2 R )-2-(4-methyl-1,3-thiazol -2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl ester: Stirring {( 2R )-2-[5-(6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidinium) at 0 °C 1-yl]carbonyl}-2-oxooxy-1,2-dihydropyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl} Add Tf ₂ O (0.091 ml, 0.54 mmol) to a solution of tributyl carbamic acid (268 mg, 0.454 mmol) and i- Pr ₂ NEt (0.116 ml, 0.68 mmol) in CH ₂ Cl ₂ (5 ml) ). Complete consumption of the starting molecule and with a period of 1 hour and quenched with saturated aqueous NaHCO _3. The organic layer was separated and the aqueous layer was washed with CHCl ₃ (2 times) and extracted. With H ₂ O and the combined organic layers were washed with brine, dried over MgSO ₄ and evaporated to give crude material, (MeOH solution of CHCl ₃ = 0 to 10%) was purified by column chromatography to give a colorless oil of the tri 4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole-fluoromethanesulfonate- 2-yl)-6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl ester (208 mg , 63% yield). MS (ESI) m / z: 723 [M+H] ⁺ .

Example 1.6.24

{(2R)-2-[5-(6-[Ethylmethyl(amino)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}carbamic acid tert-butyl ester: In a manner similar to Example 1.3.21 , from {(2R)-2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazole-2-) Tert-butyl pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid The desired compound was synthesized (126 mg, 79%).

Example 1.6.25

2-(methoxycarbonyl)-6-(2- o-oxypyrrolidin -1-yl)isonicotinic acid: in a manner analogous to Example 1.6.13 , from 6-(2- o-oxypyrrolidine- The desired compound (60 mg) was synthesized from 1-ethyl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester.

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl Methyl pyridine-2-carboxylate: synthesized in a manner analogous to Example 1.6.13 from 2-(methoxycarbonyl)-6-(2- o-oxypyrrolidin -1-yl)isonicotinic acid Compound (88 mg, 94% yield: 2 steps). MS (ESI) m / z: 415 [M+H] ⁺ .

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl Pyridin-2-carboxamidine: in a manner analogous to Example 1.6.13 , from 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 The desired compound (86 mg) was synthesized from methyl-carbonyl]-6-(2-o-oxypyrrolidin-1-yl)pyridine-2-carboxylate.

[(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Carbonyl}-6-(2-o-oxypyrrolidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl]carbamic acid Tributyl ester: in a similar manner to Example 1.6.13 , from 4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl The compound (6 mg, 41% yield: 2 steps) was synthesized from the title compound (yield: 2-p-oxypyrrolidin-1-yl)pyridine-2-carboxamide.

Example 1.6.26

2-(methoxycarbonyl)-6-(2- o -oxy-1,3-oxazolidine-3-yl)isonicotinic acid: in a manner analogous to Example 1.6.13 , from 6-(2- The desired compound (51 mg) was synthesized from oxy-1,3-1,3-oxazolidin-3-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester.

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2- oxo-1,3- oxole Methylzolidine -3-yl)pyridine-2-carboxylate: in a manner analogous to Example 1.6.13 , from 2-(methoxycarbonyl)-6-(2- o -oxy-1,3-oxazolidine -3-yl) isonicotinic acid synthesis of the desired compound (58 mg, 73% yield: 2 steps). MS (ESI) m / z: 417 [M+H] ⁺ .

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6- (2- oxo-1,3- oxa) Zoxadin -3-yl)pyridine-2-carboxamidine: in a similar manner to Example 1.6.13, from 4-{[(2R)-2-(4-methyl-1,3-thiazole-2- The desired compound (58 mg) was synthesized from methyl pyrrolidin-1-yl]carbonyl}-6-(2-oxo-1,3-oxazolidin-3-yl)pyridine-2-carboxylate.

[(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Carbonyl}-6-(2-o-oxy-1,3-oxazolidin-3-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2- yl] -carbamic acid tert-butyl ester: in a manner analogous to example 1.6.13 of from 4 - {[(2R) -2- (4- methyl-1,3-thiazol-2-yl) pyrrolidine - Synthesis of the desired compound from 1-yl]carbonyl}-6-(2-oxo-1,3-oxazolidin-3-yl)pyridine-2-carboxamide (28 mg, 30% yield: 2 step).

Example 1.6.27

2-(methoxycarbonyl)-6-(2-methyl-5- oxooxypyrrolidin- 1-yl)isonicotinic acid: in a manner similar to Example 1.6.13 , from 6-(2-A The desired compound (58 mg) was synthesized from the 5--5-oxypyrrolidin-1-yl)pyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester.

6-(2-Methyl-5-oxooxypyrrolidin-1-yl)-4-{[(2R)-2-(4-methyl- 1,3-thiazol-2-yl)pyrrolidine- Methyl 1-yl]carbonyl}pyridine-2-carboxylate: in a manner analogous to Example 1.6.13 , from 2-(methoxycarbonyl)-6-(2-methyl-5- oxoxypyrrolidin -1 -Based on the synthesis of the desired compound of isonicotinic acid (70 mg, 78% yield: 2 steps). MS (ESI) m / z: 429 [M+H] ⁺ .

6-(2-Methyl-5-oxooxypyrrolidin-1-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-yl]carbonyl}pyridine-2-carboxamidine: in a manner analogous to Example 1.6.13 , from 6-(2-methyl-5- oxoxypyrrolidin -1-yl)-4-{[ (2R)-Methyl 2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate The desired compound (70 mg) was obtained.

[(2R)-2-methyl-1-(2-{[6-(2-methyl-5-oxoxypyrrolidin-1-yl)-4-{[(2R)-2-(4) -methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl Tert- butyl carbazate : in a manner similar to the case of Example 1.6.13 , from 6-(2-methyl-5- o-oxypyrrolidin -1-yl)-4-{[(2R)-2 -(4-Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamide to synthesize the desired compound (112 mg, 99% yield: 2 steps) .

Example 1.6.28

2-(methoxycarbonyl)-6-(2-oxopiperidin-1-yl)isonicotinic acid: in a manner analogous to Example 1.6.13 , from 6-(2- o-oxypiperidine- The desired compound (211 mg) was synthesized from 1-ethyl)pyridine-2,4-dicarboxylic acid 4-t-butyl ester 2-methyl ester.

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-oxopiperidin-1-yl Methyl pyridine-2-carboxylate: required to synthesize 2-(methoxycarbonyl)-6-(2-oxopiperidin-1-yl)isonicotinic acid in a similar manner to Example 1.6.13 Compound (124 mg, 38% yield: 2 steps). MS (ESI) m / z: 429 [M+H] ⁺ .

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-oxopiperidin-1-yl Pyridin-2-carboxamidine: in a manner analogous to Example 1.6.13 , from 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 The desired compound (120 mg) was synthesized from methyl-carbonyl]-6-(2-oxopiperidin-1-yl)pyridine-2-carboxylate.

[(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Carbonyl}-6-(2-o-oxypiperidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl]carbamic acid Tributyl ester: in a similar manner to Example 1.6.13 , from 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl} -6-(2-Sideoxypiperidin-1-yl)pyridine-2-carboxamide The desired compound was synthesized (193 mg, 98% yield: 2 steps).

Example 1.6.29

2-(methoxycarbonyl)-6-(2-o-oxypyrrolidin-1-yl)isonicotinic acid: 6-(2-Sideoxypyrrolidin-1-yl)pyridine-2,4- 4-Terbutyl ester 2-methyl dicarboxylate (228 mg, 0.71 mmol) was placed in a container with TFA (3.3 mL, 43 mmol). The mixture was stirred at room temperature for 1 hour and azeotrope with toluene to give crude 2-(methoxycarbonyl)-6-(2-o-oxypyrrolidin-1-yl)isonicotinic acid (174 mg, 93%) ), which was used in the next reaction without further purification.

4-[(2-{(2R)-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl} fluorenyl)carbonyl]-6-(2-side Oxypyrrolidin-1-yl)pyridine-2-carboxylic acid: 2-(methoxycarbonyl)-6-(2-oxo-pyrrolidin-1-yl)isonicotinic acid (174 mg) at room temperature , 0.66 mmol) and [(2R)-1-indenyl-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (232 mg, 0.79 mmol) EDCI ‧ HCl (164 mg, 0.86 mmol) and HOBt (89 mg, 0.66 mmol) were added to a solution in DMF (3 ml) and the mixture was stirred overnight at the same temperature. A 1 M aqueous NaOH solution and CHCl _{3 were} added to the mixture, followed by separation of the organic layer. The aqueous layer was acidified with 1 M aqueous HCl and brine was added and then extracted with EtOH/CHCl ₃ (1:5 v/v) (3 times). The organic layer was dried of MgSO ₄ and evaporated to afford crude as a colorless oil of 4 - [(2 - {(2R ) -2 - [( tertiary-butoxycarbonyl) amino] -2-methyl-3 -Phenylpropanyl}indenyl)carbonyl]-6-(2-oxopyryrrolidin-1-yl)pyridine-2-carboxylic acid (416 mg, >100% yield), without further purification Used in the next reaction.

[(2R)-2-methyl-1-{2-[2-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) }-6-(2-Sideoxypyrrolidin-1-yl)isonicotininyl]mercapto}-1-oxooxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester : to 4-[(2-{(2R)-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl} fluorenyl)carbonyl]-6-(2) -Sideoxypyrrolidin-1-yl)pyridine-2-carboxylic acid (416 mg, 0.79 mmol) and 4-methyl-2-[(2R)-pyrrolidin-2-yl]-1,3-thiazole ( 266 mg, 1.6 mmol) EDCI HCl (303 mg, 1.6 mmol) and HOBt (107 mg, 0.79 mmol) were added to a solution in DMF (4 ml). After stirring at room temperature for 14 hours, the reaction mixture was taken with EtOAc / water. And the volatiles removed under reduced pressure the organic layer was dried over MgSO _4. Via column chromatography _{(EtOH / CHCl 3 = 0:} 100 to 5:95) of the obtained residue was purified, to give 320 mg (60%) reddish oil of [(2R) -2- methyl - 1-{2-[2-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-sideoxy Pyrrolidin-1-yl)isonicotininyl]mercapto}-1-oxooxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester.

[(2R)-2-{5-[2-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 2-sided oxypyrrolidin-1-yl)pyridin-4-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl Ester: To a stirred [(2R)-2-methyl-1-{2-[2-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine -1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl)isonicotininyl]mercapto}-1-oxo-3-phenylpropan-2-yl]amine CBr ₄ (314 mg, 0.95 mmol), PPh ₃ (248 mg, 0.95 mmol) and imidazole (64) were added to a solution of tributyl carboxylic acid (320 mg, 0.47 mmol) in CH ₂ Cl ₂ (6 ml). Mg, 0.95 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated and treated with column chromatography _{(EtOH / CHCl 3 = 0:} 100 to 5:95) of the obtained residue was purified, to give a colorless oil of [(2R) -2- {5- [ 2- { [(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl)pyridine- 4-Butyl-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester.

Example 1.6.30

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 1H-1,2,4-triazol-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]aminocarboxylic acid Third butyl ester: {(2R)-2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-butyl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester (120 mg, 0.20 A suspension of 1 H-1,2,4-triazole (68 mg, 0.99 mmol) and Cs ₂ CO ₃ (96 mg, 0.30 mmol) in NMP (2.4 ml) was placed in a container for microwave reaction in. The vessel was sealed and irradiated with microwaves at 150 ° C for 10 minutes. After cooling, H ₂ O was added, then the mixture was extracted with EtOAc. The organic layer was dried with MgSO ₄ The mixture was evaporated and treated with column chromatography _{(EtOH / CHCl 3 = 0:} 100 to 5:95) of the obtained residue was purified, to give a pale yellow solid of [(2R) -2- {5- [ 4- { [(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1H-1,2,4-triazol-1-yl Pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester (32 mg, 25% yield).

Example 1.6.31

[(2R)-2-{5-[6-(1H-imidazol-1-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Tert-butyl-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar In the manner of Example 1.6.30 , from {(2R)-2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)) Synthesis of tert-butyl ester of pyrrolidin-1-yl]carbonyl}pyridin-2-yl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid The desired compound (62 mg, 59% yield).

Example 1.6.32

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 1H-pyrazol-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: Similar to the manner of Example 1.6.30 , from {(2R)-2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl) Synthesis of tert-butyl ester of pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid The desired compound was obtained as a pale yellow oil (144 mg, yield: 91%).

Example 1.6.33

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 2H-1,2,3-triazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]aminocarboxylic acid Third butyl ester: in a similar manner to Example 1.6.30 , from {(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}amino The desired compound (116 mg, 28% yield) (more polar) was obtained as a colorless oil. MS (ESI) m/z: 642[M+H] ⁺

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 1H-1,2,3-triazol-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]aminocarboxylic acid Third butyl ester: in a similar manner to Example 1.6.30 , from {(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}amino The desired compound (86 mg, 20% yield) (less polar) was obtained as a colorless solid. MS (ESI) m / z: 642 [M+H] ⁺ .

Example 1.6.34

[(2R)-2-{5-[6-(1-methyl-1H-pyrazol-4-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazole) -2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid Tributyl ester: {(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}carbamic acid tert-butyl ester (300 mg, 0.49 mmol ), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)-1H-pyrazole (307 mg, 1.6 mmol), Pd ₂ (dba) ₃ (113 mg, 0.25 mmol), SPhos (101 mg, 0.25 mmol) and K ₃ PO ₄ (314 mg, 1.5 A suspension of mmol) in toluene (3.0 ml) was placed in a vessel for microwave reaction. The vessel was sealed and irradiated with microwaves at 130 ° C for 30 minutes. After cooling, H ₂ O and brine were added, followed by extraction of the mixture with CHCl ₃ . The organic layer was dried with MgSO ₄ The residue obtained was purified by column chromatography (EtOAc-EtOAc-EtOAcEtOAcEtOAc 6-(1-Methyl-1H-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]carbamic acid tert-butyl ester (212 mg, 66% yield ). MS (ESI) m/z: 655 [M+H] ⁺

Example 1.6.35

[(2R)-2-{5-[6-(1-methyl-1H-pyrazol-3-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazole) -2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid Tributyl ester: in a similar manner to Example 1.6.34 , from {(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}aminocarboxylic acid The desired compound (320 mg, 99% yield) was obtained as a yellow oil. MS (ESI) m / z: 655 [M+H] ⁺ .

Example 1.6.36

[(2R)-2-{5-[6-(1-methyl-1H-pyrazol-5-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazole) -2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid Tributyl ester: in a similar manner to Example 1.6.34 , from {(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}aminocarboxylic acid The desired compound (356 mg, 100% yield) was obtained as a yellow oil. MS (ESI) m / z: 655 [M+H] ⁺ .

Example 1.6.37

[(2R)-2-{5-[4-{[(4-Bromo-1,3-thiazol-2-yl)methyl](methyl)aminemethanyl}-6-(1,3- T-butyl ester of oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamate: at room temperature Down-mixed 2-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole- 2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid (160 mg, 0.33 mmol), i- Pr ₂ NEt (0.061 ml, 0.36 mmol) and 1-(4-bromo) Add - HATU (136 mg, 0.36 mmol) in a solution of -1,3-thiazol-2-yl)-N-methylmethylamine (74 mg, 0.36 mmol) in CH ₂ Cl ₂ (4.8 ml) The mixture was stirred at the temperature for 2 hours. The mixture was quenched with H ₂ O and extracted with CHCl _3. , The organic layer was washed with brine, dried over MgSO ₄ and evaporated to give the crude material by column chromatography: purification (EtOAc / hexane = 10 90 to 80:20), to give a colorless oil of [(2R) - 2-{5-[4-{[(4-bromo-1,3-thiazol-2-yl)methyl](methyl)aminemethanyl}-6-(1,3-oxazole-2- Tert-butyl pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamate (204 mg, 92% yield) . MS (ESI) m / z: 680, 682 [M+H] ⁺ .

Example 1.6.38

[(2R)-2-{5-[4-{methyl[(6-methylpyridin-3-yl)methyl]aminemethanyl}-6-(1,3-oxazol-2-yl) Pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert- butyl ester: in a manner similar to Example 1.6.37 From 2-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl - 6-(1,3-oxazol-2-yl)isonicotinic acid The desired compound (86 mg, 69% yield). MS (ESI) m / z: 610 [M+H] ⁺ .

Example 1.6.39

[(2R)-2-{5-[4-{[1-(1-methyl-1H-pyrazol-3-yl)ethyl]aminemethanyl}-6-(1,3-oxazole) Benzyl-2-pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar to Example 1.6 .37 , by 2-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole Synthesis of 2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid and 1-(1-methyl-1H-pyrazol-3-yl)ethylamine as a white powder The desired compound (80 mg, 82% yield). MS (ESI) m/z: 599[M+H] ⁺

Example 1.6.40

[(2R)-2-{5-[4-{methyl[(6-methylpyridin-2-yl)methyl]aminemethanyl}-6-(1,3-oxazol-2-yl) Pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert- butyl ester: in a manner similar to Example 1.6.37 From 2-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl - 6-(1,3-oxazol-2-yl)isonicotinic acid The desired compound (90 mg, 73% yield). MS (ESI) m / z: 610 [M+H] ⁺ .

Example 1.6.41

[(2R)-2-(5-{4-[methyl(3-methylbenzyl)aminecarbamido]-6-(1,3-oxazol-2-yl)pyridin-2-yl }-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl]carbamic acid tert- butyl ester: in a manner similar to the case of Example 1.6.37 , 2-(5) -{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-(1 , 3-oxazol-2-yl)isonicotinic acid The desired compound (90 mg, 91% yield). MS (ESI) m / z: 609 [M+H] ⁺ .

Example 1.6.42

[(2R)-2-{5-[4-{methyl[(1-methyl-1H-pyrazol-4-yl)methyl]aminemethanyl}-6-(1,3-oxazole) Benzyl-2-pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar to Example 1.6 .37 , by 2-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole -2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid The desired compound (114 mg, 94% yield).

Example 1.6.43

[(2R)-2-{5-[4-{[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl](methyl)aminemethanyl}-6-(1 , 3-oxazole-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: In a manner analogous to Example 1.6.37 , from 2-(5-{(2R)-2-[( t -butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3, 4-oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid The desired compound (110 mg, 88% yield).

Example 1.6.44

[(2R)-2-{5-[4-{[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl](methyl)aminemethanyl}-6-(1 , 3-oxazole-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: In a manner analogous to Example 1.6.37 , from 2-(5-{(2R)-2-[( t -butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3, 4-oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid The desired compound was obtained as a yellow oil (118 mg, 95% yield). MS (ESI) m / z: 655 [M+H] ⁺ .

Example 1.6.45

Methyl 6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate: analogous to Example 1.6.13 The desired compound was synthesized from 6-(methoxycarbonyl)pyridine-2-carboxylic acid (237 mg, 1.31 mmol). (325 mg, 83% yield) MS (ESI) M / Z : 332 [M + H] +.

6-{[(2R)-2-(4-Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine: similar to Example 1.6.13 By the way, methyl 6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (322 mg, 0.973 mmol) of the desired compound was synthesized. (322 mg, 100% yield) MS (ESI) M / Z : 332 [M + H] +.

[(2R)-2-methyl-1-{2-[(6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Carbonyl}pyridin-2-yl)carbonyl]indenyl}-1-oxooxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: to N-( t -butoxycarbonyl)-α Add - HATU (272 mg, 0.716 mmol) and diisopropylethylamine (0.13 mL, 0.72 mmol) to a solution of methyl-D-phenylalanine (183 mg, 0.656 mmol) in dichloromethane (5 mL) . After distillation at room temperature for 30 minutes, 6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carbon was added.醯肼 (198 mg, 0.597 mmol). After stirring at room temperature for 6 hours, the reaction mixture was diluted with ethyl acetate and washed successively with 0.2 M HCl- brine (1:1), saturated aqueous NaHCO ₃ - brine-H ₂ O (1:1:1), brine . The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give [[2,],,,,,,,,,,,,,, -methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-1-oxo-3-phenylpropan-2-yl Tert-butyl carbamic acid. (324 mg, 92% yield) MS (ESI) M / Z : 593 [M + H] +.

Example 1.6.46

Methyl 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate: analogous to Example 1.6.13 In the manner of methyl 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate [public] 200 mg, 1.19 mmol) of the desired compound. (362 mg, 92% yield) MS (ESI) M / Z : 332 [M + H] +.

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamidine: similar to Example 1.6.13 Methyl 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (359 mg, 1.08 mmol) of the desired compound. (244 mg, 68% yield) MS (ESI) M / Z : 332 [M + H] +.

[(2R)-2-methyl-1-{2-[(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Hydryl}pyridin-2-yl)carbonyl] indenyl }-1-oxo-3-phenylpropan-2-yl]carbamic acid tert- butyl ester: in a manner similar to the case of Example 1.6.45 , by 4 -{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxamide (220 mg, 0.664 mmol) Requires a compound. (378 mg, 96% yield) MS (ESI) M / Z : 593 [M + H] +.

Example 1.6.47

2-(methoxycarbonyl)-6-(pyrrolidin-1-yl)isonicotinic acid: 6-(pyrrolidin-1-yl)pyridine-2,4- in a similar manner to Example 1.6.13 The desired compound was synthesized from 4-tert-butyl ester dicarboxylate (63 mg, 0.21 mmol). (51 mg, 100% yield) MS (APCI/ESI) M/Z: 251 [M+H] ⁺ .

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6- (pyrrolidin-1-yl)pyridine-2- carboxylate: in a manner analogous to example 1.6.13, the 2- (methoxycarbonyl) -6- (pyrrolidin-1-yl) isonicotinic acid (51 mg, 0.206 mmol) synthesized desired compound. (62 mg, 75% yield) MS (APCI/ESI) M/Z: 401 [M+H] ⁺ .

4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(pyrrolidin-1-yl)pyridine-2- Formazan : in a manner similar to Example 1.6.13 , from 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl} Methyl-6-(pyrrolidin-1-yl)pyridine-2-carboxylate (62 mg, 0.155 mmol) gave the desired compound. (62 mg, 100% yield) MS (APCI/ESI) M/Z: 401 [M+H] ⁺ .

[(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Carbonyl}-6-(pyrrolidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: Analogously to the manner of Example 1.6.45 , 4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(pyrrole) The desired compound is synthesized from pyridine-1-yl)pyridine-2-carboxamidine. (99 mg, 100% yield) MS (APCI/ESI) M/Z: 662[M+H] ⁺ .

Example 1.6.48

6-(methoxycarbonyl)-1-methyl-2- oxooxy -1,2-dihydropyridine-4-carboxylic acid: in a manner analogous to Example 1.6.13 , from 1-methyl-6-side The desired compound was synthesized from oxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (146 mg, 0.546 mmol). (115 mg, 100% yield)

1-Methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-sideoxy-1,6 Methyl dihydropyridine-2-carboxylate: in a manner analogous to Example 1.6.13 , from 6-(methoxycarbonyl)-1-methyl-2- oxooxy -1,2-dihydropyridine-4 - Formic acid (115 mg, 0.546 mmol) was synthesized in the desired compound. (166 mg, 84% yield) MS (ESI) M / Z : 362 [M + H] +.

1-Methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-sideoxy-1,6 -dihydropyridine-2-carboxamidine: in a manner similar to the case of Example 1.6.13 , from 1-methyl-4-{[(2R)-2-(4-methyl-1,3-thiazole-2 Methyl-pyrrolidin-1-yl]carbonyl}-6-oxooxy-1,6-dihydropyridine-2-carboxylate (148 mg, 0.409 mmol). (148 mg, 100% yield) MS (ESI) M / Z : 362 [M + H] +.

[(2R)-2-methyl-1-{2-[(1-methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine -1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)carbonyl]indenyl}-1-oxo-3-phenylpropan-2-yl]amino Tert- butyl formate: in a manner similar to the case of Example 1.6.45 , from 1-methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine The desired compound was synthesized from -1-yl]carbonyl}-6-oxo-1,6-dihydropyridine-2-carboxamidine (164 mg, 0.464 mmol). (237 mg, 84% yield) MS (ESI) M / Z : 623 [M + H] +.

Example 1.6.49

2-(Difluoromethoxy)-6-(methoxycarbonyl)isonicotinic acid: 6-(difluoromethoxy)pyridine-2,4-dicarboxylic acid in a similar manner to Example 1.6.13 4-Terbutyl ester 2-methyl ester (313 mg, 1.03 mmol) was synthesized in the desired compound. (255 mg, 100% yield) MS (ESI) M / Z : 248 [M + H] +.

6-(Difluoromethoxy)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylic acid ester: in a manner analogous to the example 1.6.13, from 2- (difluoromethoxy) -6- (methoxycarbonyl) isonicotinic acid (255 mg, 1.03 mmol) to synthesize the desired compound. (385 mg, 94% yield) MS (ESI) M / Z : 398 [M + H] +.

6-(Difluoromethoxy)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2-yl 醯 肼: in a manner similar to the case of Example 1.6.13 , from 6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl) The desired compound was synthesized from pyrrolidin-1-yl]carbonyl}pyridine-2-carboxylate (385 mg, 0.969 mmol). (385 mg, 100% yield) MS (ESI) M / Z : 398 [M + H] +.

[(2R)-1-(2-{[6-(Difluoromethoxy)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine -1-yl]carbonyl}pyridin-2-yl]carbonyl}mercapto)-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar in the manner of Examples 1.6.45, from 6- (difluoromethoxy) -4 - {[(2R) -2- (4- methyl-1,3-thiazol-2-yl) pyrrolidine -1 -yl]carbonyl}pyridine-2-carboxamidine (383 mg, 0.964 mmol). (634 mg, 100% yield) MS (ESI) M / Z : 659 [M + H] +.

Example 1.6.50

4-(Tertidinoxycarbonyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-2-carboxylic acid: 1 - methyl-6-o-oxy-1,6-di A solution of 1 M aqueous NaOH (1.1 mL, 1.1 mmol) was added to a solution of &lt;RTI ID=0.0&gt;0&gt; After stirring for 1 hour, 1 M HCl was added and pH 5 was reached. The precipitate formed was filtered off, washed with water and dried in vacuo to give 4-(t-butoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyridine as a colorless solid. 2-formic acid. (149 mg, 73% yield) MS (ESI) M / Z : 254 [M + H] +.

1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2- oxo-1,2 -dihydropyridine-4-carboxylate: to 4-(t-butoxycarbonyl)-1-methyl-6-oxooxy-1,6-dihydropyridine-2-carboxylic acid (143 mg, 0.565 mmol HOBt (76 mg, 0.565 mmol) and EDCI.HCl (141 mg, 0.734 mmol) were added to a solution in dichloromethane (5 mL). After stirring for 30 minutes, 4-methyl-2-[(2R)-pyrrolidin-2-yl]-1,3-thiazole (105 mg, 0.621 mmol) was added. After stirring for 5 hours, the reaction mixture was concentrated in vacuo and treated with silica gel column chromatography _{(CHCl 3 / MeOH = 99:} 1 to 95: 5) to give the residue, to give a colorless oil of methyl-6 {[(2R)-2-(4-Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2-yloxy-1,2-dihydropyridine-4- Tert-butyl formate. (228 mg, 100% yield) MS (ESI) M / Z : 404 [M + H] +.

1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2- oxo-1,2 -dihydropyridine-4-carboxylic acid: to 1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl} To a solution of -2-oxo-1,2-dihydropyridine-4-carboxylate (228 mg, 0.565 mmol) in dichloromethane (0.5 mL) The mixture was stirred for 2 hours and concentrated in vacuo to give 1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine as colorless amorphous. 1-yl]carbonyl}-2-oxo-1,2-dihydropyridine-4-carboxylic acid (196 mg, quantitative). MS (ESI) M/Z: 348 [M+H] ⁺ .

[(2R)-2-methyl-1-{2-[(1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine -1-yl]carbonyl}-2-oxo-1,2-dihydropyridin-4-yl)carbonyl]indenyl}-1-oxo-3-phenylpropan-2-yl]amino Tert-butyl formate: to 1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2- Add HOBt (76 mg, 0.565 mmol) and EDCI.HCl (130 mg) to a solution of the pendant oxy-1,2-dihydropyridine-4-carboxylic acid (196 mmol, 0.565 mmol) in dichloromethane (5 mL) , 0.678 mmol). After stirring for 30 minutes, [(2R)-1-indolyl-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (182 mmol, 0.621 mmol) ). After stirring for 6 hours, and the mixture was washed successively with 0.2 M HCl- reaction was diluted with EtOAc and brine (1: 1), saturated aqueous NaHCO ₃ - brine _{-H 2 O (1: 1:} 1), washed with brine, to give a colorless amorphous Crude [(2R)-2-methyl-1-{2-[(1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)) Pyrrolidin-1-yl]carbonyl}-2-sidedoxy-1,2-dihydropyridin-4-yl)carbonyl]indenyl}-1-olyzino-3-phenylpropan-2-yl] Tert-butyl carbamic acid. (212 mg, 60% yield) MS (ESI) M / Z : 623 [M + H] +.

Example 1.6.51

4-(Tertidinoxycarbonyl)-6-o-oxy-1,6-dihydropyridine-2-carboxylic acid: 6-sided oxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4 To a solution of tert-butyl ester 2-methyl ester (320 mg, 1.26 mmol) in MeOH (3 mL) EtOAc. After stirring for 14 hours, 1 M aqueous HCl solution was added. The resulting precipitate was filtered, washed with water and dried then evaporated tolujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (243 mg, 80% yield) MS (ESI) M/Z: 240 [M+H] ⁺

6-[(2-{(2R)-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl} fluorenyl)carbonyl]-2-oxo- 1,2-Dihydropyridine-4-carboxylic acid tert-butyl ester: 4-(tert-butoxycarbonyl)-6-oxo-oxy-1,6-dihydropyridine-2-carboxylic acid (241 mg) HOBt (136 mg, 1.01 mmol) and EDCl.HCl (232 mg, 1.21 mmol) were added to a solution of 1.01 mmol) and stirred for 30 min. Add [(2R)-1-indenyl-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (325 mg, 1.11 mmol) and stir the reaction mixture 16 hours. The mixture was poured into H ₂ O and the organic layer was concentrated in vacuo and extracted with chloroform. Column chromatography using silica gel (CHCl ₃ /MeOH=99.5:0.5 to 95: 5) to give the residue, to give a colorless amorphous of 6 - [(2 - {( 2R) -2 - [( tertiary-butoxycarbonyl Amino]-2-methyl-3-phenylpropenyl}indenyl)carbonyl]-2-oxooxy-1,2-dihydropyridine-4-carboxylic acid tert-butyl ester. (373 mg, 73% yield) MS (ESI) M/Z: 515 [M+H] ⁺

6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- 2-tert-oxy-1,2-dihydropyridine-4-carboxylic acid tert-butyl ester: 6-[(2-{(2R)-2-[( t- butoxycarbonyl)amino) stirred] Addition of triphenylphosphine to a solution of -2-methyl-3-phenylpropenyl}indenyl)carbonyl]-2-oxooxy-1,2-dihydropyridine-4-carboxylic acid tert-butyl ester 161 mg, 0.612 mmol), imidazole (42 mg, 0.61 mmol) and carbon tetrabromide (203 mg, 0.612 mmol). After stirring at room temperature for 1.5 hours, the mixture was directly loaded and purified by column chromatography (hexane/EtOAc = 98:2 to 50:50) to give 6-(5-{(2R) as colorless amorphous. -2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-2-yloxy-1,2 - Dihydropyridine-4-carboxylic acid tert-butyl ester. (93 mg, 92% yield) APCI / ESI: 495[M+H] ⁺ .

Example 1.6.52

6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- 2-Phenoxy-1,2-dihydropyridine-4-carboxylic acid: to 6-(5-{(2R)-2-[( t- butoxycarbonyl)amino]-1-phenylpropan-2 a solution of -3,3,4-oxadiazol-2-yl)-2-oxo-l,2-dihydropyridine-4-carboxylic acid tert-butyl ester in MeOH (3 mL) H ₂ O (1 mL) and potassium hydroxide (103 mg, 1.84 mmol) were added. After stirring at 60 ° C for 3 hours, 1 M aqueous HCl (2 mL) was added to the reaction mixture at 0 °C. And the organic layer was extracted with a mixture of CHCl ₃ was concentrated in vacuo to give a colorless solid of 6- (5 - {(2R) -2 - [( tertiary-butoxycarbonyl) amino] -1-phenyl-propan-2- -yl}-1,3,4-oxadiazol-2-yl)-2-oxooxy-1,2-dihydropyridine-4-carboxylic acid. (73 mg, 99% yield) MS (ESI) M / Z : 441 [M + H] +.

{(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6- side Oxyl-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester: toward 6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- HOBt and EDCI.HCl were added to a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid in dichloromethane (3 mL). After stirring at room temperature for 30 minutes, 4-methyl-2-[(2R)-pyrrolidin-2-yl]-1,3-thiazole (30 mg, 0.18 mmol) was added. After 1 day stirring, the mixture was concentrated in vacuo and treated with silica gel column chromatography (CHCl ₃ / MeOH 99: 1 to 90:10) to give the residue, to give a colorless solid of {(2R) -2- [5- (4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-oxo-1,6-dihydropyridine -2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester. (72 mg, 76% yield) MS (ESI) M / Z : 591 [M + H] +.

Example 1.6.53

[(2R)-2-{5-[1-(cyclopropylmethyl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl Tert-butyl carbamic acid: to {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl Add a solution of tert-butyl carbamic acid (72 mg, 0.12 mmol) in MeCN (2 mL) EtOAc (EtOAc (EtOAc) Tetra-n-butylammonium (4.5 mmol, 0.012 mmol). After stirring at 60 ℃ 7 hours, the mixture was concentrated in vacuo and treated with silica gel column chromatography (CHCl ₃ /MeOH=99.5:0.5 to 90:10), to give colorless amorphous of [(2R) - 2-{5-[1-(cyclopropylmethyl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl }-6-Sideoxy-1,6-dihydropyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]aminocarboxylic acid Tributyl ester. (29 mg, 37% yield) MS (ACI/ESI) M/Z: 645[M+H] ⁺ .

Example 1.6.54

{(2R)-2-[5-(6-ethoxy-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}carbamic acid tert-butyl ester and {(2R)-2-[ 5-(1-Ethyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-sideoxy- 1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester: similar to the examples The mode of 1.6.53 , from {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl) ]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}amino The desired compound was synthesized from tert-butyl formate (150 mg, 0.254 mmol). (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

6-(5-{(2R)-2-[(tatabutoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole-trifluoromethanesulfonate- 2-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl ester: at 0 ° C Downward {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -Phenoxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester (100 mg, 0.169 mmol) <RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; After stirring at the same temperature for 1 hour, a saturated aqueous solution of NaHCO _{3 was} added. The mixture was extracted with CHCl ₃ and the organic layer was concentrated in vacuo to give crude <EMI ID=0.0>-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropane- 2-yl}-1,3,4-oxadiazol-2-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]carbonyl}pyridin-2-yl ester. MS (ESI) M / Z: 723 [M+H] ⁺ .

Example 1.6.56

{(2R)-2-[5-(6-[(2-methoxyethyl)amino]-4-{[(2R)-2-(4-methyl-1,3-thiazole-2 -yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl Ester: 6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxo to trifluoromethanesulfonate Diazol-2-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl ester To a solution of 60 mg, 0.083 mmol) in EtOAc (1 mL). After stirring for 1 day, the mixture was poured into water and extracted with chloroform. The organic layer was concentrated in vacuo <RTI ID=0.0></RTI> tojjjjjjjjj ]-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4- T-butyl oxazol-2-yl]-1-phenylpropan-2-yl}carbamate (30 mg, 56% yield). MS (APCI/ESI) M/Z: 648 [M+H] ⁺ .

Example 1.6.57

{(2R)-2-[5-(6-[(2-methoxyethyl)(methyl)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}amino Tert- butyl formate: 6-(5-{(2R)-2-[( tatabutoxycarbonyl )amino]-1-phenyl trifluoromethanesulfonate in a similar manner to Example 1.6.56 Prop-2-yl}-1,3,4-oxadiazol-2-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine The desired compound was synthesized from -1-yl]carbonyl}pyridin-2-yl ester (60 mg, 0.083 mmol). (52 mg, 95% yield) MS (APCI/ESI) M/Z: 662[M+H] ⁺ .

Example 1.6.58

[(2R)-2-{5-[6-(ethylamino)-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]carbamic acid tert-butyl ester: to {(2R) -2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2- Add ethylamine (80 mg) to a solution of tert-butyl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamate (150 mg, 0.246 mmol) % yield, aqueous solution; 0.1 mL, 1.2 mmol). After stirring at 130 ° C for 4 hours under microwave irradiation in a sealed tube, the mixture was concentrated in vacuo and purified by silica gel chromatography (CHCl ₃ /MeOH = 100:0 to 90:10) to give a yellow amorphous [(2R)-2-{5-[6-(ethylamino)-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]carbamic acid tert-butyl ester (72 mg, 47% ). MS (APCI/ESI) M/Z: 618 [M+H] ⁺ .

Example 1.6.59

Methyl 5-bromo-1-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate: methyl 5-bromo-2-hydroxynicotinate (1.00 g, 4.31 mmol) Methyl iodide (0.81 mL, 13 mmol) and potassium carbonate (1.19 g, 8.62 mmol) were added to a suspension in MeOH/DMF (10+10 mL). After stirring at room temperature for 14 hours, the reaction mixture was diluted with ethyl acetate and washed sequentially with H ₂ O- brine (1:1), H ₂ O- saturated aqueous NaHCO ₃ (1:1), brine and anhydrous Na ₂ SO _{4 was} dried and concentrated in vacuo. Chromatography using silica gel (CHCl ₃ / MeOH 100: 0 to 90:10), to give a beige solid of 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine - Methyl 3-carboxylate (745 mg, 70% yield). MS (ESI) M/Z: 246, 248 [M+H] ⁺ .

5-bromo-1-methyl-2-oxooxy-1,2-dihydropyridine-3-carboxamidine: 5-Bromo-1-methyl-2-oxo-oxygen at room temperature To a solution of methyl-1,2-dihydropyridine-3-carboxylate (649 mg, 2.64 mmol) in MeOH (6 mL) was added EtOAc (198 mg, 3. The mixture was stirred at the same temperature for 3 hours and poured into water. The resulting precipitate was filtered, washed with water and dried in vacuo tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjj 649 mg, quantitative). MS (ESI) M/Z: 246, 248 [M+H] ⁺ .

[(2R)-1-{2-[(5-Bromo-1-methyl-2-oxo-l,2-dihydropyridin-3-yl)carbonyl]indenyl}-2-methyl- 1-Butoxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester: to N-( t -butoxycarbonyl)-α-methyl-D-phenylalanine (734 mg, 2.63 mmol) Diisopropylethylamine (0.59 mL, 3.4 mmol) and HATU (1.10 g, 2.89 mmol) were added to a solution in dichloromethane (16 mL). The mixture was stirred for 30 minutes and 5-bromo-1-methyl-2-oxooxy-1,2-dihydropyridine-3-carboxamidine (647 mg, 2.63 mmol) was added. After stirring for 6 hours, the reaction mixture was diluted with ethyl acetate and washed sequentially with H ₂ O- brine (1:1), H ₂ O- saturated aqueous NaHCO ₃ (1:1), brine and dried over anhydrous Na ₂ SO ₄ Drying and concentrating in vacuo to give crude [(2R)-1-{2-[(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbonyl Tert-butyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (1.33 g, quantitative). MS (ESI) M/Z: 507, 509 [M+H] ⁺ .

{(2R)-2-[5-(5-Bromo-1-methyl-2-oxo-l,2-dihydropyridin-3-yl)-1,3,4-oxadiazole-2 -1 -phenylphenyl-2-yl}aminocarboxylic acid tert-butyl ester: to a stirred [(2R)-1-{2-[(5-bromo-1-methyl-2- side) Oxyl-1,2-dihydropyridin-3-yl)carbonyl]indolyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester ( 1.33 g, 2.63 mmol) was added to a solution of dichloroethane (19 mL) in a solution of s. s. (1.88 g, 7.89 mmol), followed by stirring at 120 ° C for 20 minutes under microwave irradiation. The crude product was directly purified by hydrazine gel column chromatography (hexane / EtOAc = 90:10 to 50:50) to afford ((2R)-2-[5-(5-bromo-1-) Keto-2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Tributyl ester (1.03 g, 80% yield). MS (ESI) M/Z: 495, 495 [M+H] ⁺ .

Example 1.6.60

5-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- Methyl 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate: Stirred {(2R)-2-[5-(5-bromo-1-) at room temperature Methyl-2-oxooxy-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Add palladium diacetate (135 mg, 0.602 mmol), 1,1'-bis(diphenylphosphino)ferrocene (333 mg) to a solution of tert-butyl ester (589 mg, 1.20 mmol) in MeOH/DMSO. , 0.602 mmol) and triethylamine stock solution (0.50 mL, 3.6 mmol), and the mixture was stirred at 80 ° C under a CO atmosphere for 8 hours. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was evaporated and the resulting solution was extracted three times with EtOAc. And the organic layer was washed with H ₂ O (3 times) The combined washed with brine, dried over MgSO ₄ and evaporated to give crude _{material, (99 CHCl 3 / MeOH =} : 1 to 80:20) was purified by silica gel column chromatography, to give 5-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole--male amorphous Methyl 2-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (564 mg, 100% yield). MS (ESI) M / Z: 469 [M+H] ⁺ .

5-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- 1-Methyl-6-o-oxy-1,6-dihydropyridine-3-carboxylic acid: 5-(5-{(2R)-2-[(T-butoxycarbonyl)) stirred at room temperature Amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-6-oxo-1,6-dihydropyridine- A solution of methyl 3-formate (564 mg, 1.20 mmol) in MeOH / THF (3:1) was then evaporated. The mixture was acidified with 1 M aqueous HCI (1. The residue was suspended in _{CHCl 3 / MeOH (5: 1} ) and the precipitate was filtered off. The filtrate was concentrated in vacuo to give crude 5-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1 as a beige amorphous. 3,4-oxadiazol-2-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (503 mg, 92% yield). MS (ESI) M/Z: 455 [M+H] ⁺ .

Example 1.6.61

{(2R)-2-[5-(1-methyl-5-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) }-2-Sideoxy-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tributyl: in a manner similar to that of Examples 1.6.37 from 5- (5 - {(2R) -2 - [( tertiary-butoxycarbonyl) amino] -1-phenyl-propan-2-yl} -1,3,4-oxadiazol-2-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (140 mg, 0.308 mmol). (175 mg, 94% yield).

Example 1.6.62

6-(decylcarbonyl)-1-methyl-2- oxooxy -1,2-dihydropyridine-4-carboxylic acid tert-butyl ester: in a manner similar to the example 1.6.59 , from 1-methyl -6-Phenoxy-1,6-dihydropyridine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (3.00 g, 11.2 mmol). (3.00 g, 100% yield) MS (ESI) M / Z : 268 [M + H] +.

6-[(2-{(2R)-2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropenyl}indolyl)carbonyl]-1-methyl-2 -Sideoxy -1,2-dihydropyridine-4-carboxylic acid tert-butyl ester: in a similar manner to the example 1.6.59 , from 6-(fluorenylcarbonyl)-1-methyl-2- oxooxy The desired compound was synthesized from -1,2-dihydropyridine-4-carboxylic acid tert-butyl ester (3.00 g, 11.2 mmol). (5.94 g, 100% yield).

6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- 1-Methyl-2- oxooxy -1,2-dihydropyridine-4-carboxylic acid tert-butyl ester: in a manner similar to Example 1.6.A47 Ex A60, from 6-[(2-{(2R)) -2-[(Tertidinoxycarbonyl)amino]-2-methyl-3-phenylpropanyl}indenyl)carbonyl]-1-methyl-2-oxo-1,2-di The desired compound was synthesized from hydrogen pyridine-4-carboxylic acid tert-butyl ester (5.94 g, 11.2 mmol). (5.39 g, 94% yield) MS (ESI) M / Z : 511 [M + H] +.

Example 1.6.63

6-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)- 1-Methyl-2-oxooxy-1,2-dihydropyridine-4-carboxylic acid: in a manner similar to the case of Example 1.6.52 , from 6-(5-{(2R)-2-[(third Butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-oxo-1,2-di The desired compound was synthesized from the hydrogen pyridine-4-carboxylic acid tert-butyl ester (5.39 g, 10.6 mmol). (4.80 g, quantitative) MS (ESI) M/Z: 455 [M+H] ⁺ .

Example 1.6.64

(R)-4-(5-(2-((t-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)- 5-fluoropicolinic acid: 0.9672 g (4.4 mmol) of 2-bromo-5-fluoroisonicotinic acid, 0.9458 g (4.93 mmol) of EDCI and 0.6748 g (4.994 mmol) of HOBt in 10 mL at room temperature 1.2988 g (4.43 mmol) of (R)-(1-indolyl-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid was added to the mixture in CH ₂ Cl ₂ Tributyl ester and 3.0 mL DIPEA. After the mixture was stirred at room temperature for 15 hours, H ₂ O was added and the aqueous layer was extracted with CHCl ₃ . Washed with water (2x) and the combined extracts were washed with brine, dried over Na ₂ SO _4, filtered and concentrated. Purification by flash gel chromatography ((50-60)% EtOAc/hexanes) affords: T- butyl -2-methyl-1-oxo-3-phenylpropan-2-yl)carbamate ( 6.64.1 ).

0.9211 g of (R)-(1-(2-(2-bromo-5-fluoroisonicotininyl)indolyl)-2-methyl-1-oxooxy-3 was stirred at 95 ° C under Ar - phenylpropan-2-yl) carbamic acid tert-butyl ester and 1.1806 g (4.95 mmol) Burgess reagent in 10 mL CH ₂ ClCH ₂ Cl in the solution for 25 minutes. Saturated NaHCO ₃ (25 mL) and CHCl ₃ and the layers were separated. The aqueous layer was extracted with CHCl _3. , Dried with Na ₂ SO ₄ the combined extracts were washed with brine, filtered and concentrated. Purification by flash gel chromatography ((40-50)% EtOAc/hexanes) afforded &lt;RTI ID=0.0&gt;0&gt; 3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl)carbamic acid tert- butyl ester ( 6.64.2 ).

To degassed 0.8006 g (1.677 mmol) of (R)-(2-(5-(2-bromo-5-fluoropyridin-4-yl)-1,3,4-oxadiazol-2-yl) 1-butyl-1-phenylpropan-2-yl)carbamate and 0.1 mL (0.7174 mmol) of Et ₃ N in 4 mL DMF and 4 mL EtOH (by bubbling in Ar and emptying and backfilling 3 Next, 0.1877 g (0.3385 mmol) of dppf and 0.1892 g (0.8427 mmol) of Pd(OAc) ₂ were added to the solution in the solution to degas.) After each addition, the flask was evacuated and backfilled with Ar three times. The flask was evacuated with CO and backfilled once. The mixture was stirred at 50 ° C under CO for about 3 hours. Water (5 mL) and EtOAc were added and the layers were separated. , Dried over Na ₂ SO ₄ organic layer was washed with brine, filtered and concentrated. Purification by flash gel chromatography (20% EtOAc / hexane) afforded &lt;RTI ID=0.0&gt;&gt; Ethyl-1,3,4-oxadiazol-2-yl)-5-fluoropicolinate ethyl ester ( 6.64.3 ).

To a stirred 112.7 mg of (R)-4-(5-(2-((t-butoxycarbonyl)amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole- Add 1.5 mL of 1 N NaOH to a solution of ethyl 2-yl)-5-fluoropicolinate in 5 mL of THF. The solution was stirred at room temperature for 19.5 hours. Water and CH ₂ Cl _{2 were} added and the layers were separated. The aqueous layer was extracted with CH ₂ Cl _{2 and the} aqueous layer was partially separated and H ₂ O and CH ₂ Cl _{2 were added} ; the layers were separated. The organic layer was washed with H ₂ O; 1 N HCl and saturated NaHCO _{3 were added} to pH = 2. The extract of % MeOH/10% H ₂ O/80% CHCl ₃ was extracted twice, dried over Na ₂ SO ₄ , filtered and concentrated to give (R) -4-(5-(2-((3) Butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-fluoropicolinic acid ( 6.64.4 ).

Example 1.6.65

(R)-4-(5-(2-((T-butoxycarbonyl)amino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -5-methoxypicolinic acid: 94 mg of (R)-4-(5-(2-(2-t-butoxycarbonyl)amino-1-phenylpropan-2-yl)-1 Add 3 mL of ethyl 3,4-oxadiazol-2-yl)-5-fluoropicolinate to a solution of 2 mL of THF and 1 mL of MeOH in 0.5 mL of 1 N NaOH. After 18 hours, add 1.0 mL of 1 N NaOH. (The solution was warmed for about 1 hour). The solution was stirred at 50 ° C for 45 minutes. Water and CH ₂ Cl _{2 were added} and the layers were separated but not complete. H ₂ O and CH ₂ Cl ₂ were added and the layers were separated. The organic layer was washed with H ₂ O. 1 N HCl was added to pH = 2. The aqueous layer was extracted three times with 10% MeOH / 10% H ₂ O / 80% CHCl ₃ extracts. The combined extracts were dried over Na ₂ SO ₄ Filtered and concentrated to give (R)-4-(5-(2-((t-butoxycarbonyl))amino)-1-phenylpropan-2-yl)-1,3,4-oxan Zyridin -2-yl)-5-methoxypicolinic acid ( 6.65.5 ).

Example 1.6.66

Add HOBT (328 mg, 2.141 mmol) and EDC (479 mg, 2.498 mmol) to a solution containing the acid, 5-bromo-2-fluorobenzoic acid (391 mg, 1.784 mmol) in DCM (3 mL) The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was cooled to 0 ° C and (R)-(3-(4-fluorophenyl)-1-indolyl-2-methyl-1-oxopropan-2-yl) Tributyl carbamic acid (500 mg, 1.606 mmol) and DIPEA (0.935 ml, 5.35 mmol) were added to DCM (1 mL). The reaction mixture was dark brown in color. After stirring overnight at room temperature, the DCM was removed in vacuo. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. After stirring at room temperature for 10 minutes, the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and brine and dried. The crude residue continues to the next step.

Bordeaux reagent (1.26 g, 5.27 mmol) was added to a solution containing hydrazine (1.08 g, 2.11 mmol) (20 mL) and refluxed for 3 hours, at which time the colour of the reaction became brown. The reaction mixture was then cooled, diluted with DCM, washed with brine The crude residue was subjected to column chromatography (30% ethyl acetate /hexane). The product was a yellow syrup and obtained 67% yield.

To the bromine-containing compound, (R)-(2-(5-(5-bromo-2-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(4-fluorophenyl) Addition of acetic acid to tert-butyl propan-2-yl)carbamate (700 mg, 1.416 mmol) of dioxane (Ratio: 2.96, volume: 8 ml) and water (ratio: 1.000, volume: 2.7 ml) palladium (II) (15.90 mg, 0.071 mmol) and XANTPHOS (82 mg, 0.142 mmol) , Et 3 N (1.974 ml, 14.16 mmol) and the reaction mixture was purged with carbon monoxide. The reaction mixture (yellow suspension) was then heated to 75 ° C for 3 hours, at which time the suspension was grayish green. The reaction mixture was then cooled and the dioxane was removed in vacuo. Add water and filter. The aqueous layer was basified and extracted with ethyl acetate. The aqueous layer was then acidified and extracted with EtOAc EtOAc. The organic layer was dried and evaporated to give 460 mg of acid.

The resulting acid was converted to the final compound in a manner similar to that in Example 1.7.1 .

Example 1.6.67

Add HOBT (1.163 g, 7.59 mmol) and EDC (1.699 g, 8.86 mmol) to a solution containing the acid, 5-bromo-2,4-difluorobenzoic acid (1.5 g, 6.33 mmol) in DCM (10 mL) The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was cooled to 0 ° C, and (R)-(1-mercapto-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid Butyl ester (1.671 g, 5.70 mmol) and DIPEA (3.32 ml, 18.99 mmol) were added to DCM (3 mL). The reaction mixture was dark brown in color. After stirring overnight at room temperature, the DCM was removed in vacuo. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. After stirring at room temperature for 10 minutes, the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and brine and dried. The crude residue continues to the next step.

Bordeaux reagent (629 mg, 2.64 mmol) was added to a solution containing hydrazine (500 mg, 1.06 mmol) (20 mL) and refluxed for 2 h at which time the colour of the reaction became dark brown. The reaction mixture was then cooled, diluted with DCM, washed with brine The crude residue was subjected to column chromatography (30% ethyl acetate /hexane). The product was a colorless foamy syrup and obtained 67% yield.

To the bromine-containing compound, (R)-(2-(5-(5-bromo-2,4-difluorophenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropane -2-yl)-tert-butyl 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), Et ₃ N (2.82 ml, 20.23 mmol) and the reaction mixture was purified using carbon monoxide. The reaction mixture was then heated to 75 ° C for 4 hours. The reaction mixture was then cooled, water was added and filtered. The aqueous layer was basified and extracted with ethyl acetate. The aqueous layer was then acidified and extracted with EtOAc EtOAc. The organic layer was dried and evaporated to give 360 mg of acid. The organic layer also has some products as well as some impurities. The material obtained from the organic layer was partitioned between water (basic) layer and 5% MeOH / ethyl acetate to afford 450 mg of acid.

The resulting acid was converted to the final compound in a manner similar to that in Example 1.7.1.

Example 1.6.68

The final compound was prepared using a procedure similar to that of Example 1.8.11 .

Example 1.7: Multi-step synthesis of an oxadiazole inhibitor. Example 1.7.1

Including use containing HOBT, EDCI, DIPEA of CH ₂ Cl ₂ standard coupling procedures of the coupling 7.1.38 and 7.1.39, and stirred overnight to produce a yield of 81% 7.1.40.

To a solution of 7.1.40 (2.37 g, 3.60 mmol) in dichloroethane (50 mL) was added Burgess reagent (2.57 g, 10.80 mmol) and refluxed overnight (about 16 hours). The reaction mixture was then allowed to cool to room temperature, diluted with CHCl ₃ and washed successively with saturated aqueous NaHCO ₃ and brine, dried, concentrated and purified by silica gel (1% MeOH / 99% CHCl 3), to obtain 2.12 g (92%) 7.1 .41 .

Mix a solution of 7.1.41 (2.12 g, 3.31 mmol) in 4 N HCl in 1,4-dioxane (20 mL) with 1.5 N EtOAc in MeOH (5 mL). The solution was taken for 45 minutes. The TLC indicates the initial material consumption. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue extracted with EtOAc. The organic extracts were washed with brine, dried, concentrated and purified (1% MeOH / 99% CHCl 3) on basic alumina to give 1.44 g (80%) compound 7.1.42.

Example 1.7.2

Add EDC (commercial source: sigma-aldrich) (90 mg, 0.47 mmol) and HOBT (commercial source: sigma-aldrich) to a solution of 7.2.33 (150 mg, 0.43 mmol) in CH ₃ CN. (63 mg, 0.47 mmol). After 1 hour, anhydrous hydrazine (commercial source: sigma-aldrich) (55 mg, 1.72 mmol) was added and stirred at room temperature overnight. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue was extracted with DCM. The organic extracts were washed with brine, dried, concentrated and purified by silica gel to give 85 mg 7.2.44.

EDC (commercial source: sigma-aldrich) (62 mg, 0.32 mmol) and HOBT (commercial source: sigma-) were added to a solution of 7.2.44 (85 mg, 0.23 mmol) in DCM (5 ml). Aldrich) (37 mg, 0.28 mmol). After 1 hour, acid 7.2.45 (commercial source: Peptech) (64 mg, 0.23 mmol) was added and stirred at room temperature overnight. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue was extracted with ethyl acetate. The organic extracts were washed with brine, dried, concentrated and purified on basic alumina to give 78 mg 7.2.46.

To a solution of 7.2.46 (78 mg, 0.12 mmol) in dichloroethane (5 mL) was added Bogez reagent (89 mg, 0.36 mmol) and reflux for 6 hours. The reaction mixture was then allowed to cool to room temperature, diluted with CHCl ₃ and washed successively with saturated aqueous NaHCO ₃ and brine, dried, concentrated and purified by silica gel (1% MeOH / 99% CHCl 3), to obtain 55 mg 7.2.47.

A mixture of 7.2.47 (55 mg, 0.09 mmol) in 4 N HCl in 1,4-dioxane (4 mL) and 1.5 N HCl in MeOH (5 mL). The solution was taken for 3 hours. The TLC indicates the initial material consumption. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue extracted with EtOAc. The organic extracts were washed with brine, dried, concentrated and purified (1% MeOH / 99% CHCl 3) on basic alumina to give 32 mg of the desired product 7.2.48.

Example 1.7.3

Including use containing HOBT, EDCI, DIPEA of CH ₂ Cl ₂ standard coupling procedures to make 7.3.49 and 7.3.50 coupling, and stirred overnight to produce a yield of 77% 7.3.51. The final compound 7.5.33 was synthesized from ligand 7.5.3 as described above.

Example 1.7.4

Bromide (1.0 ml, 1.44 g, 11.9 mmol, 1.25 equiv) was added to 7.4.54 (Aldrich, 2.0 g, 9.5 mmol, 1 eq.) and K ₂ CO ₃ (2.959 g, 21.4 mmol). , 2.25 equivalents) in a suspension in anhydrous DMF (10 ml). The mixture was heated to 60 ° C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and filtered over EtOAc. The organic layer was washed with water (4 times), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 2.14 g (8.6 mmol, 90%) 7.4.5 .

A solution of 7.4.55 (1.04 g, 4.2 mmol, 1 eq.) in diethyl phenylamine (5 ml) was purified with EtOAc over EtOAc . The solution was heated to 195 ° C with stirring. After 24 hours, the reaction was cooled to rt and diluted with Et ₂ O. The organic layer was washed with 1 N HCl (2×), water (3×), brine (1) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave an impure product. Recrystallization from CH ₂ Cl ₂ /hexane gave 0.579 g (2.3 mmol, 56%) 7.4.56 .

Anhydrous CH ₃ CN (10 ml) was added to a flask containing 7.4.56 (0.8369 g, 3.3 mmol, 1 eq.) and Cu(OAc) ₂ (0.7289 g, 4.0 mmol, 1.2 eq. The flask was evacuated and backfilled with O ₂ (3 times). 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 under stirring in aqueous NH _{4 OH (30%, 75 ml} ) in. After 15 minutes, the mixture was extracted with EtOAc (1×). Dried over Na ₂ SO ₄ with brine (1 time), and the organic layer was washed. The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.7338 g (2.7 mmol, 80%) 7.4.57 .

Purged with Ar 7.4.57 (0.2521 g, 0.9 mmol, 1 equiv) in dry CH ₂ Cl ₂ (10 ml) in the solution to a degassed (5 minutes). A 2nd generation Grubb catalyst (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 by flash chromatography on silica gel gave 0.166 g ( 0.677 mmol, 74%) 7.4 .

A solution of 7.4.58 (0.166 g, 0.67 mmol, 1 eq.) in MeOH (10 mL) was taken from &lt;RTI ID=0.0&gt _; 0&gt; After vigorously stirring overnight, the mixture was filtered through celite. The volatiles were removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.142 g (0.57 mmol, 85%) 7.4.59 .

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. NaOH (1 N, 0.6 ml, 0.6 mmol, 1.05 eq.) was added dropwise. After 4 hours at this temperature, the reaction was gradually warmed while stirring it overnight. The reaction was diluted with saturated aqueous NaHCO _3, and the volatiles were removed via rotary evaporation. The residue was diluted with water and with 3: 1 CH ₂ Cl ₂ / hexane (2 times) and extracted. Adjust the water layer to pH with 1 N HCl 2. The aqueous layer (2x) and extracted with 2% MeOH solution of CH ₂ Cl _2. The combined organics were appropriate and dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation to give 0.088 g (0.37 mmol, 65% ) 7.4.61 and 7.4.60 (about 1: 2) of a mixture.

Under Ar with stirring to make 7.4.61 and 7.4.60 (0.079 g, 0.33 mmol, 1 eq.) Was cooled in dry CH ₂ Cl ₂ (5 ml) in the to 0 ℃. The cooled solution was treated with EDCI HCl (0.0703 g, 0.37 mmol, 1.1 eq.) and HOBT ‧ H ₂ O (0.0497 g, 0.37 mmol, 1.1 eq.). After 1 h, the reaction was treated sequentially with EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) 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 and water and layers were separated. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave a small amount of 7.4.62 and 0.1256 g (0.25 mmol) of 7.4.63 with some impurities. Some mixed dissolving fractions were also collected.

Borges reagent (0.1426 g, 0.61 mmol, 2.5 eq.) was added under stirring to 7.4.63 (0.1256 g, 0.25 mmol, 1 eq.) in anhydrous 1,2-dichloroethane (5 ml) In the solution. The solution was heated to reflux overnight. After cooling to room temperature, _diluted with ₂ Cl CH reactants. Dried organic layer was washed with brine (1 time) ₃ solution (once) and saturated NaHCO over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.0984 g (0.2 mmol, 80%) 7.4.6 .

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 NaHCO _3. The volatiles were removed via rotary evaporation. With water and diluted with CH ₂ Cl ₂ the residue. Adjust the water layer to pH with 1 N HCl 2. The aqueous layer was extracted with CH ₂ Cl ₂ (twice). The organic layers were combined and dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation to afford &lt;RTI ID=0.0&gt ;&gt;

Under stirring 7.4.65 (0.0887 g, 0.18 mmol, 1 equiv) in dry CH ₂ Cl ₂ (5 ml) in the solution was cooled to 0 ℃. The solution was treated with HOBT ‧ H ₂ O (0.0 275 g, 0.2 mmol, 1.1 eq.). After 30 min, EDCI HCl (0.0389 g, 0.2 mmol, 1.1 eq.). After 1 h, the resulting solution was treated sequentially with EtOAc (EtOAc: EtOAc, EtOAc (EtOAc) 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 and water and layers were separated. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.0864 g (0.14 mmol, 76%) 7.4.6 .

Example 1.7.5

Lawson's reagent (commercial source: sigma-aldrich) (11.33 g, 280 mmol) was added to a guanamine (10 g, 46.67 mmol) of DME (commercial source: sigma-aldrich) (140 ml) at room temperature The reaction mixture was stirred overnight. The reaction mixture was then diluted with ethyl acetate / hexanes and washed with aqueous sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

Ethyl bromopyruvate (7.9 mL, 62.86 mmol, commercial source: sigma-aldrich) was added to thiopuramine (9.65 g, 41.91 mmol) in ethanol (150 ml). After heating at 75 ° C for 5 hours, the resulting mixture was then kept at room temperature overnight. Remove volatiles in a vacuum. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate. The organic layer was dried <RTI ID=0.0> ¹ H NMR (300 MHz, CDCl ₃ ), 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).

Boc ₂ O (4.23 g, 19.39 mmol), pyridine (2.95 mL, 37.28 mmol) was added sequentially to EtOAc (3. <RTI ID=0.0></RTI></RTI><RTIgt; The resulting reaction mixture was stirred at room temperature overnight then diluted with chloroform and washed with sodium hydrogen sulfate. The organic layer was dried <RTI ID=0.0>

Was added to THF at 0 ℃ containing ester (4 g, 12.25 mmol) of _{(50 mL) LiBH 4 (2.0} M THF solution, 18.4 mL, 36.76 mmol) was stirred and slowly warmed to overnight. The reaction mixture was diluted with ethyl acetate and carefully quenched with EtOAc EtOAc. The organic layer was separated, dried and evaporated to give crystals crystals crystals

Deoxo-Fluor (1.77 mL, 9.6 mmol) was added to a solution of the alcohol (2.1 g, 7.3 mmol) in dichloromethane (60 mL). The mixture was stirred and warmed to EtOAc EtOAc (EtOAc)EtOAc. The mixture was warmed to rt, separated and dried, concentrated and purified with EtOAc EtOAc ¹ H NMR (300 MHz, CDCl ₃ ), 5: 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).

To a fluoride (1.1 g, 3.84 mmol) in methanol (4.5 ml) was added 4 M HCl in dioxane (9.6 mL). After 1.5 hours, the volatiles were removed in vacuo. The resulting solid was used directly in the next reaction without further purification. Add PyBOP (1.03 g, 1.8 mmol), triethylamine (1) to a solution of EtOAc (EtOAc (EtOAc) mL, excess). The reaction mixture was stirred at room temperature for 16 hours. Then a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with chloroform. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product thus obtained was purified by silica gel flash chromatography to give the corresponding decylamine (623 mg). ¹ H NMR (300 MHz, CDCl ₃ ), 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).

The ester (623 mg, 1.5 mmol) was dissolved in THF: MeOH (1: 1) (15:15 mL) and H ₂ O (2.3 mL) in. Solid NaOH (180 mg, 4.5 mmol) was added and stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. A saturated NaHCO ₃ (10 mL) solution was added to the reaction mixture and extracted with toluene (to remove organic impurities). The reaction with dilute HCl (10%) was acidified aqueous mixture was extracted with EtOAc, dried over anhydrous Na ₂ SO _4. The solvent was evaporated and dried under reduced pressure to give a crude acid which was used directly in the next reaction.

Example 1.7.6

3-[5-(1-Amino-2-phenylcyclohexyl)-1,3,4-oxadiazol-2-yl] -N -methyl-N-[(4-methyl-1, 3-thiazol-2-yl)methyl]benzamide amine oxalate: 3-[5-(1-Amino-2-phenylcyclohexyl)-1,3,4- stirred at ambient temperature Oxadiazol-2-yl]benzoic acid (180 mg, 0.5 mmol), EDC (114 mg, 0.59 mmol), HOBt (80 mg, 0.59 mmol), N-methyl-1-(4-methyl-1 A mixture of 3-thiazol-2-yl)methylamine (85 mg, 0.59 mmol) in DMF (4 mL After dilution with EtOAc, washed with H ₂ O, ₃ solution and the organic layer was washed with saturated brine and NaHCO, dried over MgSO _4, and concentrated in vacuo. By silica gel chromatography _{(CHCl 3: MeOH = 100:} 0-95: 5) The residue was purified to afford an amorphous solid of the free base (44 mg), which was dissolved in EtOH, followed by addition of acetic acid (8 mg, 0.09 mmol) and traces of Et ₂ O. The resulting precipitate was collected by filtration, washed with ₂ O Et and dried in vacuo to give a colorless solid of 3- [5- (1-amino-2-phenyl-cyclohexyl) -1,3,4 Oxadiazol-2-yl]-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide amine oxalate (13 mg, 5%) ). MS (ESI) m / z: 488 [M+H] ⁺ .

3-[5-(1-Amino-2-phenylcyclohexyl)-1,3,4-oxadiazol-2-yl]benzoic acid: 3-({2-[(1-) amino-2-phenyl-cyclohexyl) carbonyl] hydrazino} carbonyl) benzoate (161 mg, 0.41 mmol) was added DBU) in a solution in _{CH 2 Cl 2 (2 mL (} 0.304 mL, 2.04 mmol) And 2-chloro-1,3-dimethylimidazolium chloride (206 mg, 1.22 mmol). The reaction mixture was allowed to warm to room temperature. After stirring at ambient temperature overnight, the mixture was partitioned between EtOAc and H ₂ O, the organic layer was washed with brine solution and with saturated NaHCO _{3, 4} and concentrated in vacuo and dried over MgSO. The residue (100 mg) was dissolved in dioxane (1 mL) and ethyl acetate (1 mL), and CsOH.H ₂ O (226 mg, 1.35 mmol) was added to the solution. The mixture was stirred at 150 ° C for 2 hours. After cooling to ambient temperature, was added 1 M aqueous HCl, then washed with brine the mixture was extracted with EtOAc, _4, and was dried over MgS04 and concentrated in vacuo, to give 3- [5- (1-amino-2-phenyl-cyclohexyl -1,3,4-oxadiazol-2-yl]benzoic acid (186 mg, 126%) was used in the next step without further purification. MS (ESI) m / z: 364[M+H] ⁺ .

Methyl 3-({2-[(1-amino-2-phenylcyclohexyl)carbonyl)indolyl}carbonyl)benzoate: 1-amino-2-phenylcyclohexane a stirred at ambient temperature Bismuth hydrochloride (180 mg, 0.59 mmol), EDC (135 mg, 0.71 mmol), HOBt (95 mg, 0.71 mmol), Et ₃ N (0.180 mL, 1.29 mmol) and 3-(methoxycarbonyl) benzoic acid (106 mg, 0.59 mmol) in a mixture of CH ₂ Cl ₂ (4 mL) in the four hours. After dilution with EtOAc, washed with H ₂ O, ₃ solution and the organic layer was washed with saturated brine and NaHCO, dried over MgSO _4, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc ) carbonyl] fluorenyl}carbonyl)methyl benzoate. MS (ESI) m / z: 396 [M+H] ⁺ .

1-Amino-2-phenylcyclohexaneformamidine dihydrochloride: tert-butyl 2-[(1-amino-2-phenylcyclohexyl)carbonyl]indolecarboxylic acid (160 mg, 0.48 Methyl) was dissolved in 4 M HCl / EtOAc. After stirring overnight, the mixture was evaporated to give 1-amino-2-phenylcyclohexanemethionidine dihydrochloride as a colorless oil. MS (ESI) m / z: 234 [M+H] ⁺ .

2-[(1-Amino-2-phenylcyclohexyl)carbonyl]indolecarboxylic acid tert- butyl ester: 1-amino-2-phenylcyclohexanecarboxylate (500 mg) stirred at ambient temperature A mixture of 1.96 mmol), EDC (450 mg, 2.35 mmol), HOBt (317 mg, 2.35 mmol) and tributyl succinate (620 mg, 4.69 mmol) in DMF (10 mL) overnight. After dilution with EtOAc,, the organic layer was dried with H ₂ O and brine over MgSO _4, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Tributyl ester (167 mg, 26%). MS (ESI) m / z: 344 [M+H] ⁺ .

Example 1.7.7

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-5-methylbenzenesulfonate : stirred at 130 ° C in a sealed tube under microwave irradiation rel-[( 1R,2R)-1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl)indolyl] TC}-2-phenylcyclopropyl]carbamic acid tert-butyl ester (55.6 mg, 0.099 mmol) and Burgess reagent (70.5 mg, 0.296 mmol) in dichloroethane (DCE) (1 mL) The mixture was allowed to stand for 20 minutes. The mixture was partitioned between CHCl ₃ and water. The organic layer was washed with aqueous saturated NaHCO ₃ and brine, dried over MgSO _4, diatomaceous earth and silica gel was dried, filtered off and the filtrate was evaporated. Silica gel column for chromatography (CHCl ₃ -MeOH, 0 to 4% MeOH linear gradient) to give a colorless gum (MS (ESI) m / z : 568.10 [M + Na] +). The gum was dissolved in MeCN (1 mL) and p-toluenesulfonic acid monohydrate (56.3 mg) was added to the solution. The mixture was stirred at 50 ° C for 1 hour. The mixture was partitioned between CHCl _{3 3} and saturated aqueous NaHCO. The organic layer was washed with brine, dried MgSO ₄ The residue was dissolved in isopropyl alcohol (IPA), and p-toluenesulfonic acid monohydrate (18.8 mg) was added to the solution. The solvent was evaporated, and the residue was crystallised eluted eluted elut elut elut elut elut elut elut elut elut elut Oxadiazol-2-yl}-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide-5-methylbenzenesulfonate (1 :1), collected by filtration, washed with EtOAc and dried (26.3 g, 60. MS (ESI) m / z: 446.2 [M+H] ⁺ .

Rel-[(1R,2R)-1-{[2-(3-(methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl) Tertyl]carbonyl}-2-phenylcyclopropyl]carbamic acid tert- butyl ester: stirring rel-(1R,2R)-1-[bis(t-butoxycarbonyl)amino group] at ambient temperature -2-phenylcyclopropanecarboxylic acid (129 mg, 0.342 mmol), 3-(fluorenylcarbonyl)-N-methyl-N-[(4-methyl-I,3-thiazol-2-yl)methyl a mixture of benzamidine (156 mg, 0.513 mmol), EDC (91.7 mg, 0.478 mmol) and EtOAc (55.4 mg, 0.410 mmol) in DMF (2 mL). Room. with 1 N HCl, ₃ solution and the organic layer was washed with saturated NaHC03 brine, dried over MgSO _4, filtered and the filtrate was evaporated. column chromatography on silica gel performed (CHCl ₃ -MeOH, 0 to 4% MeOH linear gradient) to give Rel-[(1R,2R)-1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl])aminocarbazyl) "Benzyl fluorenyl) fluorenyl]carbonyl}-2-phenylcyclopropyl]carbamic acid tert-butyl ester (55.6 mg, 28.9%).

Rel-(1R,2R)-1-[bis(t-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid: to rel-(1R,2R)-1-[bis(t-butoxycarbonyl) Add 85% KOH (126 mg, 1.92 mmol) to a solution of methylamino-2-phenylcyclopropanecarboxylate (150 mg, 0.383 mmol) in MeOH-H ₂ O (2:1, 1.5 mL) . The mixture was stirred at ambient temperature for 1.5 hours and at 70 ° C for 2 hours. The mixture was washed with Et ₂ O (twice) and acidified (pH = 3) with 1 N HCl. (Five times) residue was extracted with CHCl ₃ -MeOH. Alumina was dried over MgSO ₄ and extracts were filtered, and the filtrate was evaporated to afford a colorless gum of rel- (1R, 2R) -1- [bis (tertiary-butoxycarbonyl) amino] -2-phenyl Cyclopropanecarboxylic acid (129 mg). MS (ESI) m / z: 686.15 [M+Na] ⁺ .

Methyl rel-(1R,2R)-1-[bis(t-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylate: oxime to trimethylsulfonium oxide at ambient temperature (350 mg, 1.59 mmol NaH (63.6 mg, 60% oil solution, 63.6 mmol) was added to a suspension in DMSO (1.5 mL). After stirring for 1 hour, a solution of 2-[bis(t-butoxycarbonyl)amino]-3-phenyl acrylate (300 mg, 0.795 mmol) in DMSO ( 1.5 mL) was added to the mixture. The mixture was stirred at ambient temperature for 5 hours. The reaction was quenched by the addition of 10% citric acid. The mixture was partitioned between EtOAc and water. Washed with water (twice) and the organic layer was washed with brine, dried over MgSO _4, filtered and the filtrate was evaporated. A ruthenium column chromatography (EtOAc-hexanes, 0 to 20% EtOAc EtOAc) Methyl 2-phenylcyclopropanecarboxylate (150 mg, 48.2%). MS (ESI) m / z: 414.05 [M+Na] ⁺ .

Example 1.7.8

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-5-methylbenzenesulfonate (1:1): in a manner similar to Example 1.7.7, by rel -[(1R,2S)-1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl) The desired compound (143 mg, 61.6%) was synthesized from the decyl]carbonyl}-2-phenylcyclopropyl]carbamic acid tert-butyl ester (283 mg). MS (ESI) m / z: 446.2 [M+H] ⁺ .

Rel-[(1R,2S)-1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl) Tertyl]carbonyl}-2-phenylcyclopropyl]carbamic acid tert- butyl ester: in a manner similar to the example 1.7.7, by rel-(1R, 2S)-1-[(third butoxide) The desired compound (238 mg, 78.1%) was synthesized from carbonyl)amino]-2-phenylcyclopropanecarboxylic acid (150 mg). MS (ESI) m / z: 564.20 [M + H] +.

Rel-(1R,2S)-1-[(Tertidinoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid: in a manner similar to Example 1.7.7, by rel-(IR, 2S)-1 -[(T-Butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid ethyl ester (1.21 g). MS (ESI) m / z: 300.11 [M+H] ⁺ .

Example 1.7.9

3-(5-(2-Amino-1-methoxy-3-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((4-Methylthiazol-2-yl)methyl)benzamide amine oxalate: 2-benzyl-3-methoxy-1-[] treated with 4 N HCl / EtOAc at ambient temperature 2-(3-{Methyl[(4-methylthiazol-2-yl)methyl]aminemethanyl}benzhydryl)indenyl]-1-yloxypropan-2-ylaminocarboxylic acid The third butyl ester (40 mg, 0.069 mmol) was 1 hour. The reaction mixture was evaporated and washed with saturated aqueous NaHCO _3, extracted with EtOAc, washed with brine, dried over MgSO _4, then evaporated. The residue was dissolved in diethyl ether. To the solution, oxalic acid (6.2 mg, 0.069 mmol) was added, and the obtained solid was collected, washed with diethyl ether, and then dried in vacuo to give 3-[5-(2-amino- 1-methoxy-3-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methylthiazol-2-yl) )methyl]benzamide amine oxalate (30 mg, 76%). MS (ESI) m / z: 478.2 [M+H] ⁺ .

1-methoxy-2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl))aminomethyl)phenyl)-1,3,4-oxadiazole 3-butyl)-3-phenylpropan-2-ylaminocarboxylic acid tert- butyl ester: 3-methoxy-1-[2-(3-{methyl[(4-methylthiazole-2) -yl)methyl]aminocarbamoyl}benzhydryl)hydrazino]-1-oxoylpropan-2-ylcarbamic acid 2-benzyl ester (130 mg, 0.22 mmol) dissolved in CH ₂ Cl _{In 2} (2.6 mL), Burgess reagent (156 mg, 0.655 mmol) was then added to the solution. Was heated under microwave conditions (130 ℃, 20 min) the mixture was then diluted with CHCl ₃ The reaction was washed with water and brine, then dried over MgSO ₄ and evaporated. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) Methyl decyl}phenyl)-1,3,4-oxadiazol-2-yl]-3-phenylpropan-2-ylcarbamic acid tert-butyl ester (90 mg, 71%). MS (ESI) m / z: 600.2 [M+Na] ⁺ .

2-benzyl-3-methoxy-1- (2- (3- (methyl ((4-methyl-thiazol-2-yl) methyl) carbamoyl acyl) benzoyl) hydrazino -1-Lideoxypropan-2-ylcarbamate: to 2-benzyl-2-( t- butoxycarbonylamino)-3-methoxypropionic acid (180 mg, 0.58 mmol) Add 3-(indolylcarbonyl)-N-methyl-N-[(4-methylthiazol-2-yl)methyl]benzamide (212.5 mg, 0.7) to a solution in DMF (1.8 ml) Methyl), EDC (134 mg, 0.7 mmol) and HOBt (78.6 mg, 0.58 mmol), then stirred overnight at ambient temperature. After addition of water, the mixture was extracted with EtOAc, washed with brine, then dried over MgSO _4. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) Methyl]aminomethylmercapto}benzylidene)indenyl]-1-teroxypropan-2-ylaminocarbamic acid tert-butyl ester (130 mg, 38%). ¹ H-NMR (400 MHz, CDCl ₃ ) 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).

2-Benzyl-2-(t-butoxycarbonylamino)-3-methoxypropionic acid: 2-benzyl-2-(t-butoxycarbonylamino)-3-methoxy A solution of methyl propionate (270 mg, 0.84 mmol) in MeOH (EtOAc) (EtOAc) MeOH and evaporated, extracted with EtOAc and washed with diethyl ether the aqueous solution was acidified with aqueous KHSO _4, the organic phase was washed with brine, dried over MgSO ₄ and evaporated to give 2-benzyl-2- (tertiary-butoxycarbonyl group )-3-methoxypropionic acid (200 mg, 77%). ¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Methyl 2-benzyl-2-(t-butoxycarbonylamino)-3-methoxypropanoate: 2-benzyl-2-(t-butoxycarbonylamino) stirred at ambient temperature Methyl 3-hydroxypropionate (270 mg, 0.87 mmol), methyl trifluoromethanesulfonate (573 mg, 3.5 mmol) and 2,6-di-t-butyl-4-methylpyridine (789 mg, A mixture of 3.8 mmol) in DCE (2.7 ml) was taken overnight. With a saturated aqueous KHSO ₄ solution was quenched, extracted with EtOAc, washed with saturated aqueous NaHCO ₃ dried with brine, and dried over MgSO _4. Purify by column chromatography (0 to 30% EtOAc / hexanes) toield toield of 2-phenylmethyl-2-(t-butoxycarbonylamino)-3-methoxypropanoic acid as a colorless oil. Methyl ester (200 mg, 71%). MS (ESI) m / z: 224.15 [M-Boc+2H] ⁺ .

Example 1.7.10

(3-(5-(rel-(1S,2R)-1-amino-2-phenylcyclobutyl)-1,3,4-oxadiazol-2-yl)-N-methyl-N -((4-Methylthiazol-2-yl)methyl)benzamideamine hydrochloride: rel-(1S,2R)-1-[5-() was treated with 4 N HCl / EtOAc at ambient temperature. 3-{Methyl[(4-methylthiazol-2-yl)methyl]aminemethanyl}phenyl)-1,3,4-oxadiazol-2-yl]-2-phenylcyclobutane D-butyl carbamic acid (180 mg, 0.32 mmol) was taken for 3 h then evaporated to dryness. The residue was washed with diethyl ether then dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4-oxadiazol-2-yl}-N-methyl-N-[(4-methylthiazol-2-yl)methyl]benzamideamine hydrochloride. MS (ESI) m / z: 460.1 [M + H] +.

Rel-(1S,2R)-1-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)) amino)phenyl)phenyl)-1,3,4- Tert -butyl 2-oxazol-2-yl)-2-phenylcyclobutylcarbamate: in a similar manner to Example 1.7.9, from (1S, 2R)-1-[2-(3-{A Benzyl [(4-methylthiazol-2-yl)methyl]amine-carbamoyl}benzhydryl)hydrazinecarbonyl]-2-phenylcyclobutylcarbamic acid tert-butyl ester (230 mg, 0.4 mmol The desired compound was synthesized (190 mg, 85%). MS (ESI) m / z: 560.15 [M+H] ⁺ .

Rel-(1S,2R)-1-(2-(3-(methyl((4-methylthiazol-2-yl)methyl))aminomethyl)benzhydryl)indolylcarbonyl)-2- Tert-butyl phenylcyclobutylaminocarbamate: to rel-(1S,2R)-1-(t-butoxycarbonylamino)-2-phenylcyclobutanecarboxylic acid (200 mg, 0.69 mmol) Add 3-(indolylcarbonyl)-N-methyl-N-[(4-methylthiazol-2-yl)methyl]benzamide (313 mg, 1 mmol) to a solution in DMF (2 ml) EDC (197 mg, 1 mmol) and HOBt (93 mg, 0.69 mmol) were then stirred overnight at ambient temperature. After addition of water, the mixture was extracted with EtOAc, washed with brine, then dried over MgSO _4. The crude material was purified by silica gel column chromatography to afford </RTI></RTI><RTIgt;</RTI></RTI></RTI></RTI><RTIgt; Methyl hydrazide} benzhydryl) hydrazinocarbonyl]-2-phenylcyclobutylcarbamic acid tert-butyl ester (230 mg, 58%). MS (ESI) m / z: 578.15 [M+H] ⁺ .

Example 1.7.11

3-{5-[rel-(1R,2R)-1-amino-2-phenylcyclobutyl]-1,3,4-oxadiazol-2-yl}-N-methyl-N- [(4-Methylthiazol-2-yl)methyl]benzamide: by rel-(1R,2R)-1-[5-(3-(A), similar to the method of Example 1.7.10 [[4-methylthiazol-2-yl)methyl]amine-methylmethyl}phenyl)-1,3,4-oxadiazol-2-yl]-2-phenylcyclobutylaminocarboxylic acid tert-butyl ester (390 mg, 0.7 mmol) to synthesize the desired compound (220 mg, 64%) MS (ESI) m / z:. 460.1 [m + H] +.

Rel-(1R,2R)-1-[5-(3-{methyl[(4-methylthiazol-2-yl)methyl]aminemethanyl}phenyl)-1,3,4-oxa Tert-butyl 2-oxazol-2-yl]-2-phenylcyclobutylcarbamate: in a similar manner to Example 1.7.9, by rel-(1R, 2R)-1-[2-(3- {methyl[(4-methylthiazol-2-yl)methyl]amine-carbamoyl}benzhydryl)hydrazinocarbonyl]-2-phenylcyclobutylcarbamic acid tert-butyl ester (230 mg, 0.4 mmol) of the desired compound (390 mg, 81%). MS (ESI) m / z: 560.15 [M+H] ⁺ .

Rel-(1R,2R)-1-(2-(3-(methyl((4-methylthiazol-2-yl)methyl))aminomethyl)benzhydryl)indolecarbonyl)-2- Tert-butyl phenylcyclobutylcarbamate: to rel-(1R,2R)-1-( t- butoxycarbonylamino)-2-phenylcyclobutanecarboxylic acid (300 mg, 1 mmol) Add 3-(indolylcarbonyl)-N-methyl-N-[(4-methylthiazol-2-yl)methyl]benzamide (470 mg, 1.5 mmol) to a solution in DMF (3 ml) EDC (296 mmol, 1.5 mmol) and HOBt (139 mg, 1 mmol) were then stirred overnight at ambient temperature. After addition of water, the mixture was extracted with EtOAc, washed with brine, then dried over MgSO _4. The crude material was purified by silica gel column chromatography to give </RTI></RTI><RTIgt;</RTI></RTI><RTIgt; Methyl hydrazide} benzhydryl) hydrazinocarbonyl]-2-phenylcyclobutylcarbamic acid tert-butyl ester (500 mg, 84%). MS (ESI) m / z: 578.15 [M+H] ⁺ .

Example 1.7.12

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 amine oxalate (1:1): to a stirred 3-{5-[( 4E)-2-Amino-1,5-diphenylpent-4-en-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( To a solution of 4-methyl-1,3-thiazol-2-yl)methyl]benzamide (90 mg, 0.16 mmol) in Et ₂ O was added oxalic acid (14 mg, 0.16 mmol). The precipitate formed was filtered off, washed with ₂ O Et, and dried in vacuo to give a colorless solid of 3- {5 - [(4E) -2- amino-1,5-diphenyl-pent -4 -en-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl] Benzamide amine oxalate (1:1) (0.077 g, 75%). MS (ESI) m / z: 495[M+H] ⁺ .

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: to {(4E)-2-[5-(3-{methyl[(4) -methyl-1,3-thiazol-2-yl)methyl]amine-methylmethyl}phenyl)-1,3,4-oxadiazol-2-yl]-1,5-diphenylpentane- A solution of 4 M hydrochloric acid in dioxane (5 mL) was added to &lt;RTI ID=0.0&gt;&gt; After stirring overnight, the reaction mixture was poured into saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO _4, filtered and concentrated in vacuo to give a colorless oil of the title compound (481 mg, quantitative). MS (APCI/ESI) m/z: 550 [M+H] ⁺ .

{(4E)-2-[5-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}phenyl)-1,3,4 - oxadiazol-2-yl]-1,5-diphenylpent-4-en-2-yl}carbamic acid tert-butyl ester: by way similar to the example 1.7.9, by {(4E -2-Benzyl-1-[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl)hydrazine The title compound (0.510 g, 86%) was obtained. MS (APCI/ESI) m/z: m/z 648 [MH] ^- .

{(4E)-2-Benzyl-1-[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethano}benzamide] Tert-butyl]-1-oxo-5-phenylpent-4-en-2-yl}carbamic acid tert-butyl ester: to a stirred N-( t- butoxycarbonyl)-α- Add hexafluorophosphate O-(7-) to a solution of [(2E)-3-phenylprop-2-en-1-yl]phenylalanine (0.370 g, 0.970 mmol) in CH ₂ Cl ₂ (5 mL) Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl (HATU) (0.443 g, 1.17 mmol) and iPr ₂ NEt (0.24 mL, 1.36 mmol). The mixture was stirred for 15 minutes and 3-(decylcarbonyl)-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide was added (0.443 g, 1.46 Mm). After stirring overnight, the reaction mixture was poured with water andEtOAc. The organic layer was washed successively with brine and aqueous saturated NaHCO _3, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo to give a colorless oil of {(4E) -2- phenyl-1- [2- ( 3-{Methyl[(4-methyl-1,3-thiazol-2-yl)methyl]amine-methylmethyl}benzhydryl)indenyl]-1-yloxy-5-phenylpentyl T-butyl 4--4-en-2-ylcarbamate (0.610 g, 94%). MS (APCI/ESI) m/z: 690 [M+Na] ⁺ .

N-(Tertidinoxycarbonyl)-α-[(2E)-3-phenylprop-2-en-1-yl]phenylalanine: to a stirred N-(t-butoxycarbonyl)-α- A solution of [(2E)-3-phenylprop-2-en-1-yl]phenylalanine ethyl ester (0.395 g, 0.965 mmol. After stirring at 50 ° C for 3 days, the reaction mixture was concentrated in vacuo. A 1 M aqueous HCl solution was added and the mixture was evaporated. The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAcHHHHHH Propi-2-en-1-yl]phenylalanine (0.370 g, 100%). MS (APCI/ESI) m/z: 380 [MH] ^- .

N-(Tertidinoxycarbonyl)-α-[(2E)-3-phenylprop-2-en-1-yl]ethyl phenylalanine: to a stirred α-[(2E)-3-benzene To a solution of ethyl propyl-2-en-1-yl phenylalanine (0.750 g, 1.02 mmol) in dioxane (5 mL) was added Boc ₂ O (0.635 g, 2.91 mmol). After stirring at 50 ° C for 1 day, the reaction mixture was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) Ethyl phenylprop-2-en-1-yl]phenylalanine (0.400 g, 40%). MS (ESI) m / z: 410 [M+H] ⁺ .

Ethyl α-[(2E)-3-phenylprop-2-en-1-yl]phenylalanine: To a stirred (E)-N-(4-chlorobenzylidene)-L-phenylalanine Add ethyl ester (4.00 g, 12.7 mmol) in MeCN (100 mL). [(1E)-3-bromoprop-1-en-1-yl]benzene (3.12 g, 15.8 mmol), K ₂ CO ₃ (4.38 g, 31.7 mmol) and tetrabutylammonium bromide (0.408 g, 1.27 mmol). After stirring 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 sequentially with water and brine. And concentrated in vacuo organic layer was dried over anhydrous Na ₂ SO _4. The residue was dissolved in THF (40 mL) EtOAc (EtOAc) After stirring for 1 hour, the aqueous layer was washed with Et ₂ O, neutralized and extracted with CH _{2 2} Cl. And concentrated in vacuo organic layer was dried over anhydrous Na ₂ SO _4. The residue was purified by EtOAc EtOAc (EtOAcEtOAcEtOAcEtOAc Ethyl phenylalanine (0.750 g, 19%). MS (APCI/ESI) m/z: 310 [M+H] ⁺ .

Example 1.7.13

3-[5-(2-Amino-1,5-diphenylpentan-2-yl)-1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4 -methyl-1,3-thiazol-2-yl)methyl]benzamide oxalate (1:1): 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-thiazole A solution of 2-yl)methyl]benzamide (0.100 g, 0.331 mmol) in EtOH (10 mL) was passed through H-Cube (registered trade) reactor (Pd/C CatCart; 1.0 mL/min; Atmospheric pressure H ₂ ; room temperature). The solution was concentrated in vacuo and purified by column chromatography (MeOH / CHCl ₃ 1:99 to 10:90). The residue was dissolved in Et ₂ O and acetic acid (0.016 g, 0.178 mmol). The precipitate formed was filtered off, washed with ₂ O Et, and dried in vacuo to give a colorless solid of 3- [5- (1,5-diphenyl-2-amino-2-yl) - 1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide amine oxalate (1:1) (0.072 g, 62%). MS (ESI) m/z: 552 [MH] ^- .

Example 1.7.14

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 amine oxalate (1:1): to {2-[5-(3-{methyl[(4-methyl) -1,3-thiazol-2-yl)methyl]amine-methylmethyl}phenyl)-1,3,4-oxadiazol-2-yl]-1,3-diphenylpropan-2-yl A solution of 4 M hydrochloric acid in dioxane (5 mL) was added to the tributyl succinate (0.240 g, 0.385 mmol). After stirring overnight, the reaction mixture was poured into saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ dried and concentrated in vacuo. The residue was dissolved in Et ₂ O and oxalic acid (0.035 g, 0.39 mmol) was then. The precipitate formed was filtered off, washed with ₂ O Et, and dried in vacuo to give a colorless solid of 3- [5- (1,3-diphenyl-2-amino-2-yl) - 1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide amine oxalate (1:1) (0.180 g, 76%). MS (ESI) m / z: 524[M+H] ⁺ .

{2-[5-(3-{Methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}phenyl)-1,3,4-oxadiazole Tert-butyl 2-yl]-1,3-diphenylpropan-2-yl}carbamate: by way of a similar procedure to Example 1.7.9, from {2-benzyl-1-[2 -(3-{Methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanoyl}benzhydryl)indenyl]-1-oxo-3-benzene The title compound (0.241 g, 98%) was obtained. MS (APCI/ESI) m/z: 622 [MH] ^- .

{2-Benzyl-1-[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzylidene) fluorenyl Tert-butyl 3-oxo-3-phenylpropan-2-yl}carbazate: to a stirred α-benzyl-N-( t -butoxycarbonyl)phenylalanine (0.240 g) , 0.675 mmol) in CH ₂ Cl ₂ (5 mL) was added HATU (0.333 g, 0.878 mmol) and _{iPr 2 NEt (0.18 mL, 1.01} mmol). The reaction mixture was stirred for 15 min and 3-(decylcarbonyl)-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide (0.267 g, 0.877 mmol). After stirring overnight, the reaction mixture was poured into water, extracted with EtOAc and washed successively with saturated aqueous NaHCO ₃ and brine. Dried over anhydrous Na ₂ SO _4, and the organic layer was concentrated in vacuo to afford {2-benzyl-a pale yellow oil of 1- [2- (3- {methyl [(4-methyl-1, 3-thiazol-2-yl)methyl]amine-methylmethyl}benzhydryl)indenyl]-1-oxo-3-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester (0.254 g, 59%). MS (APCI/ESI) m/z: m/z 640 [MH] ^- .

Example 1.7.15

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]benzimidamide oxalate (1:1): to rel-{(1R, 2R)-1-[5-( 3-{Methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanoyl}phenyl)-1,3,4-oxadiazol-2-yl]-2 To a solution of tert-butyl phenylcyclopentyl}aminocarbamate (0.214 g, 0.362 mmol) was added 4 M hydrochloric acid in dioxane (5 mL). After stirring overnight, the reaction mixture was poured into saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ dried and concentrated in vacuo. The residue was dissolved in Et ₂ O and oxalic acid (0.033 g, 0.36 mmol) was then. The precipitate formed was filtered off, washed with ₂ O Et, and dried in vacuo to give a beige solid of rel-3- {5 - [( 1R, 2R) -1- amino-2-phenyl-cyclopentyl -1,3,4-oxadiazol-2-yl}-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide Diacid salt (1:1) (0.190 g, 93%). MS (ESI) m / z: 474 [M+H] ⁺ .

Rel-{(1R,2R)-1-[5-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}phenyl)-1 , 3,4-oxadiazol-2-yl]-2-phenylcyclopentyl}aminocarboxylic acid tert-butyl ester: in a manner similar to that of Example 1.7.9, by rel-[(1R, 2R)- 1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl)indolyl]carbonyl}-2- The title compound (0.214 g, 82%) was obtained. MS (APCI/ESI) m/z: 4574 [M+H] ⁺ .

Rel-[(1R,2R)-1-{[2-(3-{methyl[(4-methyl-1,3-thiazol-2-yl)methyl]aminemethanyl}benzhydryl) Tertyl]carbonyl}-2-phenylcyclopentyl]aminocarboxylic acid tert-butyl ester : to a stirred rel-(1R,2R)-1-[(t-butoxycarbonyl)amino]-2 Add HATU (0.224 g, 0.589 mmol) and _{iPr 2 NEt (0.13 mL, 0.74} mmol) (3 mL) solution of phenyl ₂ Cl ₂ cyclopentanecarboxylic acid (0.150 g, 0.491 mmol) in CH -. The reaction mixture was stirred for 15 minutes and 3-(decylcarbonyl)-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide (0.224 g, 0.687 mmol). After stirring overnight, the reaction mixture was poured into water, extracted with EtOAc and washed successively with saturated aqueous NaHCO ₃ and brine. Concentrated in vacuo and the organic layer was dried over anhydrous Na ₂ SO _4, to give a pale yellow oil of rel - [(1R, 2R) -1 - {[2- (3- { methyl [(4-methyl -1,3-thiazol-2-yl)methyl]aminemethylmercapto}benzylidene)indenyl]carbonyl}-2-phenylcyclopentyl]aminocarboxylic acid tert-butyl ester (0.270 g, 93 %). MS (APCI/ESI) m/z: 640 [MH] ^- .

Rel-(1R,2R)-1-[(Tertidinoxycarbonyl)amino]-2-phenylcyclopentanecarboxylic acid : ethyl isocyanoacetate (2.6 mL, 23.9 mmol) in MeCN (77 mL K ₂ CO ₃ (19.8 g, 144 mmol), Bu ₄ NHSO ₄ (1.63 g, 4.79 mmol) and (1,4-dibromobutyl)benzene (6.99 g, 23.9 mmol) were added to the solution. The mixture was heated at 80 ° C until all starting electrophiles had been consumed. The reaction mixture was cooled and filtered through celite to remove insoluble solids. The solid material was washed with acetonitrile and the filtrate was evaporated. The residue was dissolved in diethyl ether and washed with water and brine, then dried over MgSO _4. The residue was purified with EtOAc EtOAc EtOAc (EtOAc)

To a solution of the product from the previous step, EtOAc (EtOAc) The reaction mixture was stirred until the starting material was completely consumed. The reaction mixture was concentrated in vacuo and EtOAc EtOAc m. After 5 minutes, Boc ₂ O (7.19 g, 32.9 mmol) was added. Was stirred at ambient temperature for 1 day, the reaction mixture was diluted and washed with KHSO ₄ solution with dichloroethane, washed with aqueous NaHCO ₃ and brine. The organic layer was dried over MgSO ₄ and the solvent evaporated to give a residue which was purified by flash column chromatography, to give a white solid by the amine protecting Boc (3.21 g).

A solution of the product from the previous step in EtOAc (EtOAc) (EtOAc) The reaction mixture was heated under reflux for 5 hours. The mixture was allowed to cool to room temperature and water (5 mL) was added. The aqueous layer was washed with dichloromethane, followed by extraction with dichloromethane and acidified with aqueous KHSO _4. The organic layer was concentrated in vacuo to give crystal crystal crystal crystal crystal crystal crystal crystals . MS (ESI) m / z: 306 [M+H] ⁺ .

Example 1.7.16

A 100 ml round bottom flask was charged with methyl 5-iodo-2-methoxybenzoate (Aldrich, 0.5 g, 1.712 mmol) and stirring. A solution of THF/MeOH (7 ml: 3 ml) was added with stirring. The resulting solution was treated with NaOH (1 M, 3.42 mL, 3.42 mmol). After stirring overnight, the solution was taken to EtOAc (1 EtOAc) (EtOAc) Separate the layers. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and EtOAc (EtOAc:EtOAc:EtOAc:

A 100 ml round bottom flask (3 times) containing 5-iodo-2-methoxybenzoic acid (0.4599 g, 1.654 mmol) and a stir bar was evacuated and backfilled with Ar. 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 ‧ H ₂ O (0.279 g, 1.819 mmol). After 1 hour, (R)-(1-mercapto-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester (0.461 g, 1.571) was added sequentially. Methyl) and DIPEA (0.867 ml, 4.96 mmol). 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 EtOAc and water and layers were separated. The organic layer was washed with water (2 times), brine (1 time) and volatiles were removed via rotary evaporation. Purification by flash chromatography, eluting with EtOAc / hexanes afforded (R)-(1-(2-(5-iodo-2-methoxybenzylidenyl) decyl)-2-methyl-1 -Phenoxy 3-phenylpropan-2-yl)carbamic acid tert-butyl ester (0.7363 g, 1.331 mmol, 80% yield).

To a 10-20 ml microwave vial was charged (R)-(1-(2-(5-iodo-2-methoxybenzylidenyl)indolyl)-2-methyl-1-oxo- T-butyl 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 emptied and backfilled with Ar (3 times). Anhydrous 1,2-dichloroethane (6 ml) was added. The vial was sealed with a lid and the contents were gently shaken to dissolve. The resulting solution was irradiated at 120 ° C for 12 minutes. After cooling to room temperature, the solution was transferred to a round bottom flask and volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc and saturated aqueous NaHCO _3. Separate the layers. The organic layer was washed with water (2 times) and brine (1 time). The volatiles were removed via rotary evaporation. Purification by flash chromatography, eluting with EtOAc / EtOAc to afford (R)-(2-(5-(5-iodo-2-methoxyphenyl)-1,3,4- T-butyl oxazol-2-yl)-1-phenylpropan-2-yl)carbamate (0.6141 g, 1.147 mmol, 86% yield).

Into a 100 ml round bottom flask was charged (R)-(2-(5-(5-iodo-2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-1- Phenylpropan-2-yl)carbamic acid tert-butyl ester (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 backfilled with Ar (3 times). Dioxane (6 ml) and water (2 ml) were combined and purified with Ar to degas, and the obtained solution was added to the flask. After stirring for 2-3 minutes, has been purified by the Ar degassed _{Et 3 N (1.599 ml, 11.47} mmol) treating the resulting dark green solution. The flask was sealed with a septum and then consolidated with an electrical tape. The mixture was purged with CO for 3 minutes with stirring, and the resulting mixture was heated to 75 ° C under stirring with CO. After stirring for 4 hours, the brown solution was allowed to cool to room temperature. Dioxane was removed via rotary evaporation. The residue was diluted with water and filtered over EtOAc. Rinse the filter pad with dilute NaOH (pH~9). The combined aqueous fractions were adjusted to pH = 4-5 with 3N HCl and a white precipitate formed. The mixture was extracted with EtOAc (1×) and the layers were separated. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganic material was filtered off, and the volatile material was removed by rotary evaporation to afford (R)-3-(5-(2-((t-butoxycarbonyl)amino)-1-phenylpropene as a white foam. 2-yl)-1,3,4-oxadiazol-2-yl)-4-methoxybenzoic acid (0.5 g, 1.103 mmol, 96% yield).

Discharge and backfill with (R)-3-(5-(2-((t-butoxycarbonyl))amino)-1-phenylpropan-2-yl)-1,3,4-oxa A 25 ml round bottom flask (3 times) of oxazol-2-yl)-4-methoxybenzoic acid (0.040 g, 0.088 mmol) and stirring. Anhydrous DCM (5 mL) was added and the solution was cooled to 0 ° C under distillation. The solution was treated with EDCI HCl (0.019 g, 0.097 mmol) and HOBT ‧ H ₂ O (0.015 g, 0.097 mmol). After 1 hour, 1-(2,5-dimethyloxazol-4-yl)-N-methylmethanamine (0.012 g, 0.088 mmol) and DIPEA (0.046 ml, 0.265 mmol). 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 EtOAc and water and layers were separated. The organic layer was washed with water (2 times), brine (1 time) and volatiles were removed via rotary evaporation. Purification by flash chromatography eluting with EtOAc / MeOH affords (R)-(2-(5-(5-((2,5-dimethyloxazol-4-yl)methyl)) Aminomethylmercapto)-2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl)carbamic acid tert-butyl ester (0.0393) g, 0.068 mmol, 77% yield).

(R)-(2-(5-(5-((2,5-dimethyloxazol-4-yl)methyl)(methyl)aminecarbamyl) is charged with Ar emptied and backfilled -2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl)carbamic acid tert-butyl ester (0.0393 g, 0.068 mmol) and A 25 ml round bottom flask with stirring bar (3 times). Anhydrous DCM (0.5 mL) was added with stirring. The resulting solution was treated with TFA (0.5 mL, large excess). After 1 hour, the volatiles were removed via rotary evaporation. The residue was partitioned between saturated aqueous NaHCO ₃ and EtOAc. After stirring for a few minutes, the layers were separated. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganic material was filtered off, and the volatile material was removed by rotary evaporation to give (R)-3-(5-(2-amino-1-phenylprop-2-yl)-1 as a viscous white solid. 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).

Example 1.7.17

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.18

The compound was synthesized in a similar manner to Example 1.7.2.

real Example 1.7.19

The compound was synthesized in a similar manner to Example 1.7.2.

Example 1.7.20

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.11

1 N NaOH (0.16 ml, 0.16 mmol, 1.5 eq.) was added to a stirred solution of EtOAc (EtOAc, EtOAc. After 3 hours, the volatiles were removed via rotary evaporation. Add 1 N HCl to pH = 5-6 to give a white precipitate. The mixture was extracted with EtOAc (1×) and the layers were separated. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics were filtered off and the volatiles were removed via rotary evaporation to afford acid (100%).

The final removal of the protecting group was carried out in a similar manner to Example 1.7.1.

Example 1.7.22

Add EDCI HCl (0.0161 g, 0.084 mmol, 1.1 eq.) and HOBT ‧ H ₂ O (0.0114 g, 0.084 mmol, 1.1 eq.) to the stirred acid (0.0473 g, 0.077 mmol, 1 eq) at 0 °C In a solution of anhydrous CH ₂ Cl ₂ (5 ml). After 1 h, MeNH ₂ ‧ HCl (Aldrich, 0.015 g, 0.23 mmol, 3 eq.) and DIPEA (0.07 ml, 0.05 g, 0.38 mmol, 5 eq. 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 / layers are separated between H ₂ O. The organic layer was washed with water (2×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography on silica gel gave 0.0365 g (0.058 mmol, 75%) of decylamine.

The final removal of the protecting group was carried out in a similar manner to Example 1.7.1.

Example 1.7.23

The compound was synthesized in a similar manner to Example 1.7.22.

Example 1.7.24

The compound was synthesized in a similar manner to Example 1.7.22.

Example 1.7.25

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.26

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.27

The compound was synthesized in a similar manner to Example 1.7.22.

Example 1.7.28

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.29

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.30

A flask (3 times) containing the starting material (0.0402 g, 0.08 mmol, 1 eq.), NaCN (0.0196 g, 0.4 mmol, 5 eq.) and stirring. Anhydrous DMSO (2.5 ml) was added and the resulting mixture was heated to 180 °C with stirring. After 5 hours, the reaction was allowed to cool to room temperature. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (3×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification by flash chromatography gave 0.0207 g (0.042 mmol, 53%).

Example 1.7.3

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.32

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.33

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.3

The compound was synthesized in a similar manner to Example 1.7.1.

Example 1.7.35

A flask containing the starting material (0.0571 g, 0.082 mmol, 1 eq.) and a stir bar (3 times) was drained and backfilled with Ar. Anhydrous DMC (0.5 ml) was added. The resulting solution was treated with HCl (4.0 M 1,4-dioxane solution, 0.5 ml, large excess) with stirring. After 1 hour, the volatiles were removed via rotary evaporation. The residue was partitioned between saturated aqueous NaHCO ₃ / and the layers were separated between EtOAc. The organic layer was washed with water (1×), brine (1×) and dried over Na ₂ SO ₄ . The inorganics are filtered off and the volatiles are removed via rotary evaporation. Purification via flash chromatography gave 0.033 g (0.061 mmol, 74%).

Example 1.7.36

The compound was synthesized in a similar manner to Example 1.7.17.

Example 1.7.37

The compound was synthesized in a similar manner to Example 1.7.17.

Example 1.7.38

The compound was synthesized in a manner similar to the method of Example 1.7.17 using methyl 5-bromo-2-methoxynicotinate (Combi-Blocks) as a starting material.

Example 1.7.39

The compound was synthesized in a manner similar to the method of Example 1.7.17 using methyl 5-bromo-2-methoxynicotinate (Combi-Blocks) as a starting material.

Example 1.7.40

The compound was synthesized in a manner similar to the method of Example 1.7.17 using methyl 5-bromo-2-methoxynicotinate (Combi-Blocks) as a starting material.

Example 1.7.11

The compound was synthesized in a manner similar to the procedure of Example 1.7.17 using 5-bromo-2-(trifluoromethoxy)benzoic acid (Combi-Blocks) as starting material.

Example 1.7.42: Synthesis of 3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5- (1-methyl-1H imidazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone

The protecting group of the Boc protected compound was removed using a procedure similar to that described in Example 1.7.2 to give the final product.

Example 1.7.4

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.44

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.5

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.46

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.77

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.48

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.49

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.7.5

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.751

{(2 R )-2-[5-(6-cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1- Benzyl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester: at 0 ° C [(2 R )-1-{2-[(6-Cyclopropyl-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine) -1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (417 mg , 0.66 mmol) CBr ₄ (437 mg, 1.32 mmol), PPh ₃ (346 mg, 1.32 mmol) and imidazole (89 mg, 1.32 mmol) in CH ₂ Cl ₂ (10 ml) and at room temperature The mixture was stirred for 2 hours. The starting molecule is completely consumed and the volatiles are evaporated to give the crude product. This material was purified by column chromatography (hexane solution of EtOAc = 0 to 100%), to give a white solid and contains a large amount of O = PPh {(2 R) -2- [3 the 5- (6- cyclopropylamino 4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4 - Tetylene oxazol-2-yl]-1-phenylpropan-2-yl}carboxylate, which was used in the next reaction without further purification. MS (ESI) m / z: 615 [M+H] ⁺ .

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-cyclopropylpyridine- 4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enate (1:1): Stirred {( 2R )-2-[5-(6-cyclopropyl-4-{[(2 R )-2-(4-methyl- 1) at room temperature , 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl} TCA (0.8 ml) was added to a solution of butyl carbamic acid ( 405 mg, 0.66 mmol) in CH ₂ Cl ₂ (0.4 ml) and the mixture was stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalents relative to free form) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield solid was collected, washed with IPE and dried under reduced pressure to give an off-white solid of (2- {5 - [(2 R) -2- amino - 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-cyclopropylpyridin-4-yl)[(2 R )-2-(4-methyl -1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enedioate (1:1) (145 mg, 35% yield, 4 steps ).

Example 1.7.5

[(2 R )-2-{5-[6-(2-Cyanophenyl)-4-{[(2 R )-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]carbamic acid tert-butyl ester: Similar to the manner of Example 1.7.51 , from [(2 R )-1-(2-{[6-(2-cyanophenyl)-4-{[(2 R )-2-(4-methyl) -1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]carbonyl}indenyl)-2-methyl-1-oxo-3-phenylpropane-2 The desired compound was synthesized from the 3-butyl carbamic acid terephthalate (194 mg, 0.281 mmol). MS (ESI) m / z: 676 [M+H] ⁺ .

2-(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[( 2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)benzonitrile (2 E )-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.51 , from [(2 R )-2-{5-[6-(2-cyanophenyl)-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl} The desired compound was synthesized from tert-butyl-1-phenylpropan-2-yl]carbamate (188 mg, 0.278 mmol). (50 mg, 26% yield, 6 steps).

Example 1.7.5

[(2 R )-2-{5-[4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third Butyl ester: in a similar manner to Example 1.7.50 , from [( 2R ) -2 -methyl-1-(2-{[4-{[(2 R )-2-(4-methyl-1) , 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]carbonyl}indenyl)-1-yloxy The desired compound was synthesized from tributyl -3-phenylpropan-2-yl]carbamate (160 mg, 0.250 mmol). (116 mg, 72% yield) MS (ESI) m / z : 642 [M + H] +.

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E ) -but-2- enedioate (1:1): in a similar manner to Example 1.7.50 , from [(2 R )-2-{5-[4-{[(2 R )-2-( 4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3, The desired compound was synthesized from tert-butyl 4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamate (116 mg, 0.180 mmol). (85 mg, 72% yield).

Example 1.7.5

{(2 R )-2-[5-(6-methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1- Benzyl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester: similar to Example 1.7. The mode of 50 , from [(2 R )-1-{2-[(6-methoxy-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl) Pyrrolidin-1-yl]carbonyl}pyridin-2-yl)carbonyl]indenyl}-2-methyl-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (292 mg, 0.469 mmol) of the desired compound. (160 mg, 56% yield) MS (ESI) m / z : 605 [M + H] +.

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enate (1:1): in a manner similar to Example 1.7.50 , from {(2 R )-2-[5-(6-methoxy-4-{[(2 R )-2-(4-) -1,3-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropane-2 The desired compound was synthesized from the butyl carbamic acid tert-butyl ester (160 mg, 0.265 mmol). (120 mg, 73% yield).

Example 1.7.5

N -(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[( 2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl) -N -methylmethanesulfonamide (2 E ) -but-2- enedioate (1:1): in a manner similar to the case of Example 1.7.50 , from {( 2R )-2-[5-(6-[methyl(methylsulfonyl)amine) -4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3, The desired compound was synthesized from the tert-butyl 4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carboxylate (117 mg, 0.172 mmol). (67 mg, 56% yield).

Example 1.7.5

4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl) -6-[Methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid: 4-(5-{( 2R )-2-[(T-butoxycarbonyl)) stirred at room temperature Amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid A solution of the ester (99 mg, 0.18 mmol) in EtOAc. The reaction was quenched with 1 M aqueous EtOAc ( 1. The mixture was evaporated to give crude 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3 as a white solid. 4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid, which was used in the next reaction without further purification.

{( 2R )-2-[5-(2-[methyl(methylsulfonyl)amino]-6-{[(2 R )-2-(4-methyl-1,3-thiazole- 2-yl)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Butyl ester: 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3 stirred at room temperature , 4-oxadiazol-2-yl)-6-[methyl(methylsulfonyl)amino]pyridine-2-carboxylic acid (96 mg, 0.18 mmol), i- Pr ₂ NEt (0.068 ml, 0.40 mmol Addition of HATU to a solution of 4-methyl-2-[( 2R )-pyrrolidin-2-yl]-1,3-thiazole (36 mg, 0.22 mmol) in CH ₂ Cl ₂ (1 ml) (82 mg, 0.22 mmol) and the mixture was stirred at the same temperature overnight. The mixture was quenched with H ₂ O and the organic layer was separated. , Saturated aqueous NaHCO ₃ and the organic layer was CHCl _{3 (3} times) and the aqueous layer was extracted with aqueous KHSO ₄ (pH ₄₎ of the combined washed with brine, dried over MgSO ₄ and evaporated to give the crude material by column chromatography (EtOAc Purification of hexane solution = 20 to 80% to give {( 2R )-2-[5-(2-[methyl(methylsulfonyl)amino]-6-{[ (2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)-1,3,4-oxadiazole-2 -yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert-butyl ester (62 mg, 50% yield). MS (ESI) m / z: 622 [M+H] ⁺ .

N -(4-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-{[(2R ) -2- (4-methyl-1,3-thiazol-2-yl) pyrrolidin-l-yl] carbonyl} pyridin-2-yl) - N - methyl-methanesulfonamide Amides (2 E) - butoxy -2-enedioic acid salt (1:1): Stirred {( 2R )-2-[5-(2-[methyl(methylsulfonyl)amino]-6- ) at room temperature {[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)-1,3,4-oxadiazole TTA (4 ml) was added to a solution of 2-butyl]-1-phenylpropan-2-yl}-carbamic acid tert-butyl ester (62 mg, 0.090 mmol) in CH ₂ Cl ₂ (2 mL) The mixture was stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalents relative to free form) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield solid was collected, washed with IPE and dried under reduced pressure to give an off-white solid of N - (4- {5 - [ (2 R) -2- amine 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-{[(2 R )-2-(4-methyl-1,3-thiazole 2-yl) pyrrolidin-l-yl] carbonyl} pyridin-2-yl) - N - methyl-methanesulfonamide Amides (2 E) - but-2-ene acid salt (1: 1) (25 mg , 40% yield).

Example 1.5.7

4-(5-{(2 R )-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl) -6-methoxypyridine-2-carboxylic acid: in a similar manner to Example 1.7.56 , from 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1- The desired compound was synthesized from methyl phenylpropan-2-yl}-1,3,4-oxadiazol-2-yl)-6-methoxypyridine-2-carboxylate (650 mg, 1.39 mmol). MS (ESI) m / z: 668[M+H] ⁺ .

{(2 R )-2-[5-(2-methoxy-6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1- Tert-butyl]carbonyl]pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid: similar to Example 1.7. Form 56 , from 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole The desired compound was synthesized from 2-yl)-6-methoxypyridine-2-carboxylic acid (630 mg, 1.39 mmol). (677 mg, 81% yield) MS (ESI) m / z : 605 [M + H] +.

(4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 2-()-[( 2R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone ( 2E )-but-2-enedioate (1:1): in a manner similar to Example 1.7.56 , by {(2 R )-2-[5-(2-methoxy-6-{[(2 R )-2-(4-A) -1,3-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropane-2 The desired compound was synthesized from the butyl carbamic acid tert-butyl ester (246 mg, 0.407 mmol). (125 mg, 50% yield).

Example 1.7.58

[(2 R )-2-{5-[4-{[(2 R )-2-(4-ethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third Butyl ester : in a similar manner to Example 1.7.56 , from 2-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}- The desired compound was synthesized from 1,3,4-oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid (120 mg, 0.244 mmol). (147 mg, 92% yield). MS (ESI) m / z: 657 [M+H] ⁺ .

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-ethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)- But-2-enicate (1:1): in a similar manner to Example 1.7.56 , from [(2 R )-2-{5-[4-{[(2 R )-2-(4) -ethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4 -Dioxazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester (147 mg, 0.244 mmol). (91 mg, 60% yield).

Example 1.7.59

[( 2R ) -2-{5-[4-{[(2 R )-2-(4-cyclopropyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}- 6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid Tributyl ester: in a manner similar to the case of Example 1.7.5 , from 2-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl} -1,3,4-oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid (120 mg, 0.244 mmol). MS (ESI) m/z: 266[M+H] ⁺ .

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-cyclopropyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2-enedioate (1:1): in a similar manner to Example 1.7.56 , from [(2 R )-2-{5-[4-{[(2 R )-2-( 4-cyclopropyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3 The desired compound was synthesized as the tert-butyl 4-oxoxadiazol-2-yl}-1-phenylpropan-2-yl]carbamate (163 mg, 0.244 mmol). (94 mg, 56% yield, 2 steps).

Example 1.7.60

[(2 R )-2-{5-[4-({(2 R )-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl) }carbonyl)-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl] Tert-butyl carbazate : in a similar manner to Example 1.7.56 , from 2-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropene- The desired compound was synthesized from 2-yl}-1,3,4-oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid (100 mg, 0.203 mmol).

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl]{( 2R )-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl}A Ketone (2E)-but-2-enedioate (1:1): in a similar manner to Example 1.7.56 , from [(2 R )-2-{5-[4-({(2 R ) -2-[4-(Methoxymethyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl}carbonyl)-6-(1,3-oxazol-2-yl)pyridine- The desired compound was synthesized from the 3-butyl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester (120 mg, 0.179 mmol). (12 mg, 10% yield, 2 steps).

Example 1.7.61

{(2 R )-2-[5-(4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2 , 3'-bipyridyl-6-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester: at room temperature Stirred {( 2R )-2-[5-(6-chloro-4-{[(2 R )-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}carbamic acid tert-butyl ester (120 mg, 0.197 mmol) Add pyridin-3-yl to a solution in toluene (1.5 ml) Acid (73 mg, 0.59 mmol), Pd ₂ (dba) ₃ (36 mg, 0.039 mmol) and SPhos (65 mg, 0.158 mol) and the mixture was irradiated at 150 ° C for 30 minutes. The starting molecule is completely consumed and the volatiles are evaporated to give the crude product. By column chromatography (hexane solution of EtOAc = 20 to 100%, followed MeOH solution of CHCl ₃ = 0 to 10%) This material was purified to give a colorless oil of {(2 R) -2- [5 -(4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2,3'-bipyridin-6-yl Tris-butyl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamate (74 mg, 58% yield). MS (ESI) m / z: 552 [M+H] ⁺ .

(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,3'-bipyridine -4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1): Stirred {( 2R )-2-[5-(4-{[(2 R )-2-(4-methyl-1,3-thiazole-2 ) at room temperature -yl)pyrrolidin-1-yl]carbonyl}-2,3'-bipyridyl-6-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl } carbamic acid tert-butyl ester (74 mg, 0.114 mmol) was added in CH ₂ Cl _{2 (2} ml) in a solution of TFA (4 ml) and the mixture was stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalents relative to free product) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield solid was collected, washed with IPE and dried under reduced pressure to give an off-white solid of (6- {5 - [(2 R) -2- amino - 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,3'-bipyridin-4-yl)[(2 R )-2-(4-A Base-1,3-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone ( 2E )-but-2-enedioate (1:1) (50 mg, 66% yield).

Example 1.7.62

{(2 R )-2-[5-(4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2 , 4'-bipyridyl-6-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester: similar to Example 1.7 .61 , by {(2 R )-2-[5-(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Tert-butyl-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (240 mg , 0.394 mmol) of the desired compound. (124 mg, 48% yield) MS (ESI) m / z : 652 [M + H] +.

(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,4'-bipyridine -4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1): in a manner similar to the case of 1.7.61 , by {(2 R )-2-[5-(4-{[(2 R )-2-(4-methyl-1,3-) Thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2,4'-bipyridin-6-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropene- The desired compound was synthesized from 2-butylaminobutyl carbamate (124 mg, 0.190 mmol). (53 mg, 42% yield).

Example 1.7.63

[(2 R )-2-{5-[4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -(pyrimidin-5-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar In the manner of Example 1.7.61 , from {(2 R )-2-[5-(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazole-2-) Pyrrolidin-1-yl]carbonyl}thiaridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl The desired compound was synthesized from the ester (200 mg, 0.328 mmol). (180 mg, 84% yield) MS (ESI) m / z : 597 [M- t -Bu + H] +.

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrimidine-5- Pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.61 , from [(2 R )-2-{5-[4-{[(2 R )-2-(4-methyl-1) , 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(pyrimidin-5-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}- The desired compound was synthesized from tert-butyl 1-phenylpropan-2-yl]carbamate (180 mg, 0.276 mmol). (104 mg, 47% yield).

Example 1.7.64

{(2 R )-2-[5-(6-methyl-4-{[(2 R )-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}aminocarboxylic acid tert- butyl ester: similar to the example 1.7.61 By the way {(2 R )-2-[5-(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-butyl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (150 mg, 0.246 Mmol) Synthesis of the desired compound. (144 mg, 99% yield) MS (ESI) m / z : 589 [M- t -Bu + H] +.

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methylpyridine-4 -yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1 :1): in a manner similar to the case of 1.7.61 , by {(2 R )-2-[5-(6-methyl-4-{[(2 R )-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} The desired compound was synthesized from tert-butyl carbamic acid (144 mg, 0.245 mmol). (54 mg, 37% yield).

Example 1.7.65

[ (2 R )-2-{5-[6-(1,1-Dioxylyl-1,2-thiazolidin-2-yl)-4-{[(2 R )-2-(4- Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropene- 3-butyl]aminobutyl carboxylic acid tert-butyl ester: Stirred {( 2R )-2-[5-(6-chloro-4-{[(2 R )-2-(4-) at room temperature Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropene- Add 2-, thiazolidine-1,1-dioxide (90 mg, 0.74) to a solution of 2-butylaminobutyl carbamate (150 mg, 0.246 mmol) in dioxane (3 ml) Methyl), Pd ₂ (dba) ₃ (113 mg, 0.12 mmol), Xantphos (214 mg, 0.37 mmol) and K ₃ PO ₄ (157 mg, 0.74 mmol) and the mixture was irradiated with microwaves at 150 ° C for 30 minutes. Complete consumption of the starting molecule and the volatiles evaporated to give the crude material was purified by column chromatography (hexane-EtOAc = solution of 20 to 100%) to give a colorless oil of [(2 R) -2- { 5-[6-(1,1-Dioxylyl-1,2-thiazolidin-2-yl)-4-{[(2 R )-2-(4-methyl-1,3-thiazole- 2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third Butyl ester (144 mg, 84% yield). MS (ESI) m / z: 694[M+H] ⁺ .

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,1- Dioxylyl-1,2-thiazolidin-2-yl)pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]methanone (2E)-but-2-enedioate (1:1): stirred [(2 R )-2-{5-[6-(1,1- ) at room temperature Dioxyl-1,2-thiazolidin-2-yl)-4-{[(2 R )-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]carbamic acid tert-butyl ester (144 mg, 0.208 mmol) TFA (4 ml) was added to a solution of CH ₂ Cl ₂ (2 ml) and the mixture was stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalent to the free amine) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield a solid, was collected and washed with IPE and dried under reduced pressure to give an off-white solid of [2- {5 - [(2 R) -2- amino - 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,1-dioxoindol-1,2-thiazolidin-2-yl)pyridine 4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enedioic acid Salt (84 mg, 57% yield).

Example 1.7.6

{( 2R )-2-[5-(6-[(methylsulfonyl)amino]-4-{[(2 R )-2-(4-methyl-1,3-thiazole-2- Tert-butyl pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid : in a manner similar to Example 1.7.65 , from {( 2R )-2-[5-(6-chloro-4-{[(2 R )-2-(4-methyl-1,3-thiazole) -2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Tributyl acrylate (150 mg, 0.246 mmol) was synthesized as the desired compound. (112 mg, 68% yield) MS (ESI) m / z : 668 [M + H] +.

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-yl]carbonyl}pyridin-2-yl)methanesulfonamide (2E)-but-2-enedioic acid Salt (1:1): in a manner similar to Example 1.7.65 , from {( 2R )-2-[5-(6-[(methylsulfonyl)amino]-4-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl] The desired compound was synthesized from tert-butyl 1-phenylpropan-2-yl}carbamate (112 mg, 0.168 mmol). (51 mg, 45% yield).

Example 1.7.67

{(2 R )-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]-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: at room temperature To the stirred {( 2R )-2-[5-(2-methoxy-6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Triacyl-1-yl]carbonyl}pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid in CCl ₄ NBS (94 mg) was added to the solution in (1.32 ml) and the mixture was stirred at 70 ° C for 1 hour. The starting molecule was completely consumed and the volatiles were evaporated. Column chromatography (EtOAc hexanes = 0 to 66) %) Purification of the obtained crude material to give (( 2R )-2-[5-(2-{[(2 R )-2-(5-bromo-4-methyl-1,3) as a colorless oil. -thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropene- 2-Base} tert-butyl carbamic acid (222 mg, 74% yield) which was used immediately in the next reaction.

{(2 R )-2-[5-(2-{[(2 R )-2-(4,5-Dimethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) }-6-Methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester: at room temperature Down-mixed {(2 R )-2-[5-(2-{[(2 R )-2-(5-bromo-4-methyl-1,3-thiazol-2-yl)pyrrolidine) -1-yl]carbonyl}-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid To a solution of butyl ester (111 mg, 0.162 mmol) in toluene (1.39 ml), trimethylborane (102 mg, 0.81 mmol), Pd ₂ (dba) ₃ (74 mg, 0.081 mmol), SPhos (133 mg, 0.33 mmol) and _{3 PO 4 (103 mg, 0.49} mmol) and the mixture was stirred at 110 ℃ 30 K min. Complete consumption of the starting molecule and the volatiles evaporated to give the crude material was purified by column chromatography (hexane-EtOAc = solution of 10 to 80%) to give a colorless oil of {(2 R) -2- [ 5-(2-{[(2 R )-2-(4,5-Dimethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-methoxypyridine- 4-Bisyl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (98 mg, 98% yield). MS (ESI) m / z: 620 [M+H] ⁺ .

(4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 2-()-[( 2R )-2-(4,5-dimethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Acid salt (1:1): Stirred {( 2R )-2-[5-(2-{[(2 R )-2-(4,5-dimethyl-1, 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropane 2-yl} carbamic acid tert-butyl ester (98 mg, 0.158 mmol) was added TFA (1.3 ml) in CH ₂ Cl ₂ (2.7 ml) was and stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalent to the free amine) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield solid was collected, washed with IPE and dried under reduced pressure to give an off-white solid of (4- {5 - [(2 R) -2- amino - 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridin-2-yl)[(2 R )-2-(4,5- Dimethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone ( 2E )-but-2-enedioate (1:1) (56 mg, 56% yield) .

Example 1.7.6

[(2 R )-2-{5-[2-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -(1,3-oxazol-2-yl)pyridin-4-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third Butyl ester: A solution of 1,3-oxazole (0.19 ml, 2.88 mmol) in THF (3 ml) was placed in a container and placed under reduced pressure at -78 ° C for 30 minutes to remove dissolved O _{2 in} THF. To the stirred oxazole/THF solution, n-BuLi (1.6 M hexane solution, 1.08 ml, 1.72 mmol) was added at -78 ° C and the mixture was stirred at the same temperature for 1 hour. ZnCl ₂ (1.0 M in THF, 1.72 ml, 1.72 mmol) was added to the mixture, which was warmed to 0 ° C and stirred at this temperature for 15 min. To this stirred solution was added 4-(5-{( 2R )-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-trifluoromethanesulfonate- 1,3,4-oxadiazol-2-yl)-6-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl Pyridin-2-yl ester (208 mg, 0.288 mmol) in THF (0.5 ml, freshly opened without degassing) and Pd(PPh ₃ ) ₄ (333 mg, 0.288 mmol) and heated at 80 ° C 1 hour. Complete consumption of the starting molecule and quenched with MeOH and the volatiles evaporated to give the crude material was purified by column chromatography (hexane-EtOAc = solution of 20 to 100%) to afford contain some byproducts of [(2 R) -2-{5-[2-{[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3 - oxazol-2-yl)pyridin-4-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester, which is not After further purification, it was used in the next reaction.

[4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-2-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)- But-2-enedioate (1:1): Stirred [( 2R )-2-{5-[2-{[(2 R )-2-(4-methyl ) at room temperature -1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1,3-oxazol-2-yl)pyridin-4-yl]-1,3,4-oxo Add TFA (1 ml) to a solution of tert-butyl oxazol-2-yl}-1-phenylpropan-2-yl]carbamate (184 mg, 0.287 mmol) in CH ₂ Cl ₂ (2 mL) The mixture was stirred for 1 hour. The volatiles were evaporated and the residue was purified mpjjjjjjjj This material was dissolved in EtOH (1 ml) and fumaric acid (1 equivalent to the free amine) was added. The mixture was stirred at room temperature for one hour and the EtOH was evaporated to yield a solid, was collected and washed with IPE and dried under reduced pressure to give an off-white solid of [4- {5 - [(2 R) -2- amino - 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3-oxazol-2-yl)pyridin-2-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enedioate (1:1) (97 mg , 51% yield).

Example 1.7.69

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]carbonyl}-6-( 2-sided oxypyrrolidin-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl Ester: in a similar manner to Example 1.7.51 , from [(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-) Thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-yloxy-3 -Phenylpropan-2-yl]carbamic acid tert-butyl ester to synthesize the desired compound (56 mg, 99%).

1-(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-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.51 , from [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3) -thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl)pyridin-2-yl]-1,3,4-oxadiazole-2 The desired compound (30 mg, 52% yield) was obtained from m.p.-l-phenylpropan-2-yl]carbamic acid.

Example 1.7.70

[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-( 2-sided oxy-1,3-1,3-oxazolidin-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl] Tert- butyl carbazate : in a similar manner to Example 1.7.51 , from [(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-A) -1,3-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxy-1,3-oxazolidin-3-yl)pyridin-2-yl]carbonyl The desired compound (27 mg, 99%) was synthesized from the decyl-l-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester.

3- (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-yl]carbonyl}pyridin-2-yl)-1,3-oxazolidin-2-one (2E) -but-2- enedioate (1:1): in a similar manner to Example 1.7.51, from [(2R)-2-{5-[4-{[(2R)-2-(4- Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxy-1,3-oxazolidine-3-yl)pyridin-2-yl] -1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester The desired compound (13 mg, 47% yield).

Example 1.7.11

[(2R)-2-{5-[6-(2-methyl-5-oxooxypyrrolidin-1-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]amine Tert- butyl carboxylic acid: in a manner similar to the example 1.7.51 , from [(2R)-2-methyl-1-(2-{[6-(2-methyl-5- oxoxypyrrolidine ) -1-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]carbonyl}肼The desired compound (86 mg, 79% yield) was obtained from the title compound. MS (ESI) m / z: 672[M+H] ⁺ .

1-(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-yl]carbonyl} pyridin-2-yl)-5-methylpyrrolidin-2-one (2E)- But-2- enicate (1:1): in a similar manner to Example 1.7.A1 Ex A9, from [(2R)-2-{5-[6-(2-methyl-5-side oxygen) Pyryryryl-1-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]carbamic acid tert-butyl ester The desired compound (15 mg, 26% yield).

Example 1.7.12

[(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]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl Ester: in a similar manner to Example 1.7.51 , from [(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-) Thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-oxopiperidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-yloxy-3 -Phenylpropan-2-yl]carbamic acid tert-butyl ester to synthesize the desired compound (134 mg, 71% yield). MS (ESI) m / z: 672[M+H] ⁺ .

1-(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-yl]carbonyl}pyridin-2-yl)piperidin-2-one (2E)-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.51 , from [(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]-1,3,4-oxadiazole-2 The desired compound (8.4 mg, 6.1% yield) was obtained from the title compound.

Example 1.7.73

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-yl]carbonyl}pyridin-2-yl)-N-methylacetamide (2E)-butyl-2 - enedic acid salt (1:1): at { ° C to {(2R)-2-[5-(6-[ethyl)amino(methyl)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- phenyl propan-2-yl} carbamic acid tert-butyl ester (126 mg, 0.20 mmol) in CH added TFA (1.5 ml, 19 mmol) 2 Cl 2 (0.7 mL) in the solution, and at room temperature The mixture was stirred for 3 hours. All solvents were azeotroped with toluene. Using column chromatography (silicon dioxide _{NH-, EtOH / CHCl 3 = 1:} 99) The residue was purified to give the desired compound 60 mg of a colorless oil. The compound (60 mg) was coagulated with fumaric acid to give N-(6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1 as a white powder. ,3,4-oxadiazol-2-yl}-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine 2-yl)-N-methylacetamide (2E)-but-2-enedioate (1:1) (45 mg, 35% yield).

Example 1.7.74

1-(4-{5-[(2R)-2-amino-1-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)pyrrolidin-2-one (2E)-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[2-{[(2R)-2-(4-methyl-1,3) -thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2-o-oxypyrrolidin-1-yl)pyridin-4-yl]-1,3,4-oxadiazole-2 The desired compound (60 mg, 19% yield) was obtained as a white powder.

Example 1.7.55

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-1,2 ,4-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E )-but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(2R)-2-(4) -methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1H-1,2,4-triazol-1-yl)pyridin-2-yl]-1 , 3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester The desired compound (40 mg, 100% yield) was obtained as white powder.

Example 1.7.76

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-imidazole-1 -yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Diacid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[6-(1H-imidazol-1-yl)-4-{[(2R) -2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}- The desired compound (21 mg, 34% yield) was obtained as a beige powder.

Example 1.7.77

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-pyrazole- 1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2- Olelic acid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1, 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1H-pyrazol-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl The desired compound (74 mg, 50% yield) was obtained as a white powder.

Example 1.7.78

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(2H-1,2 ,3-triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E )-but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(2R)-2-(4) -methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]-1 , 3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester The desired compound (38 mg, 43% yield) was obtained as white powder.

Example 1.7.79

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-1,2 ,3-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E )-but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(2R)-2-(4) -methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(1H-1,2,3-triazol-1-yl)pyridin-2-yl]-1 , 3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester The desired compound (73 mg, 62% yield).

Example 1.7.80

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[6-(1-methyl-1H-pyrazole- 4-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3 The desired compound (115 mg, 55% yield) was obtained as a pale yellow powder.

Example 1.8.11

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[6-(1-methyl-1H-pyrazole- 5-yl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3 The desired compound (202 mg, 61% yield) was obtained as a white powder.

Example 1.7.82

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-(1,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate ( 1:1): in a manner similar to the case of Example 1.7.73 , from [(2R)-2-{5-[4-{[(4-bromo-1,3-thiazol-2-yl)methyl]( Methyl)amine-mercapto}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropane The desired compound (56 mg, 52% yield) was obtained as a white powder.

Example 1.7.83

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 6-methylpyridin-3-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1) : in a similar manner to the example 1.7.73 , from [(2R)-2-{5-[4-{methyl[(6-methylpyridin-3-yl)methyl]aminemethanyl}-6 -(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third The desired compound (56 mg, 52% yield) was obtained as a white powder.

Example 1.7.84

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[1-(1-A -1H-pyrazol-3-yl)ethyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1 ): in a manner similar to the example 1.7.73 , from [(2R)-2-{5-[4-{[1-(1-methyl-1H-pyrazol-3-yl)ethyl]amine A Mercapto}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl] The desired compound (64 mg, 77% yield) was obtained as a white powder.

Example 1.7.85

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 6-methylpyridin-2-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1) : in a similar manner to the example 1.7.73 , from [(2R)-2-{5-[4-{methyl[(6-methylpyridin-2-yl)methyl]aminemethanyl}-6 -(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid third The desired compound (75 mg, 85% yield) was obtained as a white powder.

Example 1.7.86

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 1-methyl-1H-pyrazol-4-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate ( 1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{methyl[(1-methyl-1H-pyrazol-4-yl)methyl) Aminomethyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2 The desired compound (89 mg, 76% yield) was obtained as a white powder.

Example 1.7.87

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(1,5-di) Methyl-1H-pyrazol-4-yl)methyl]-N-methyl-6-(1,3-oxazol-2-yl)isonicotinamine amide (2E)-but-2-ene Acid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(1,5-dimethyl-1H-pyrazole-4-) Methyl](methyl)aminemethanyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl} The desired compound (47 mg, 42% yield) was obtained as a white powder.

Example 1.7.88

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(1,3-di) Methyl-1H-pyrazol-5-yl)methyl]-N-methyl-6-(1,3-oxazolyl- 2-yl)isonicotinium amide (2E)-but-2-ene Acid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[4-{[(1,3-dimethyl-1H-pyrazole-5-) Methyl](methyl)aminemethanyl}-6-(1,3-oxazol-2-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl} The desired compound (97 mg, 80% yield) was obtained as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.43 (0.7H, s), 8.42 (0.3H, s), 8.27 (0.7H, s), 8.25 (1H, s), 8.19 (0.3H, s), 7.57 (1H, 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 1.7.89

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone: at 0 Down to [(2R)-2-{5-[6-(1-methyl-1H-pyrazol-3-yl)-4-{[(2R)-2-(4-methyl-1, °C) 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]amine carbamic acid tert-butyl ester (310 mg, 0.47 mmol) was added TFA (3.0 ml, 39 mmol) in CH ₂ Cl ₂ (1.0 mL) in the solution, and the mixture was stirred at room temperature for 3 hours. The volatiles were azeotroped with toluene. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc The solid was wet-milled with EtOH to give [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2 as a white powder. -yl}-6-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl) Pyrrolidin-1-yl]methanone (96 mg, 37% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ), 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

{(2R)-2-[5-(6-[(4-Methoxybenzyl)amino]-4-{[(2R)-2-(4-methyl-1,3-thiazole- 2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Butyl ester: {(2R)-2-[5-(6-chloro-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1- Tert-butyl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (300 mg, 0.49 mmol) A solution of 1-(4-methoxyphenyl)methanamine (203 mg, 1.5 mmol) in NMP (1.5 ml) was placed in a container for microwave reaction. The vessel was sealed and irradiated with microwaves at 140 ° C for 30 minutes. After cooling, H ₂ O and brine were added, followed by extraction of the mixture with CHCl ₃ . The organic layer was dried with MgSO ₄ The residue obtained was purified by column chromatography (EtOAc-EtOAc) elute 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]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (76 mg, 22% yield) . MS (ESI) m / z: 710 [M+H] ⁺ .

(2-Amino-6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}pyridine-4- ()((2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1 ): to {(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]-1-phenylpropan-2-yl}amino To a solution of tert-butyl formate (73 mg, 0.10 mmol) in EtOAc (EtOAc) (EtOAc) After cooling, a saturated aqueous solution of NaHCO ₃ and brine were added, and then mixture was extracted with CHCl ₃ . The organic layer was dried with MgSO ₄ The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc The obtained white solid was combined with fumaric acid to give (2-amino-6-{5-[(2R)-2-amino-1-phenylprop-2-) as a white powder. -1,3,4-oxadiazol-2-yl}pyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 Methyl ketone (2E)-but-2-enedioate (1:1) (35 mg, 56% yield, 2 steps).

Example 1.7.91

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 1-methyl-1H-pyrazol-3-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate ( 1:1): 2-(5-{(2R)-2-[(Tertidinoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4 at room temperature -oxadiazol-2-yl)-6-(1,3-oxazol-2-yl)isonicotinic acid (80 mg, 0.16 mmol) and N-methyl-1-(1-methyl-1H - pyrazol-3-yl) methanamine (31 mg, 0.24 mmol) was added in CH ₂ Cl ₂ (3.2 ml) in a solution of EDCI‧HCl (47 mg, 0.24 mmol) and HOBt (22 mg, 0.16 mmol) And the mixture was stirred overnight at the same temperature. 0.1 M aqueous HCl and CHCl _{3 were} added to the mixture and the organic layer was separated. The aqueous layer was extracted with CHCl _3. , Dried with saturated aqueous NaHCO ₃ and the combined organic layers were washed with brine and MgSO ₄ and evaporated. The residue was purified with EtOAcqqqq elut elut TFA (2.0 m) was added to a solution of the obtained solid in CH ₂ Cl ₂ (1.0 mL), and the mixture was stirred at room temperature for 3 hours. The volatiles were azeotroped with toluene. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) The compound was coagulated with fumaric acid to give 2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxo as a white powder. Zin-2-yl}-N-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-6-(1,3-oxazol-2-yl)iso-smoke Base decylamine (2E)-but-2-enedioate (1:1) (28 mg, 28% yield).

Example 1.7.92

Rel-{(2R)-2-[5-(6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine- 2-Bisyl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert- butyl ester: in a manner similar to the example 1.7.51 , by [ (2R)-2-methyl-1-{2-[(6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) The desired compound was synthesized as the tert-butyl ester of pyridin-2-yl)carbonyl]indolyl}-1-oxo-3-phenylpropan-2-yl]carbamate (321 mg, 0.542 mmol). (270 mg, 87% yield) MS (ESI) M / Z : 575 [M + H] +.

(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-1-yl]methanone 2-hydroxypropane-1,2,3-tricarboxylate (1:1): Similar to the manner of Example 1.7.51 , by rel-{(2R)-2-[5-(6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Tert-butyl-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carboxylic acid tert-butyl ester (267 mg , 0.464 mmol) of the desired compound. (143 mg, 46% yield)

Example 1.7.93

Rel-{(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine- 2-Bisyl-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid tert- butyl ester: in a manner similar to the example 1.7.51 , by [ (2R)-2-methyl-1-{2-[(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) Pyridine-2-yl)carbonyl]indenyl}-1-oxo-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (375 mg, 0.633 mmol) was synthesized. (320 mg, 88% yield) MS (ESI) M / Z : 575 [M + H] +.

(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-1-yl]methanone 2-hydroxypropane-1,2,3-tricarboxylate (1:1): Similar to the manner of Example 1.7.51 , by rel-{(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Tert-butyl-1-yl]carbonyl}pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}carbamic acid tert-butyl ester (317 mg , 0.552 mmol) of the desired compound. (299 mg, 82% yield)

Example 1.7.94

Rel-[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6 -(pyrrolidin-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: Similar to the manner of Example 1.7.51 , from [(2R)-2-methyl-1-(2-{[4-{[(2R)-2-(4-methyl-1,3-thiazole-2) -yl)pyrrolidin-1-yl]carbonyl}-6-(pyrrolidin-1-yl)pyridin-2-yl]carbonyl}indenyl)-1-oxo-3-phenylpropan-2-yl The desired compound (45 mg, 47% yield) was synthesized from the butyl succinate (99 mg, 0.15 mmol). MS (APCI/ESI) M/Z: 644 [M+H] ⁺ .

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrrolidine-1- Pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Acid salt (1:1): in a manner similar to the case of 1.7.51 , by rel-[(2R)-2-{5-[4-{[(2R)-2-(4-methyl-1, 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-(pyrrolidin-1-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}- The desired compound was synthesized from tributyl butyl 1-phenylpropan-2-ylcarbamate (45 mg, 0.070 mmol). (35 mg, 76% yield)

Example 1.7.55

Rel-{(2R)-2-[5-(1-methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl) ]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}amino Tert- butyl formate: in a similar manner to Example 1.7.51 , from [(2R)-2-methyl-1-{2-[(1-methyl-4-{[(2R)-2-) 4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)carbonyl]indenyl}-1 -Phenoxy-3-phenylpropan-2-yl]carbamic acid tert-butyl ester (235 mg, 0.377 mmol). (228 mg, 100% yield) MS (ESI) M / Z : 605 [M + H] +.

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-4-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): in a manner similar to Example 1.7.51 , by rel-{(2R)-2-[5-(1-methyl-4-{[(2R)-2-(4-methyl -1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazole The desired compound was synthesized from the tert-butyl 2-yl]-1-phenylpropan-2-yl}carbamate (226 mg, 0.374 mmol). (211 mg, 91 mmol)

Example 1.7.96

Rel-[(2R)-2-{5-[6-(difluoromethoxy)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Tert-butyl-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester: similar In the manner of Example 1.7.51 , from ((R)-1-(2-(6-(difluoromethoxy)-4-((R)-2-(4-methylthiazol-2-yl))) Pyridine-1-carbonyl)pyridinecarboxylidene)-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester (634 mg, 0.962 mmol) The desired compound is synthesized. (480 mg, 78% yield) MS (ESI) M/Z: 641 [M+H] ⁺

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(difluoromethoxy Pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl) pyrrolidin-1-yl]methanone (2E)-but-2-enedioic acid Salt (1:1): in a manner similar to Example 1.7.51 , by rel-[(2R)-2-{5-[6-(difluoromethoxy)-4-{[(2R)-2 -(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1- The desired compound was synthesized from tert-butyl phenylpropan-2-yl]carbamate (488 mg, 0.762 mmol). (386 mg, 77% yield)

Example 1.7.97

{(2R)-2-[5-(1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl) }-2-Sideoxy-1,2-dihydropyridin-4-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropan-2-yl}aminocarboxylic acid Tributyl ester: in a manner similar to the example 1.7.51 , from ((R)-2-methyl-1-(2-(1-methyl-6-((R)))) Thiazol-2-yl)pyridine-1-carbonyl)-2-oxoyl-1,2-dihydropyridine-4-carboxy)indolyl)-1-oxo-3-phenylpropan-2-yl The butyl butyl carbamate (210 mg, 0.337 mmol) was synthesized to the desired compound. (86 mg, 42% yield) MS (ESI) M / Z : 605 [M + H] +.

4-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-6-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): in a similar manner to Example 1.7.51 , from {(2R)-2-[5-(1-methyl-6-{[(2R)-2-(4-methyl-) 1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2-yloxy-1,2-dihydropyridin-4-yl)-1,3,4-oxadiazole-2 The desired compound was synthesized from the 3-butyl-1-phenylpropan-2-yl}aminocarbamate (86 mg, 0.14 mmol). (69 mg, 79% yield)

Example 1.7.98

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}pyridine-2(1H)-one (2E)-butyl- 2-enedioic acid salt (1:1): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[1-(cyclopropylmethyl)-4-{[(2R) )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-sideoxy-1,6-dihydropyridin-2-yl]-1 , 3,4-oxadiazol-2-yl}-1-phenylpropan-2-yl]carbamic acid tert-butyl ester (55 mg, 0.085 mmol). (24 mg, 43% yield)

Example 1.7.99

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-ethyl-4-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): in a similar manner to Example 1.7.73 , from {(2R)-2-[5-(1-ethyl-4-{[(2R)-2-(4-methyl-) 1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-6-o-oxy-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazole-2 The desired compound was synthesized from the 3-butyl-1-phenylpropan-2-yl}aminocarbamate (35 mg, 0.057 mmol). (24 mg, 66% yield)

Example 1.7.100

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-ethoxypyridine-4 -yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1: 1): in a manner similar to Example 1.7.73 , from {(2R)-2-[5-(6-ethoxy-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}amino The desired compound was synthesized from tert-butyl formate (106 mg, 0.171 mmol). (90 mg, 83% yield)

Example 1.7.101

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-[(2-methoxy) Ethylethyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-butyl 2- enedenedioic acid salt (1:1): in a manner similar to the example 1.7.73 , from {(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-oxa The desired compound was synthesized from the tert-butyl oxazol-2-yl]-1-phenylpropan-2-yl}carbamate (24 mg, 0.036 mmol). (20 mg, 81% yield)

Example 1.7.102

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-[(2-methoxy) (ethyl)amino(methyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone 2E)-but-2- enedioate (1:1): in a similar manner to Example 1.7.73 , from {(2R)-2-[5-(6-[(2-methoxyethyl) (methyl)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}aminocarboxylic acid tert-butyl ester (52 mg, 0.079 mmol). (44 mg, 82% yield)

Example 1.7.103

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-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): in a similar manner to Example 1.7.73 , from [(2R)-2-{5-[6-(ethylamino)-4-{[(2R)-2-(4- Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl]-1,3,4-oxadiazol-2-yl}-1-phenylpropene- The desired compound was synthesized from 2-butylaminobutyl carbamate (72 mg, 0.12 mmol). (33 mg, 44% yield)

Example 1.7.104

3-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-5-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): in a similar manner to Example 1.7.73 , from {(2R)-2-[5-(1-methyl-5-{[(2R)-2-(4-methyl-) 1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}-2-yloxy-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazole-2 The desired compound was synthesized from the 3-butyl-1-phenylpropan-2-yl}carbamate (173 mg, 0.286 mmol). (93 mg, 52% yield)

Example 1.7.105

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-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioate (1:1 ): in a manner similar to the example 1.7.73 , from {(2R)-2-[5-(4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)) Pyrrolidin-1-yl]carbonyl}-6-oxo-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1-phenylpropene- The desired compound was synthesized from 2-butylaminobutyl carbamate (50 mg, 0.085 mmol). (39 mg, 77% yield)

Example 1.7.106

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 -Sideoxy-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide: to N -methyl- N- (3-pyridylmethyl)amine (6.1 Mg, 0.05 mmol) and 6-(5-{(2R)-2-[(t-butoxycarbonyl)amino]-1-phenylpropan-2-yl}-1,3,4-oxadiazole -2-yl)-1-methyl-2-oxooxy-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) Diisopropylethylamine (30.8 μL, 0.18 mmol) was added to the solution. The reaction mixture was stirred at room temperature 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 room temperature for 30 minutes and concentrated in vacuo. The residue was purified directly by LC-MS (EtOAc EtOAc EtOAc EtOAc) -oxadiazol-2-yl}-N,1-dimethyl-2-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide.

Example 1.7.107

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- oxooxy -1,2-dihydropyridine-4-carboxamide: in a manner similar to Example 1.7.106 , from 6- The desired compound was synthesized from methyl-2-pyridinemethylmethylamine (6.8 mg, 0.05 mmol).

Example 1.7.108

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-butyl-1-methyl -2- Sideoxy -N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-4-carboxamide : in a manner similar to Example 1.7.106 , from N- (4-pyridine The desired compound was synthesized from the methylmethyl)-1-butylamine hydrochloride (10.0 mg, 0.05 mmol).

Example 1.7.109

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-4-{[ 2-(3-Methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one: in a similar manner to Example 1.7.106 , The desired compound was synthesized from 3-methyl-5-(2-pyrrolidinyl)-1,2,4-oxadiazole (7.7 mg, 0.05 mmol).

Example 1.7.110

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-butyl-1-methyl -2- Sideoxy -N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide: in a manner similar to Example 1.7.106 , from N-(3-pyridine The desired compound was synthesized from methylamine-1-butanamine (8.2 mg, 0.05 mmol).

Example 1.7.111

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 - pendant oxy-N-(1H-pyrazol-5-ylmethyl)-1,2-dihydropyridine-4-carboxamide: in a manner analogous to Example 1.7.106 , from methyl-(2H The desired compound was synthesized from pyrazol-3-ylmethyl)-amine (5.6 mg, 0.05 mmol).

Example 1.7.112

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 -Sideoxy -N-[1-(2-thienyl)ethyl]-1,2-dihydropyridine-4-carboxamide: in a manner similar to Example 1.7.106, from N -methyl- The desired compound was synthesized from 1-(2-thienyl)ethylamine hydrochloride (8.8 mg, 0.05 mmol).

Example 1.7.113

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(2,5-di Methyl-1,3-oxazol-4-yl)methyl]-N,1-dimethyl-2-oxooxy-1,2-dihydropyridine-4-carboxamide: similar to the example The desired compound was synthesized from N -[(2,5-dimethyl-1,3-oxazol-4-yl)methyl] -N -methylamine (7.0 mg, 0.05 mmol).

Example 1.7.114

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(t-butyl)- N-((4-Methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: required to synthesize in a similar manner to Example 1.4.11 and Example 1.7.1 . Compound.

Example 1.7.115

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((4-methylthiazole) 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 4 N HCl in dioxane.

Example 1.7.116

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(fluoromethyl)benzene ((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: in a manner similar to Example 1.4.10 and Example 1.7.1 The desired compound is synthesized.

Example 1.7.117

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-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

(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-1-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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1,3,4 -oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: similar to Example 1.4.17 , Example 1.7 The desired compound was synthesized in the manner of .1 and Example 1.6.8 .

Example 1.7.121

5-(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) 2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-1,3,4-oxadiazole-2(3H)-one: similar to Example 1.4.17 , The desired compound was synthesized in the manner of Example 1.7.1 and Example 1.6.8 .

Example 1.7.122

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-fluoroethyl Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-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

1-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-Methylthiazol-2-yl)pyrrolidine-1-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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazole- 1-(1)Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: The desired compound was synthesized in a similar manner to Example 1.6.9 .

Example 1.7.125

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(isoxazole-5 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: synthesized in a manner similar to Example 1.7.123 and Example 1.4.15 . Requires a compound.

Example 1.7.126

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1,1-di Fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: synthesized in a similar manner to Example 1.4.14 and Example 1.7.1 The desired compound.

Example 1.7.127

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(isoxazole-3 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: synthesized in a manner similar to Example 1.4.16 and Example 1.7.1 Requires a compound.

Example 1.7.128

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazole- 3-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: synthesized in a similar manner to Example 1.7.123 and Example 1.4.15 . The desired compound.

Example 1.7.129

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2- (4-Methylthiazol-2-yl)pyrrolidine-1-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

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropane Base-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: The final compound was prepared using a procedure analogous to the procedure of Example 1.7.1 .

Example 1.7.131

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5- bromophenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone: The compound was synthesized in a similar manner to Example 1.7.1 .

Example 1.7.132

(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-1-yl)methanone: The compound was synthesized in a similar manner to Example 1.7.1 .

Example 1.7.133

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol -4-yl)methyl)-4,5-difluoro-N-methylbenzamide: Prepared according to procedure similar to Example 1.7.16 using commercially available chemical as starting material. The compound.

Example 1.7.134

(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-1-yl)methanone: using a commercially available chemical as a starting material, in a manner similar to the method of Example 1.7.16 This compound was prepared.

Example 1.7.13 5

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluoro Phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone: to the acid containing 5-bromo-2-fluorobenzoic acid (391 mg, 1.784 DCM (3 ml), HOBT (328 mg, 2.141 mmol) and EDC (479 mg, 2.498 mmol) were added to the mixture and the mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was cooled to 0 ° C and (R)-(3-(4-fluorophenyl)-1-indolyl-2-methyl-1-oxopropan-2-yl) Tributyl carbamic acid (500 mg, 1.606 mmol) and DIPEA (0.935 ml, 5.35 mmol) were added to DCM (1 mL). The reaction mixture was dark brown in color. After stirring overnight at room temperature, the DCM was removed in vacuo. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. After stirring at room temperature for 10 minutes, the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and brine and dried. The crude residue continues to the next step.

Bordeaux reagent (1.26 g, 5.27 mmol) was added to a solution containing hydrazine (1.08 g, 2.11 mmol) (20 mL) and refluxed for 3 hours, at which time the colour of the reaction became brown. The reaction mixture was then cooled, diluted with DCM, washed with brine The crude residue was subjected to column chromatography (30% ethyl acetate /hexane). The product was a yellow syrup and obtained 67% yield.

To the bromine-containing compound, (R)-(2-(5-(5-bromo-2-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(4-fluorophenyl) Addition of acetic acid to di-butyl propyl-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) (15.90 mg, 0.071 mmol) and XANTPHOS (82 mg, 0.142 mmol) , Et 3 N (1.974 ml, 14.16 mmol) and the reaction mixture was purged with carbon monoxide. The reaction mixture (yellow suspension) was then heated to 75 ° C for 3 hours, at which time the suspension was grayish green. The reaction mixture was then cooled and the dioxane was removed in vacuo. Add water and filter. The aqueous layer was basified and extracted with ethyl acetate. The aqueous layer was then acidified and extracted with EtOAc EtOAc. The organic layer was dried and evaporated to give 460 mg of acid.

The resulting acid was converted to the final compound in a manner similar to that in Example 1.7.1 .

Example 1.7.136

(R)-5-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-2,4-difluoro-N-methylbenzamide: To the acid containing, 5-bromo-2,4-difluorobenzoic acid (1.5 g, 6.33 HOBT (1.163 g, 7.59 mmol) and EDC (1.699 g, 8.86 mmol) were added to a solution. After 1 hour, the reaction mixture was cooled to 0 ° C, and (R)-(1-mercapto-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid Butyl ester (1.671 g, 5.70 mmol) and DIPEA (3.32 ml, 18.99 mmol) were added to DCM (3 mL). The reaction mixture was dark brown in color. After stirring overnight at room temperature, the DCM was removed in vacuo. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. After stirring at room temperature for 10 minutes, the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and brine and dried. The crude residue continues to the next step.

Bordeaux reagent (629 mg, 2.64 mmol) was added to a solution containing hydrazine (500 mg, 1.06 mmol) (20 mL) and refluxed for 2 h at which time the colour of the reaction became dark brown. The reaction mixture was then cooled, diluted with DCM, washed with brine The crude residue was subjected to column chromatography (30% ethyl acetate /hexane). The product was a colorless foamy syrup and obtained 67% yield.

To the bromine-containing compound, (R)-(2-(5-(5-bromo-2,4-difluorophenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropane -2-yl)-tert-butyl 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), Et ₃ N (2.82 ml, 20.23 mmol) and the reaction mixture was purified using carbon monoxide. The reaction mixture was then heated to 75 ° C for 4 hours. The reaction mixture was then cooled, water was added and filtered. The aqueous layer was basified and extracted with ethyl acetate. The aqueous layer was then acidified and extracted with EtOAc EtOAc. The organic layer was dried and evaporated to give 360 mg of acid. The organic layer also has some products as well as some impurities. The material obtained from the organic layer was partitioned between water (basic) layer and 5% MeOH / ethyl acetate to afford 450 mg of acid.

The resulting acid was converted to the final compound in a manner similar to that in Example 1.7.1 .

Example 1.7.137

( R)-4-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-5-fluoro-N-methylpyridinecarboxamide: The compound was synthesized in a similar manner to Example 1.8.2.

Example 1.7.138

(R)-4-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-5-methoxy-N-methylpyridinecarboxamide: The compound was synthesized in a similar manner to Example 1.8.2.

Example 1.7.139

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(( 2,5-Dimethyloxazol-4-yl)methyl)-4,5-difluoro-N-methylbenzamide: A commercially available chemical was used as the starting material, in a similar manner to Example 1.7. The method of 16 was used to prepare the compound.

Example 1.7.140

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-4,5 -difluorophenyl)((S)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone: using commercially available chemical as starting material, similar to Example 1.7 The method of .16 is used to prepare the compound.

Example 1.7.141

5-(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-1,3,4-oxadiazole-2(3H)-one: similar The desired compound was synthesized in the manner of Example 1.4.17 , Example 1.7.1 and Example 1.6.8 .

Example 1.7.142

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,4-difluorophenyl ((R)-2-(4-Methyloxazol-2-yl)pyrrolidin-1-yl)methanone: The final compound was prepared using a procedure similar to the procedure of Example 1.8.11 .

Example 1.7.143

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-(3 -Methylbenzyl)-6-(1,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1): similar to Example 1.7 .73 , by [(2R)-2-(5-{4-[methyl(3-methylbenzyl)aminomethyl)]-6-(1,3-oxazol-2-yl) Synthesis of the desired compound in the form of a white powder in the form of the tert-butyl pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl]carbamate 58 mg, 65% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (1.1H, s ), 4.49 (0.9H, s), 3.40 (2H, br.s), 3.15 (1.1H, 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 an oxazole inhibitor. Example 1.8.1

In the entire solution was added at room temperature to 8.1.67 (3.5 g, 19.53 mmol) in _{THF (50 mL) NaBH 4 (} 1.85 g, 48.82 mmol) and cooled to 0 ℃. I ₂ (4.96 g, 19.53 mmol) of THF (10 mL) was then added over 30 min then refluxed for 40 hr. The reaction was cooled to 0 &lt;0&gt;C and quenched with EtOAc over EtOAc. Evaporate all solvents. The residue was dissolved in 15 mL of 5N NaOH and reflux for 2.5 h. Then allowed to cool to room temperature and extracted with _{CH 2 Cl 2 (4 × 20} mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The coarse 8.1.668 (3.2 g) continues to the next step.

Add (Boc) ₂ O (4.66 g, 21.33 mmol) of CH ₂ Cl ₂ (80 mL) to 8.1.68 (3.2 g, 19.39 mmol) in CH ₂ Cl ₂ (20 mL) The solution was stirred in M NaOH (100 mL) overnight. The layers were separated and the _aqueous layer was extracted with CH ₂ Cl. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude material was purified by silica gel (40% EtOAc / 60% hexane) to afford 4.4 g (85%, two steps) 8.1.69 .

Add Et ₃ N (6.9 mL, 49.81 mmol), SO3, to a solution of 8.1.69 (4.4 g, 16.60 mmol) in CH ₂ Cl ₂ -DMSO (5:1, 85 mL). Py (6.6 g, 41.51 mmol). After stirring overnight, the reaction mixture was diluted with ether and washed with 10% NaHSO4, saturated NaHCO _3, brine, dried and concentrated over Na ₂ SO _4. Crude aldehyde 8.1.70 (4.1 g, 94%) was used in the next step without purification.

Water (25 drops), trimethylammonium iodide (3.34 g, 16.37 mmol) were added sequentially to a solution of 8.1.70 (4.1 g, 15.59 mmol) in CH ₃ CN (60 mL) at room temperature. And potassium hydroxide (2.19 g, 38.97 mmol). Was stirred at 60 deg.] C in a sealed tube 3 hours the reaction was diluted with ethyl acetate and washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude material was purified on silica gel (50% EtOAc / 50% hexane) to give 900 mg (21%) 8.1.71.

Stirring 8.1.71 (4.1 g, 15.59 mmol) in a sealed tube at 60 deg.] C and NH ₄ OH (30 mL) in EtOH (30 mL) in the solution 16 hours. All solvent was evaporated and purified (10% MeOH / 90% CHCl 3) on basic alumina to give 900 mg (94%) 8.1.72.

All starting materials and reagents were combined in DCM at room temperature, then cooled to about 0 ° C in an ice water bath and DIEA was added and the mixture was warmed to room temperature overnight. The next _{morning, TLC (MeOH / CHCl 3,} 1: 9) indicated the reaction was complete Chedi, 8.1.73 of the product showed a single spot. After washing with bicarbonate and water, DCM was replaced with EtOAc and the solution was washed with 10% EtOAc EtOAc. 8.1 mg (82%) of 401 mg as a foam solid was obtained.

20 ml of dry DCM containing the above mixture was stirred at room temperature (about 21 ° C) for 5 hours, then aliquots were dissolved in 5% NaOH and TLC (10% MeOH in CHCl ₃ ) showed to be exactly at s. There are new spots on the spot. Proton NMR indicated the reaction was complete. There is a new signal group in the 4.5-4.8 ppm region (CH ₂ C=O). However, an additional 20 ml of DCM was added (due to the presence of some solids) and the mixture was stirred overnight. The next day, 5% NaOH (20 ml), saturated NH ₄ Cl were added sequentially and the mixture was stirred for additional 1 hour. The organic layer was separated, washed with water and dried over Na ₂ SO _4. The solvent was removed in a rotator followed by 40 ml of toluene and stripped in a rotator to remove potentially residual water. The yield of the yellow solid was 360 mg (>100%, containing only 20% toluene according to NMR). The estimated yield was 80% 8.1.74 (single spot on TLC).

The ketone 8.1.74 was heated with about 9 g of polyphosphoric acid (PPA) in a 20 ml open vial at 100 ° C for 1 hour to allow CO ₂ and t -BuOH to be released via Boc decomposition. Foaming was observed. By TLC (10% MeOH solution of CHCl ₃₎ monitoring the progress of the reaction. The starting material disappeared after 20 minutes, while the removal of Boc amine was detected in a sample treated sequentially with water, 20% NaOH and EtOAc. The temperature was set to 110 ° C and the reaction mixture (yellow) was stirred in a closed vial at this temperature for 9 hours. That the dark brown reaction mixture was cooled to about 40 ℃, diluted with 20 ml of water, followed by addition of 28 g 20% NaOH to pH ~ 9 and the cloudy mixture was washed with 2 × 20 ml EtOAc and the organic layer was extracted with yellow ₂ SO ₄ dried with Na. After removing the solvent in the spinner, 160 mg of yellow material (93% crude material) was obtained. This material was purified on a 4 g CombiFlash cartridge with EtOAc ( EtOAc ) EtOAc ( EtOAc ) ¹ H NMR (CDCl ₃ ) δ 8.74 and 8.62 (s, 1H); 8.32 and 8.10 (s, 2H), 7.79 and 7.71 (s, 1H); 7.22 (m, 4 H); 6.98 (m, 2H); 6.80 (m, 2H); 5.70 and 5.20 (t, 1H); 3.75 (m, 2H); 3.10 (dd, 2H, J = 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 the central benzene ring protons behave as two guanamine rotamer signals.

Example 1.8.2: (R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl -5-(oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide

8.2.1 was coupled with 8.2.2 using a standard coupling procedure including CH ₂ Cl ₂ containing HOBT, EDCI, DIPEA, and stirred overnight to obtain 8.2.3 , deprotected with 30% TFA in CH ₂ Cl ₂ solution. The base is continued for 1 hour to obtain (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N- 5-[(oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide.

Example 1.8.3

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.4

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.5

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.6

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.7

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.8

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.9

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.10

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.11

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.12

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.13

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.14

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.15

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.16

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.17

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.18

The compound was synthesized in a similar manner as in Example 1.8.2.

Example 1.8.19

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.8.20

The compound was synthesized in a manner similar to that in Example 1.7.1.

Example 1.8.21

Add 3-methoxyphenyl to the iodide (100 mg, 0.12 mmol) in toluene (9 ml), water (3 ml) (3:1 ratio) Acid (21 mg, 0.14 mmol) (commercial source: Sigma-Aldrich), K ₃ PO ₄ (commercial source: Sigma-Aldrich) (76 mg, 0.36 mmol), 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). The reaction mixture was then heated under reflux for 4 hours. The reaction mixture was then cooled, diluted with diethyl ether and filtered over EtOAc. The filtrate was partitioned between diethyl ether and water. The organic layer was dried, evaporated and purified by column to afford 50 mg.

The protecting group of the obtained Boc compound was removed using a procedure similar to that described in Example 1.7.2 to give the final product.

Example 1.8.22

Follow the above procedure to make the iodine compound and 2-methoxyphenyl The acid (commercial source: Sigma-Aldrich) was coupled and the protecting group of the resulting Boc compound was removed using a procedure similar to that described in Example 1.7.2 to give the final product.

Example 1.8.23

According to the above procedure, the iodine compound and furan 2- The acid (commercial source: Sigma-Aldrich) was coupled to give a coupled product.

An aqueous solution of phosphoric acid (20 μL) was added to DCM (1 ml) containing Boc compound (10 mg, 0.016 mmol) and stirred at room temperature for 3 hr. The reaction mixture was then cooled and basified to pH 8 with 50% aqueous sodium hydroxide. The aqueous solution was then extracted with DCM. The organic layer was dried, evaporated and subjected to column purification to give the final product.

Example 1.8.24

Add furan 3- in order to iodide (100 mg, 0.12 mmol) in dioxane (9 ml), water (3 ml) (3:1 ratio) Acid (16 mg, 0.14 mmol) (commercial source: Sigma-Aldrich), K ₃ PO ₄ (commercial source: Sigma-Aldrich) (76 mg, 0.36 mmol), 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). The reaction mixture was then heated to 130 ° under microwave conditions for 40 minutes. The reaction mixture was then cooled, diluted with diethyl ether and filtered over EtOAc. The filtrate was partitioned between diethyl ether and water. The organic layer was dried, evaporated and purified by column to give a coupled product. The protecting group of the obtained Boc compound was removed using a procedure similar to that described in Example 1.7.2 to give the final product.

Example 1.8.25

According to the above procedure, the iodine compound and pyrimidine 5- The acid (commercial source: Frontier Scientific) was coupled and using a procedure similar to that of Example 1.7.2, the Boc group was removed using 4N HCl to give the final product.

Example 1.8.26

According to the above procedure, the iodine compound and pyridine 3- The acid (commercial source: matrix Scientific) was coupled and the Boc group was removed using 4 N HCl using a procedure analogous to Example 1.7.2 to give the final product.

Example 1.8.27

According to the above procedure, the iodine compound and pyridine 3- The acid (commercial source: Combiphos catalysts) was coupled and the Boc group was removed using 4 N HCl using a procedure analogous to Example 1.7.2 to give the final product.

Example 1.8.28

According to the above procedure, the iodine compound and pyridine 3- The acid (commercial source: Synthonix) was coupled and the Boc group was removed using 4 N HCl using a procedure analogous to the procedure of Example 1.7.2 to give the final product.

Example 1.8.29

HOBT (49 mg, 0.36 mmol), EDCI (81 mg, 0.42 mmol), and EtOAc. The acid (150 mg, 0.30 mmol) and DIPEA (0.1 ml) were then added to the reaction mixture and stirred overnight, then worked up and purified by column column to afford a 78% yield.

Removal of the protecting group of the resulting Boc protected compound as in Example 1.7.2 afforded the final product.

Example 1.8.30

The final compound was prepared using a procedure similar to that in Example 1.8.9 .

Example 1.8.31

Add HOBT (352 mg, 2.301 mmol) and EDC (515 mg, 2.68) to a solution containing the acid, 2-fluoro-5-(methoxycarbonyl)benzoic acid (380 mg, 1.918 mmol) in DCM (3 mL) (mmol) and the reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was cooled to 0 ° C, and (R)-(1-mercapto-2-methyl-1-oxo-3-phenylpropan-2-yl)carbamic acid Butyl ester (506 mg, 1.726 mmol) and DIPEA (1.005 ml, 5.75 mmol) were added to DCM (1 mL). After stirring overnight at room temperature, the DCM was removed in vacuo. The reaction mixture was then diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate was added. After stirring at room temperature for 10 minutes, the aqueous layer was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with water and brine and dried. The crude residue was purified by column chromatography (EtOAc EtOAc EtOAc)

Bordeaux reagent (629 mg, 2.64 mmol) was added to hydrazine (500 mg, 1.056 mmol) in DCC (10 ml) and refluxed for 4 h at which time the reaction colour became brown, then the reaction mixture was cooled with DCM Dilute, wash with aqueous sodium bicarbonate, water, brine and dry. The crude residue was subjected to column chromatography (50% ethyl acetate /hexane). The product was a yellow syrup and was obtained in 62% yield.

To the ester-containing, (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluorobenzoic acid Add methyl caustic soda (101 mg, 2.53 mmol) to MeOH (300 mg, 0.844 mmol) in MeOH (ratio: 3.00, volume: 3 ml) and water (ratio: 1.000, volume: 1 mL) and stir at room temperature The reaction mixture was carried out for 4 hours. The reaction mixture was then acidified and extracted with ethyl acetate. The organic layer was dried and evaporated to give the title compound as a brown solid.

The resulting acid was converted to the final compound in a manner similar to that in Example 1.7.1 .

Example 1.8.32

The final compound was prepared using a procedure similar to that in Example 1.8.31 .

Example 1.8.33

The final compound was prepared using a procedure similar to that in Example 1.8.31 .

Example 1.8.34

The final compound was prepared using a procedure similar to that in Example 1.8.31 .

Example 1.8.35

The final compound was prepared using a procedure similar to that in Example 1.8.31 .

Example 1.8.36

The final compound was prepared using a procedure similar to that in Example 1.8.31 .

Example 1.9: Supplementary compound. Example 1.9.1: 3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(( R)-1-(4-fluorophenyl)ethyl)-5-(N-methylmethanesulfonylamino)benzamide

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.40 (br s, 1H), 8.14 (br s, 1H), 8.05 (br s, 1H), 7.82 (d, J = 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 = 14 Hz, 1H) , 3.12 (d, J = 14 Hz, 1H), 2.94 (s, 3H), 2.39 (s, 2H), 1.67 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H).

Example 1.9.2: (R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5- (Evil Zin-2-yl)-N,N-dipropyl benzamide

¹ H NMR (300 MHz, CDCl ₃ ) 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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5- (Evil Zin-2-yl)-N-((R)-1-phenylethyl)benzamide

¹ H NMR (300 MHz, CDCl ₃ ) 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), 7.02-7.279m, 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-1-yl)(3-(Pyrazin-2-yl)-5-(5-pyrrolidine- 2-yl)-1,3,4-oxadiazol-2-yl)phenyl)methanone

¹ H NMR (300 MHz, CDCl ₃ ) 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-1-yl)(3-(Pyrazin-2-yl)-5-(5-((S) )-pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)methanone

¹ H NMR (300 MHz, CDCl ₃ ), 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 (width unimodal, 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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'- (2-(5-methylfuran-2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile

To a solution of dimethyl 5-iodoisophthalate 76 (commercial source: Matrix Scientific) (2 g, 6.25 mmol) in 15 mL of THF was added 2-cyano-phenylzinc bromide (commercial source: Sigma) - Aldrich) (15 mL, 7.5 mmol, 0.5 M THF) and EtOAc (triphenylphosphine) palladium (commercial source: Sigma-Aldrich) (71 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered, diluted with MeOH, filtered to give a second batch of a total of between 1.2 g (65%) 5- (cyanophenyl) isophthalate 77.

The (155 mg, 3.86 mmol) NaOH was added to a stirred solution of diester 77 (1.2 g, 4.07 mmol, in _{1: 3:. 3 H 2} O / MeOH / THF (25 ml) was at room temperature the reaction mixture was stirred overnight. the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and saturated _aqueous NaHC03. the reaction mixture was extracted with EtOAc. with concentrated HCl aqueous layer was adjusted to PH value of about 3, and the reaction with 10% MeOH \ 90% CHCl ₃ (5 times) the mixture was extracted. the combined organic layers were washed with brine, dried and concentrated to give 0.9 g (79%) 78 monobasic acids.

To 2-(5-methyl-2-furyl)pyrrolidine 79 (commercial source: ACB Blocks Ltd.) (54 mg, 0.36 mmol) and 78 (100 mg, 0.36 mmol) in CH ₂ Cl HOBT (48 mg, 0.36 mmol) and EDC (82 mg, 0.42 mmol), DIPEA (0.186 mL, 1.07 mmol) were added to the solution in ₂ (8 mL) and stirred at room temperature. Overnight. All the solvent was evaporated; the residue was diluted with EtOAc and washed with IN HCl and saturated aqueous NaHCO ₃ with 0.5 N. The organic layer was washed with brine, dried, concentrated and purified by silica gel (50% EtOAc / 50% hexane) to give 120 mg (77%) 80.

To a solution of the stirred ester 80 (120 mg, 0.28 mmol) in THF (3 mL). After stirring for 1 hour, the medium was adjusted to pH with 1 N HCl. 4 and extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation, to give 110 mg (94% yield) 81.

Add HOBT (19 mg, 0.14 mmol), EDC (33 mg, to a solution of 81 (60 mg, 0.14 mmol) and 82 (42 mg, 0.14 mmol) in CH ₂ Cl ₂ (8 mL). 0.17 mmol) and DIPEA (0.075 mL, 0.43 mmol) were stirred overnight at room temperature. The solvent was removed via rotary evaporation. With saturated aqueous NaHCO ₃ and the mixture was quenched residue was extracted with EtOAc. The organic layer was washed with brine, dried and over Na ₂ SO _4. The inorganics were filtered off and the solvent was removed via rotary evaporation. Purification by flash chromatography on silica gel gave 80 mg (82%) of product 83 .

Bordeaux reagent (85 mg, 0.35 mmol) was added to a solution of 83 (80 mg, 0.12 mmol) in dichloromethane (5 mL) and refluxed for 5 h. The reaction mixture was then allowed to cool to room temperature, diluted with CHCl ₃ and washed successively with saturated aqueous NaHCO ₃ and brine, dried, concentrated and purified by silica gel (1% MeOH / 99% CHCl 3), to obtain 60 mg (76%) 84 .

Stir a mixture of 84 (60 mg, 0.09 mmol) in 4 N HCl in 1,4-dioxane (3 mL) and 1.5 N HCl in MeOH (1 mL). The solution was for 45 minutes. The TLC indicates the initial material consumption. All the solvent was evaporated; with quenched with saturated aqueous NaHCO ₃ and the residue extracted with EtOAc. The organic extracts were washed with brine, dried, concentrated and purified by silica gel (2% MeOH / 98% CHCl 3), to obtain 30 mg (59%) 85. ¹ H NMR (300 MHz, CDCl ₃ ) 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 single peaks, 3H) .

Example 1.9.7

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-(3 -Methylbenzyl)-6-(1,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate (1:1): similar to Example 1.7 .73 , by [(2R)-2-(5-{4-[methyl(3-methylbenzyl)aminomethyl)]-6-(1,3-oxazol-2-yl) Synthesis of the desired compound in the form of a white powder in the form of the tert-butyl pyridin-2-yl}-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl]carbamate 58 mg, 65% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (1.1H, s) , 4.49 (0.9H, s), 3.40 (2H, br.s), 3.15 (1.1H, 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 Compound Example 2.1

(2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)amine)methyl)phenyl)-1,3,4-oxadiazol-2-yl) T-butyl -1-phenylpropan-2-yl)carbamate. ¹ H NMR (300 MHz, CDCl ₃ ) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(pyridin-3-yl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.88 (br s, 1H), 8.72 (br s, 1H), 8.38-7.80 (m, 4H) 7.48 (s, 1H), 7.36-7.20 (m, 3H) , 7.12-7.00 (m, 2H), 6.98 (br s, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 3.40-3.24 (m, 1H), 3.20-3.06 (m, 1H), 2.57-2.40 (m, 4H), 2.24-1.80 (m, 4H), 1.74-1.62 (two single peaks, 3H).

Example 2.5

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 0.6) H), 4.94-4.84 (m, 0.4H), 4.00-3.80 (m, 2H), 3.64-3.54 (m, 1H), 3.38-3.20 (m, 1H), 3.18-3.04 (m, 1H), 2.43 -2.04 (m, 4H), 2.04-1.70 (m, 4H), 1.67 (s, 3H).

Example 2.6

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-methylphenyl) ( (R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99-7.72 (m, 2H), 7.55 (s, 1H), 7.29-7.19 (m, -4H), 7.05-7.00 (m, 2H), 6.80-6.77 ( m,1H), 5.69-5.65 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.93-3.87 (m, 1H), 3.81-3.74 (m, 1H), 3.59-3.49 (m, 1H) ), 3.30-3.21 (m, 1H), 3.11-3.03 (m, 1H), 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

(3-Methyl-5-(5-((R)-2-(methylamino)-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96-7.69 (m, 2H), 7.54 (s, 1H), 7.29-7.16 (m, 4H), 7.02-7.00 (m, 2H), 6.80-6.76 (m) , 1H), 5.69-5.65 (m, 0.7H), 5.14 - 5.11 (m, 0.3H), 3.90-3.89 (m, 1H), 3.80-3.72 (m, 1H), 3.58-3.49 (m, 1H) , 3.19-3.16 (m, 2H), 2.46-2.25 (m, 10H), 2.21-2.04 (m, 3H), 1.99-1.90 (m, 1H), 1.77 (m, 2H), 1.61-1.55 (m, 3H).

Example 2.8

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2 -(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99-7.72 (m, 2H), 7.55 (s, 1H), 7.29-7.19 (m, 4H), 7.05-7.00 (m, 2H), 6.80-6.77 (m) , 1H), 5.69-5.65 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.93-3.87 (m, 1H), 3.81-3.74 (m, 1H), 3.59-3.49 (m, 1H) , 3.30-3.21 (m, 1H), 3.11-3.03 (m, 1H), 2.47-2.26 (m, 5H), 2.24-2.03 (m, 3H), 1.65-1.59 (two single peaks, 3H).

Example 2.9

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyrazine-2- ()Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 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, 1H), 3.31-3.23 (m, 1H), 3.12-3.05 (m, 1H), 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

N-(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-N-methylmethanesulfonamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12-7.52 (m, 3H), 7.31-7.21 (m, 4H), 7.04-7.01 (m, 2H), 6.79-6.72 (m, 1H), 5.66-5.62 (m, 0.6H), 5.20-5.17 (m, 0.3H), 3.91-3.80 (m, 1H), 3.63-3.55 (m, 1H), 3.39-3.20 (m, 4H), 3.10-3.03 (m, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(fluoromethyl)benzene ()(R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 0.6) H), 5.57 (s, 1H), 5.41 (s, 1H), 5.19-5.08 (m, 0.4H), 3.98-3.84 (m, 1H), 3.84-3.74 (m, 1H), 3.59-3.48 (m , 1H), 3.30-3.18 (m, 1H), 3.16-3.00 (m, 1H), 2.47-2.06 (m, 5H), 2.24-1.80 (m, 3H), 1.72-1.60 (two single peaks, 3H ).

Example 2.12

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-chlorophenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62-2.42 (m, 10H), 3.04-3.26 (m, 2H), 3.24-3.82 (m, 2H), 5.62-5.72 (m, 1H), 6.80 (s) , 1H), 6.84-7.21 (m, 5H), 7.74 (s, 1H), 8.02-8.18 (m, 2H).

Example 2.13

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.21-8.64 (m, 4H), 8.49-8.10 (m, 2H), 7.34-7.33 (m, 1H), 7.08-6.88 (m, 5H), 5.76 (m) , 0.6H), 5.28 (m, 0.3H), 4.02-3.93 (m, 1H), 3.71-3.42 (m, 1H), 3.36-3.28 (m, 1H), 3.18-3.15 (m, 1H), 2.51 -2.45 (m, 3H), 2.36-1.83 (m, 5H), 1.73 (m, 3H).

Example 2.14

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((2R,4S) 4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.42 (s, 3H), 2.42 (s, 3H), 2.68-2.86 (m, 2H), 3.02-3.26 (m, 1H), 3.61-4.14 (m, 3H) ), 5.28 (d, 1H, J = 42 Hz), 5.62-5.72 (m, 1H), 6.81 (s, 1H), 7.01-7.06 (m, 2H), 7.21-7.28 (m, 3H), 7.51 7.60 (m, 1H), 7.72-7.74 (m, 1H), 8.10-8.22 (m, 2H).

Example 2.15

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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 , 1H), 3.30-3.16 (m, 1H), 3.16-3.02 (m, 1H), 2.50-2.30 (m, 4H), 2.24-1.80 (m, 4H), 1.64-1.62 (two single peaks, 3H ).

Example 2.16

1-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) 2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)pyrrolidin-2-one. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38-8.14 (m, 2H), 7.98-7.90 (m, 1H), 7.28-7.15 (m, 4H), 7.04-7.02 (m, 2H), 6.78-6.74 (m, 1H), 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, 1H), 3.10-3.03 (m, 1H), 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

(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-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.33 (m, 2H), 7.30-7.16 (m, 5H), 7.05-7.02 (m, 3H), 6.80-6.68 (m, 1H), 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, 1H), 3.33-3.21 (m, 1H), 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

(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-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.61 (m, 1H), 7.27-7.20 (m, 4H), 7.12 (m, 1H), 7.02-6.99 (m, 2H), 6.76-6.68 (m) , 1H), 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, 1H) , 2.91 (s, 3H), 2.43 - 2.31 (m, 5H), 2.17 - 7.75 (m, 5H), 1.63 (s, 3H).

Example 2.19

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-methoxyphenyl) ((R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.76-7.51 (m, 2H), 7.28-7.20 (m, 4H), 7.03-6.91 (m, 2H), 6.78-6.76 (m, 1H), 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, 1H), 3.28-3.19 (m, 1H), 3.10-3.02 (m, 1H), 2.43-2.28 (m, 5H), 2.22-1.90 (m, 5H), 1.64-1.61 (m, 3H).

Example 2.20

3'-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'-((R)- 2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65 (s, 3H), 1.95-2.46 (m, 7H), 3.06-3.30 (m, 1H), 3.60-3.75 (m, 2H), 3.90-3.93 (m) , 1H), 5.66-5.70 (m, 1H), 6.78 (s, 1H), 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.

(7-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) Alkan-5-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 5.66 -5.63 (m, 0.6H), 5.04 (m, 0.3H), 4.29-4.12 (m, 2H), 3.95-3.86 (m, 1H), 3.55-3.33 (m, 1H), 3.28-3.20 (m, 1H), 3.09-2.90 (m, 2H), 2.82-2.54 (m, 1H), 2.44-2.29 (m, 5H), 2.23-1.73 (m, 7H), 1.64-1.62 (m, 3H).

Example 2.22

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrrole-1 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06-8.02 (m, 2H), 7.82-7.75 (m, 1H), 7.37-7.18 (m, 5H), 7.05-6.95 (m, 3H), 6.81-6.58 (m, 1H), 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, 1H), 3.34-3.22 (m, 1H), 3.12-3.06 (m, 1H), 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

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-2-hydroxyphenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.63-10.50 (m, 1H), 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, 1H), 3.73-3.66 (m, 1H), 3.55-3.46 (m, 1H), 3.31-3.25 (m, 1H), 3.12-3.08 (m, 1H), 2.47-2.17 (m, 5H), 2.12-1.60 (m, 3H).

Example 2.24

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropane Base-N-((4-methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.182 (s, 1 H), 8.067 (d, J = 3.9 Hz, 1 H), 7.735 (d, J = 7.8 Hz, 1 H), 7.559 (t, J = 7.8, 15.6 Hz, 1 H), 7.024-6.861 (m, 5 H), 5.019 (s, 2 H), 3.232 (d, J = 13.5 Hz, 1 H), 3.056 (d, J =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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-4,4-difluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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) , J = 13.5 Hz, 1 H), 3.086 (d, J = 13.5 Hz, 1 H), 2.945 (m, 2 H), 2.443 (s, 3 H), 1.655 (s, 3 H).

Example 2.26

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-( (4-Methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.184 (s, 1 H), 8.068 (d, J = 7.8 Hz, 1 H), 7.756 (d, J = 7.8 Hz, 1 H), 7.557 (t, J = 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, J = 13.2 Hz, 1 H), 3.086 (d, J = 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5-(N -Methylmethylsulfonylamino)-N-((4-methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.056 (m, 2 H), 7.791 (m, 1 H), 7.213 (m, 3 H), 7.02 (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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- Phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopentyl-N-( (4-Methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) 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) , 1H), 4.90 (wide single peak, 2H), 4.12-4.10 (m, 1H), 3.27 (d, 1H), 3.09 (d, 1H), 2.04-1.60 (m, 12H), 1.44 (m, 2H) ).

Example 2.30

(4-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)((R )-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62 (s, 3H), 1.95-2.46 (m, 7H), 3.07-3.61 (m, 3H), 5.62-5.64 (m, 1H), 6.85 (s, 1H) ), 7.01-7.14 (m, 2H), 7.21-7.38 (m, 3H), 7.60 (s, 1H), 8.40 (s, 1H), 8.86 (s, 1H).

Example 2.31

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-methyl- 1H-pyrazol-4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 6.83 (s, 1H), 7.01-7.04 (m, 2H), 7.18-7.22 (m, 2H), 7.48 (s, 1H), 7.71-7.82 (m, 3H) ), 7.98 (s, 1H), 8.14 (s, 1H).

Example 2.32

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-imidazole-1 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16-7.97 (m, 2H), 7.78-7.72 (m, 1H), 7.39-7.36 (m, 1H), 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, 1H) , 3.35-3.23 (m, 1H), 3.13 - 3.07 (m, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-5- ()Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32-8.26 (m, 1H), 8.01-7.91 (m, 2H), 7.62-7.53 (m, 1H), 7.30-7.19 (m, 4H), 7.06-7.03 (m, 2H), 6.82-6.79 (m, 1H), 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, 1H), 3.31-3.23 (m, 1H), 3.13-3.06 (m, 1H), 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

(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-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 7.981 (s, 1 H), 7.914 (s, 1 H), 7.077 (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

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)((R )-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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) , 1H), 6.82 (s, 1H), 6.88-7.10 (m, 2H), 7.21-7.38 (m, 3H), 8.42 (s, 1H), 8.88 (s, 1H), 9.30 (s, 1H).

Example 2.36

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-2-(4-(fluoromethyl)thiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.729 (s, 1 H), 8.405 (s, 1 H), 8.329 (s, 1 H), 7.808 (s, 1 H), 7.744-7. (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), 1.99 (m, 1 H), 1.670 (s, 3 H).

Example 2.37

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-imidazole-2 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64-8.54 (m, 1H), 8.34-7.90 (m, 2H), 7.39-7.17 (m, 4H), 7.06-7.01 (m, 4H), 6.77-6.68 (m, 1H), 5.66-5.59 (m, 0.7H), 5.26-5.24 (m, 0.2H), 3.89-3.81 (m, 1H), 3.63-3.55 (m, 1H), 3.45-3.22 (m, 1H), 3.12-3.05 (m, 1H), 2.61-2.26 (m, 5H), 2.19-1.92 (m, 3H), 1.63 (broad single peak, 3H).

Example 2.38

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) Alk-7-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.40 (m, 1H), 7.33-7.19 (m, 4H), 7.05-6.88 (m, 2H), 6.78-6.75 (m, 1H), 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, 1H), 3.62-3.53 (m, 1H), 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

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((R )-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (CDCl ₃ ) δ 8.74 and 8.62 (s, 1H); 8.32 and 8.10 (s, 2H), 7.79 and 7.71 (s, 1H); 7.22 (m, 4H); 6.98 (m, 2H), 6.80 (m, 2H); 5.70 and 5.20 (t, 1H); 3.75 (m, 2H); 3.10 (dd, 2H, J = 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyridin-2-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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) , 1H), 6.81 (s, 1H), 7.03-7.05 (m, 2H), 7.22-7.34 (m, 4H), 7.83-7.85 (m, 2H), 8.27 (s, 1H), 8.40 (s, 1H) ), 8.70-8.75 (m, 2H).

Example 2.41

(2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)amine)methyl)phenyl)-1,3,4-oxadiazol-2-yl) T-butyl -1-phenylpropan-2-yl)carbamate. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.21-7.95 (m, 2H), 7.76-7.48 (m, 1H), 7.28-7.19 (m, 3H), 7.05-7.02 (m, 2H), 7.02-6.75 (m,1H), 5.67-5.63 (m, 0.6H), 5.15-5.13 (m, 0.3H), 3.94-3.76 (m, 1H), 3.60-3.43 (m, 4H), 3.29-3.22 (m, 1H), 3.12-3.05 (m, 1H), 2.49-2.32 (m, 4H), 2.23-1.95 (m, 5H), 1.66-1.64 (m, 3H).

Example 2.42

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-methyl- 1H-pyrrol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11-7.86 (m, 2H), 7.76-7.42 (m, 1H), 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, 1H), 3.11-3.04 (m, 1H), 2.47-2.31 (m, 4H), 2.24-1.93 (m, 3H), 1.77 (width unimodal, 3H), 1.66-1.63 (m, 3H).

Example 2.43

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-( (4-Methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.707 (s, 1 H), 8.403 (s, 1 H), 8.301 (s, 1 H), 7.78 (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

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H, J = 51 Hz), 5.83-5.88 (m, 1H), 6.85-7.03 (m, 4H), 7.30 (s, 2H), 7.80 (s, 1H), 8.34 (s, 1H), 8.40 (s, 1H), 8.74 (s, 1H).

Example 2.45

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Pyrazin-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.66 (s, 3H), 2.45 (s, 3H), 2.79-2.91 (m, 2H), 3.06-3.29 (m, 2H), 3.90-4.19 (m, 2H) ), 5.31 (d, 1H, J = 51 Hz), 5.84-5.89 (m, 1H), 6.86-7.05 (m, 7H), 8.33 (s, 1H), 8.43 (s, 1H), 8.61 (s, 1H), 8.69 (s, 1H), 8.76 (s, 1H), 9.15 (s, 1H).

Example 2.46

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2 -(4-Methylthiazol-2-yl)piperidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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) , 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(5-methyl- 1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H) ), 3.77-3.93 (m, 2H), 5.63-5.67 (m, 1H), 6.74 (s, 1H), 6.99-7.01 (m, 2H), 7.20-7.25 (m, 3H), 8.20 (s, 1H) ), 8.33 (s, 1H), 8.47 (s, 1H).

Example 2.48

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-isopropyl-N-( (4-Methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) 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 , 1H), 4.92-4.45 (m, 2H), 4.07 (m, 1H), 3.26 (d, 1H), 3.08 (d, 1H), 2.42 (s, 3H), 1.09 (s, 3H), 1.24 1.19 (m, 6H).

Example 2.49

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((2R) , 4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80 (s, 0.8H), 8.72 (s, 0.2H), 8.38 (two single peaks, 1.7H), 7.98 (s, 0.3H), 7.80 (s, 1H), 7.34-7.20 (m, 4H), 7.00-6.92 (m, 2H), 6.82 (s, 1H), 6.80 (s, 1H), 5.92-5.82 (m, 1H), 5.40 (br s, 0.5) H), 5.20 (br s, 0.5H), 4.17-3.84 (m, 2H), 3.20-3.00 (m, 2H), 2.94-2.84 (m, 1H), 2.84-2.78 (m, 1H), 2.46 ( s, 3H), 1.78 (br s, 2H), 1.53 (s, 3H).

Example 2.50

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 5-Methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) 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

(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-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) 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

3-[5-(1-Amino-2-phenylcyclohexyl)-1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4-methyl-1, 3-thiazol-2-yl)methyl]benzamide.

Example 2.53

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

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.

Example 2.55

3-(5-(2-Amino-1-methoxy-3-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((4-Methylthiazol-2-yl)methyl)benzamide.

Example 2.56

3-(5-( rel -(1S,2R)-1-amino-2-phenylcyclobutyl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((4-Methylthiazol-2-yl)methyl)benzamide.

Example 2.57

3-(5-( rel -(1R,2R)-1-amino-2-phenylcyclobutyl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((4-Methylthiazol-2-yl)methyl)benzamide.

Example 2.58

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.

Example 2.59

3-[5-(2-Amino-1,5-diphenylpentan-2-yl)-1,3,4-oxadiazol-2-yl]-N-methyl-N-[(4 -Methyl-1,3-thiazol-2-yl)methyl]benzamide.

Example 2.60

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.

Example 2.61

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.

Example 2.62

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5- (Evil Oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.72 (s, 1H), 8.64 -8.50 (m, 2H), 8.34 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 7.28-7.00 (m, 3H), 7.04-6.98 (m , 2H), 4.96 (s, 1.4H), 4.68 (s, 0.6H), 3.36-3.20 (m, 1H), 3.36-3.02 (m, 4H), 1.67 (s, 3H).

Example 2.63

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 2-methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.48-8.20 (m, 3H), 7.80 (m, 1H), 7.32 (s, 1H), 7.28-6.98 (m, 3H), 7.04-6.98 (m, 2H), 4.92 (s, 1H), 4.54 (s, 1H) ), 3.36-3.22 (m, 1H), 3.20-3.02 (m, 4H), 2.78-2.72 (two single peaks, 3H), 2.00 (br s, 2H), 1.67-1.66 (two single peaks, 3H) ).

Example 2.64

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 2-methyloxazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 8. 8.18 (m, 3H), 7.80 (m, 1H), 7.60, 7.60 (two single peaks, 1H), 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, 1H), 3.20-3.02 (m, 4H), 2.52-2.40 (two single peaks, 3H), 1.80 (br s, 2H), 1.67 ( s, 3H).

Example 2.65

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 8.42-8.00 (m, 2H), 7.80 (s, 1H), 7.36 (s, 1H), 7.30-7.00 (m, 3H), 7.08-6.98 (m, 2H), 6.92 (s, 1H), 5.00 (s, 1.3) H), 4.78 (s, 0.7H), 3.37-3.22 (m, 1H), 3.22-3.00 (m, 4H), 2.42 (s, 3H), 1.90 (br s, 2H), 1.66 (s, 3H) .

Example 2.66

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((R)-1- (4-Methylthiazol-2-yl)ethyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.62 ( s, 1H), 8.58 (s, 1H), 7.80 (s, 1H), 7.32-7.20 (m, 3H), 7.06-7.00 (m, 2H), 6.82 (s, 1H), 5.64-5.58 (m, 1H), 3.30 (d, J = 14.8 Hz, 1H), 3.10 (d, J = 14.8 Hz, 1H), 2.43 (s, 3H), 2.02 (br s, 2H), 1.74 (d, J = 7.2 Hz) , 3H), 1.66 (s, 3H).

Example 2.67

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl -N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H ), 8.42-8.20 (m, 2H), 7.8 (s, 1H), 7.32 (s, 1H), 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 5-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.77 (s, 1H), 8.40-8.00 (m, 2H), 7.80 (s, 1H), 7.40 (s, 1H) 7.32 (s, 1H), 7.30-7.00 (m, 3H), 7.06-6.98 (m, 2H), 4.97 (s, I. 4H), 4.72 (s, 0.6H), 3.37-3.24 (m, 1H), 3.20.-3.00 (m, 4H), 2.44 (s, 3H), 1.90 (br s, 2H), 1.67 (s, 3H) ).

Example 2.69

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.42-8.20 (m, 2H), 7.8 (s, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.30-7.20 (m, 3H), 7.08-6.98 (m, 2H), 4.82 (s, 1.3) H), 4.56 (s, 0.7H), 3.36-3.24 (m, 1H), 3.20-3.04 (m, 4H), 2.2 (s, 3H), 1.80 (br s, 2H), 1.67 (s, 3H) .

Example 2.70

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H) , 8.22(s,1H), 8.18(s,1H), 7.79(s,1H),7.31(s,1H),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, 1H), 3.12 (d, J = 14.8 Hz, 1H), 3.12 (s, 3H), 2.42 (s, 3H) , 2.41 (s, 3H), 1.80 (br s, 2H), 1.67 (s, 3H).

Example 2.71

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- Phenyl)((R)-4-(4-methylthiazol-2-yl)oxazolidine-3-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.92 (s, 1H ), 8.82 (s, 1H), 8.70 (s, 1H), 7.82 (s, 1H), 7.80 (d, J = 9 Hz, 1H), 7.33 (s, 1H), 7.26-7.20 (m, 4H) , 7.06-7.00 (m, 2H), 6.92 (s, 1H), 5.8-5.72 (m, 1H), 4.77 (d, J = 6.2 Hz, 2H), 3.36 (d, J = 14.8 Hz, 1H), 3.16 (d, J = 14.8 Hz, 1H), 2.46 (s, 3H), 1.82 (br s, 2H), 1.69 (s, 3H).

Example 2.72

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(( 2,5-Dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.83 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.32 (s, 1H), 7.06-6.90 (m, 4H), 4.60 (s, 1.3H) , 4.24 (s, 0.7H), 3.28 (d, J = 14.8 Hz, 1H), 3.08 (d, J = 14.8 Hz, 1H), 3.12 (s, 3H), 2.42 (s, 3H), 2.41 (s) , 3H), 1.84 (br s, 2H), 1.65 (s, 3H).

Example 2.73

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) 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, J = 14.8 Hz, 1H), 3.10 (d, J = 14.8 Hz, 1H), 3.14 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 1.68 (s, 3H).

Example 2.74

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (s, 1H), 8.80-8.20 (m, 5H), 7.32-7.20 (m, 3H), 7.14-7.00 (m, 2H), 6.92 (s, 1H), 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 3-Methyl-1,2,4-oxadiazol-5-yl)methyl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.18-8.10 (m, 2H), 7.70-7.62 (m, 1H), 7.62-7.57 (m, 1H), 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, J = 14.8 Hz, 1H), 3.10 (d, J = 14.8 Hz, 1H), 3.18 (s, 3H), 2.44 (s, 3H), 1.78 (s, 2H), 1.66 (s, 3H).

Example 2.76

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-N-methyl-5-(pyridin-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.82-7.80 (m, 6H ), 7.36-7.30 (m, 1H), 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, J) =14.8 Hz, 1H), 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-chloro-N-(2 ,5-Dimethyloxazol-4-yl)methyl)-N-methylbenzamide: [M+H]: 480.180.

Example 2.78

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-chlorophenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone: [M+H]: 508.157.

Example 2.79

(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-1-yl)methanone: [M+H]: 526.148.

Example 2.80

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(t-butyl)- N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((4-methylthiazole) -2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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, J = 13.5 Hz, 1 H), 3.088 (d, J = 13.5 Hz, 1 H), 2.350 (s, 3 H), 1.623 (s, 3 H).

Example 2.82

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(fluoromethyl)benzene ((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-( (4-Methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 9.126 (s, 1 H), 8.712-8.674 (m, 2 H), 8.559 (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, J = 13.2 Hz, 1 H), 3.123 (d, J = 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

(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-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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), 7.852 (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), 3.774 (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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclobutyl-N-( (4-Methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.733 (s, 1 H), 8.273 (s, 1 H), 8.196 (m, 1 H), 7.860 (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, J = 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1,3,4 -oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 9.272 (br, 0.7 H), 8.871 (br, 0.3 H), 8.507 (s, 0.7 H), 8.403 (s, 0.3H), 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), 3.719 (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

5-(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-1,3,4-oxadiazole-2(3H)-one: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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), 8.05 (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), 3.12 (m, 1 H), 2.42 (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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-fluoroethyl Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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), 2.42 (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

1-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)ethanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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, 0.65 H), 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), 2.42 (s, 3 H), 2.311 (s, 1 H) ), 2.141 (m, 2 H), 1.985 (m, 1H), 1.659 (s, 3H).

Example 2.90

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazole- 1-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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).

real Example 2.91

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(isoxazole-5 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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), 1.69, 1.645 (m, 3 H).

Example 2.92

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1,1-di Fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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), 2.40 (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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(isoxazole-3 -yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ +CD ₃ OD) 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), 3.78 (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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazole- 3-(yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: LC/MS RT: 6.23, m/z 540.

Example 2.95

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2- (4-Methylthiazol-2-yl)pyrrolidin-1-carbonyl)benzonitrile: LC/MS RT: 5.68, m/z 499.184.

Example 2.96

5-(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R) -2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-1,3,4-oxadiazole-2(3H)-one: LC/MS RT: 5.63, m/z 572.200.

Example 2.97

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2- Ethyl (4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoate. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80-8.60 (m, 1H), 8.41-8.07 (m, 2H), 7.29-7.19 (m, 4H), 7.05-7.02 (m, 2H), 6.91-6.71 (m, 1H), 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, 1H), 3.31-3.23 (m, 1H), 3.12-3.05 (m, 1H), 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

(3-(5-((R)-2-Amino-1-cyclohexylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2 -(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80-8.60 (m, 1H), 8.24-7.94 (m, 2H), 7.76-7.41 (m, 2H), 6.79-6.75 (m, 1H), 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, 1H), 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

(3-(5-((R)-2-Amino-1-cyclohexylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.76-8.64 (m, 1H), 8.41 - 8.04 (m, 2H), 7.81 - 7.74 (m, 1H), 7.32 - 7.27 (m, 1H), 6.81-6.74 (m, 1H), 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, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(thiazol-2-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.63-8.60 (m, 1H), 8.41-7.88 (m, 3H), 7.46-7.7.39 (m, 1H), 7.27-7.20 (m, 3H), 7.20 -7.03 (m, 2H), 6.81-6.74 (m, 1H), 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, 1H), 3.31-3.23 (m, 1H), 3.12-3.05 (m, 1H), 2.45-2.27 (m, 4H), 2.20-2.11 (m, 5H), 1.67-1.64 (m, 3H).

Example 2.101

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5-(( R)-2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45-8.37 (m, 1H), 8.32-7.81 (m, 2H), 7.28-7.20 (m, 4H), 7.04-7.02 (m, 2H), 6.79-6.76 (m, 1H), 6.68-6.39 (m, 1H), 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, 1H), 3.29-3.21 (m, 1H), 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

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2- (4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.54-8.45 (m, 1H), 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 (width single peak, 1H), 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, 1H), 3.29-3.19 (m, 1H), 3.17-3.05 (m, 1H), 2.49-2.26 (m, 4H), 2.24-1.76 (m, 6H), 1.65-1.63 (m, 3H) ).

Example 2.103

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N,N-dimethyl-5 -((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.25-7.98 (m, 2H), 7.78-7.51 (m, 1H), 7.33-7.15 (m, 4H), 7.03-7.01 (m, 2H), 6.79-6.74 (m, 1H), 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, 1H), 3.29-2.91 (m, 8H), 2.44 - 2.26 (m, 4H), 2.23 - 1.92 (m, 3H), 1.90-1.70 (width unimodal, 3H), 1.65-1.62 (m, 3H).

Example 2.104

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(thiazol-2-yl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67-8.62 (m, 1H), 8.32-8.16 (m, 2H), 7.94 - 7.93 (m, 1H), 7.44 (m, 1H), 7.28-7.21 (m) , 3H), 7.04-7.02 (m, 2H), 6.92-6.88 (m, 1H), 5.01 (width single peak, 1.3H), 4.74 (width single peak, 0.7H), 3.31-3.27 (m, 1H) , 3.19-3.08 (m, 4H), 2.46 (m, 3H), 2.10 - 1.80 (m, 2H), 1.67 (broad single peak, 3H).

Example 2.105

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(2-fluoroethyl) -N-((4-Methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.73-8.72 (m, 1H), 8.42-8.20 (m, 2H), 7.79 (s, 1H), 7.33-7.32 (m, 1H), 7.31-7.19 (m , 4H), 7.05-7.02 (m, 2H), 6.93-6.86 (m, 1H), 5.09-4.82 (m, 4H), 3.98-3.70 (m, 2H), 3.31-3.27 (m, 1H), 3.12 -3.08 (m, 3H), 2.44 (width single peak, 3H), 1.90 to 1.60 (m, 8H).

Example 2.106

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-ethyl-5-(( R)-2-(4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45-8.37 (m, 1H), 8.31 - 7.72 (m, 2H), 7.25-7.14 (m, 4H), 7.04-6.95 (m, 2H), 6.79-6. (m, 1H), 6.65-6.34 (m, 1H), 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, 1H), 3.11-3.04 (m, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(thiazol-2-yl) Phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67-8.55 (m, 1H), 8.35-7.94 (m, 3H), 7.47-7.46 (m, 1H), 7.26-7.22 (m, 4H), 7.05-7.04 (m, 2H), 6.86-6.56 (m, 1H), 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, 1H), 3.13 - 3.08 (m, 1H), 2.94 - 2.79 (m, 2H), 2.45 - 2.21 (m, 3H), 2.04-1.74 (m, 2H), 1.67 (single single peak, 3H).

Example 2.108

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Thiazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.69-8.28 (m, 1H), 8.35-7.94 (m, 3H), 7.48-7.46 (m, 1H), 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, 1H), 3.11-3.06 (m, 1H), 2.95-2.80 (m, 2H), 2.46-2.19 (m, 3H), 2.10- 1.72 (m, 6H).

Example 2.109

3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2- (4-Methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.67-8.58 (m, 1H), 8.35-7.98 (m, 2H), 7.26-7.17 (m, 5H), 6.98 (m, 2H), 6.76 -6.69 (m, 1H), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-hydroxyphenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66-7.45 (m, 2H), 7.39-7.15 (m, 4H), 7.03-6.90 (m, 2H), 6.80-6.75 (m, 1H), 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, 1H), 3.27-3.17 (m, 1H), 3.10-3.02 (m, 1H), 2.48-2.32 (m, 5H), 2.24-1.88 (m, 3H), 1.63-1.60 (m, 3H).

Example 2.111

(3-(5-((S)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.73-8.63 (m, 1H), 8.41-8.03 (m, 2H), 7.81-7.74 (m, 1H), 7.32-7.19 (m, 3H), 7.06-7.03 (m, 2H), 6.82-6.74 (m, 1H), 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, 1H), 3.32-3.24 (m, 1H), 3.13-3.06 (m, 1H), 2.45-2.41 (m, 4H), 2.27-2.11 (m, 2H), 2.03-1.64 (m, 6H).

Example 2.112

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((S)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71-8.61 (m, 1H), 8.39-8.00 (m, 2H), 7.79-7.73 (m, 1H), 7.30-7.20 (m, 3H), 7.01 (m) , 2H), 6.79-6.72 (m, 1H), 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, 1H) , 3.30-3.22 (m, 1H), 3.11-3.06 (m, 1H), 2.44-2.41 (m, 4H), 2.25-1.91 (m, 5H), 1.65-1.62 (m, 3H).

Example 2.113

(3-(5-((S)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- ()Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.72-8.61 (m, 1H), 8.40-8.01 (m, 2H), 7.80-7.73 (m, 1H), 7.31-7.17 (m, 3H), 7.05-7.02 (m, 2H), 6.80-6.73 (m, 1H), 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, 1H), 3.31-3.23 (m, 1H), 3.12-3.05 (m, 1H), 2.44-2.39 (m, 4H), 2.26-1.89 (m, 5H), 1.66-1.62 (m, 3H).

Example 2.114

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(dimethylamino) -N-Methyl-N-((4-methylthiazol-2-yl)methyl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36-7.19 (m, 5H), 7.01 (m, 2H), 6.89 (m, 1H), 4.98 (single singular, 1.1H), 4.73 (width singular, 0.9H), 3.28-3.23 (m, 1H), 3.14-3.00 (m, 10H), 2.44-2.41 (m, 3H), 2.08 (width unimodal, 2H), 1.64 (s, 3H).

Example 2.115

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(N-methylmethanesulfonate Amidino)-N-((4-methylthiazol-2-yl)methyl)benzamide. [M+H]=541.1.

Example 2.116

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-4-methoxy-N-methylbenzamide. [M+H] = 476.2.

Example 2.117

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-methoxyphenyl) ((R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone. [M+H] = 504.2.

Example 2.118

(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-1-yl)methanone. [M+H] = 522.2.

Example 2.119

(R)-5-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-6-methoxy-N-methylnicotinium amide. [M+H] = 477.2.

Example 2.120

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-methoxypyridine-3 -())((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. [M+H]=505.2.

Example 2.121

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-methoxypyridine-3 -yl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone. [M+H] = 523.2.

Example 2.122

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-N-methyl-4-(trifluoromethoxy)benzamide. [M+H] = 530.2.

Example 2.123

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-methyl- 1H-imidazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 6.80 (s, 1H), 6.86- 7.38 (m, 7H), 8.40 (s, 1H), 8.22 (s, 1H), 8.40 (s, 1H).

Example 2.124

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl ]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61 (s, 3H ), 1.81-2.42 (m, 6H), 3.10-3.38 (m, 2H), 3.56-3.64 (m, 1H), 3.81-3.98 (m, 2H), 5.63-5.76 (m, 1H), 6.80-8.36 (m, 14H).

Example 2.125

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-3'-methoxy-[ 1,1'-biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ 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

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-2'-methoxy-[ 1,1'-biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(furan-2-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-iodophenyl)(( R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 3.53-3.92 (m, 2H), 5.62-5.66 (m, 1H), 6.81 ( s, 1H), 7.04-7.22 (m, 2H), 7.23-7.26 (m, 3H), 8.05 (s, 1H), 8.08 (s, 1H), 8.38 (s, 1H).

Example 2.129

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-ethyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 8.18-8.23 (m, 1H), 8.76 (s, 1H).

Example 2.130

(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-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60 (s, 3H), 1.82 - 2.42 (m, 6H), 3.20-3.84 (m, 5H), 5.61-5.72 (m, 1H), 6.78-7.22 (m, 6H), 8.0-8.41 (m, 3H).

Example 2.131

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-nitrophenyl) ( (R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62 (s, 3H), 1.98-2.41 (m) , 6H), 3.10-3.32 (m, 2H), 3.52-3.61 (m, 1H), 3.98-4.02 (m, 2H) 55.61-5.66 (m, 1H), 6.78-7.24 (m, 6H), 8.18- 8.92 (m, 3H).

Example 2.132

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(furan-3-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 3.79-3.96 (m, 2H), 5.69-5.71 (m, 1H) ), 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

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyrimidin-5-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.63 (s, 1H), 1.94-2.40 (m, 5H), 2.42-3.26 (m, 2H), 3.42-3.56 (m, 1H), 3.58-3.92 (m, 2H), 5.66-5.70 (m, 1H), 6.8 (s, 1H) ), 7.02-7.21 (m, 2H), 7.22-7.26 (m, 4H), 7.43 (s, 1H), 7.56-7.61 (m, 1H), 7.75-7.77 (m, 1H), 7.94-8.22 (m , 2H).

Example 2.134

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyridin-3-yl) Phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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,1H),3.64-3.95(m,2H),5.67-5.71(m,1H ), 6.81 (s, 1H), 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, 1H).

Example 2.135

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5-(N -Methylamine sulfonyl)-N-((4-methylthiazol-2-yl)methyl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(pyridin-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) 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

(3-(5-((R)-2-amino-1-(2-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60 (s, 3H), 1.76-2.42 (m, 6H), 3.10-4.12 (m, 5H), 5.61-5.78 (m, 1H), 6.79-7.38 (m, 6H), 8.10-8.82 (m, 4H) , 9.20 (s, 1H).

Example 2.138

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(2-methylthiazole) -4-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 6.76-7.36 (m, 14H), 7.51 (s, 1H), 8.18-8.28 (m, 2H), 8.60 (s, 1H).

Example 2.139

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(4,5-di Methylthiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ^I H NMR (300 MHz, CDCl ₃ ) δ 1.60 (s, 3H), 2.01-2.42 (m, 6H), 3.10-3.32 (m, 2H), 3.58-3.62 (m, 1H), 3.92-4.02 (m, 2H), 5.68-5.82 (m, 1H) ), 6.72-7.31 (m, 7H), 8.20 (s, 1H), 8.44-8.60 (m, 1H).

Example 2.140

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((3-fluoropyridine- 2-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.6 (s, 3H), 3.10-3.38 ( m, 5H), 4.70 (s, 1H), 5.0 (s, 1H), 7.0 (m, 2H), 7.20-7.31 (m, 6H), 7.80 (d, 1H), 8.22-8.61 (m, 3H) , 8.71 (s, 1H)

Example 2.141

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5- (Evil Oxazol-2-yl)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60 (s, 3H) , 3.04-3.38 (m, 5H), 5.029s, 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluoro-N-methyl- N-((4-Methylthiazol-2-yl)methyl)benzamide: m/z: M ⁺ : 466.169.

Example 2.143

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-4-fluoro-N-methylbenzamide: m/z: M ⁺ : 464.207.

Example 2.144

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluorophenyl)(( R)-2-(4-Methylthiazol-2-yl)pyrrolidin-1-yl)methanone: m/z: M ⁺ : 492.183.

Example 2.145

(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluorophenyl)(( R)-2-(4-Methyloxazol-2-yl)pyrrolidin-1-yl)methanone: m/z: M ⁺ : 476.206.

Example 2.146

(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-1-yl)methanone: m/z: M ⁺ : 510.174.

Example 2.147

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-( (2,5-Dimethyloxazol-4-yl)methyl)-4-fluorobenzamide: m/z: M ⁺ : 490.222.

Example 2.148

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-cyclopropylpyridine- 4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

2-(6-{5-(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[(2 R )-2-(4-Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)benzonitrile (2 E )-but-2-ene Acid salt (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (0.6H, s), 8.22 (0.6H, s), 8.06 (1.8H, m), 7.90 (2H, m), 7.73 (1H, m), 7.20 (3.6H, m), 7.05 (2.4H, m), 6.62 (2H, s), 5.50 (0.6H, dd, J = 4.4 Hz), 5.33 (0.4H, m) , 3.76 (1.2H, m), 3.61 (0.8H, m), 3.12 (2H, m), 2.41 (1H, m), 2.37 (1.8H, s), 2.16 (1H, 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

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E ) -but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 4.0 Hz), 5.23 (0.4H, m), 3.67 (2H, m), 3.15 (2H, m), 2.41 ( 1H, m), 2.37 (1.8H, m), 2.16 (1.2H, m), 2.14 (1H, m), 1.99 (2H, m), 1.50 (3H, s). MS (ESI) M/Z: 271.8 [M+2H] ⁽²⁺⁾ /2.

Example 2.151

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2 E )-but-2-enate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

N -(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[( 2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl) -N -methylmethanesulfonamide (2 E ) -but-2-enedionate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

N -(4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-{[( 2 R )-2-(4-Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]-carbonyl}pyridin-2-yl) -N -methylmethanesulfonamide (2 E -but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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 (0.6) H, dd, J = 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 (1H, 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

(4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 2-() R )[( 2R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate ( 1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 4.0 Hz), 4.08 (0.5H, m), 4.01 (1.5H, s), 3.91 (0.5H, m), 3.78 (1H, m), 3.65 (1.5H, s), 3.11 (2H, m), 2.42 (1H, m ), 2.34 (1.5H, m), 2.23 (1.5H, m), 2.06 (2H, m), 1.83 (1H, m), 1.48 (3H, m). MS (ESI) M/Z: 505.3 [M+H] ⁺ .

Example 2.155

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-ethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)- But-2-ene diacid salt (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (0.6H, s), 8.39 (0.4H, s), 8.31 (0.6H, s), 8. (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 (2.4) H, m), 6.62 (2H, s), 5.50 (0.6H, dd, J = 4.0 Hz), 5.26 (0.4H, m), 3.69 (2H, m), 3.15 (2H, m), 2.72 (1.2) H, q, J = 7.4 Hz), 2.47 (1H, m), 2.40 (0.8H, m), 2.15 (1H, m), 1.99 (2H, m), 1.50 (3H, m), 1.24 (1.8H) , t, J = 7.4 Hz), 0.99 (1.2H, t, J = 7.8 Hz). MS (ESI) M/Z: 556.4 [M+H] ⁺ .

Example 2.156

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2 R )-2-(4-cyclopropyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl]{( 2R )-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl}A Ketone (2E)-but-2-enedioate (1:1): MS (ESI) m/z: 572[M+H] ⁺ .

Example 2.158

(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,3'-bipyridine -4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.43 (0.6H, s), 9.23 (0.4H, s), 8.74 (0.6H, dd, J = 2.7 Hz), 8.70 (0.4H) , dd, J = 2.7 Hz), 8.60 (0.6H, dt, J = 8.0, 1.8 Hz), 8.42 (0.4H, dt, J = 8.0, 1.8 Hz), 8.37 (0.6H, s), 8.14 (0.6 H, s), 8.05 (0.4H, s), 7.87 (0.4H, s), 7.59 (1H, m), 7.21 (3.6H, m), 7.07 (2.4H, m), 6.61 (2H, s) , 5.50 (0.6H, dd, J = 4.0 Hz), 5.31 (0.4H, m), 3.77 (1H, m), 3.58 (1H, m), 3.15 (2H, m), 2.43 (1H, m), 2.38 (1.8H, s), 2.18 (1H, 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

(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,4'-bipyridine -4-yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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 (0.4 H, 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, J = 4.0 Hz), 5.29 (0.4H, m), 3.76 (1H, m), 3.58 (1H, m), 3.15 (2H, m), 2.44 (1H, m), 2.37 (1.8H, s), 2.17 (1H, 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

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrimidine-5- Pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Diacid salt (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.61 (1.2H, s), 9.44 (1H, 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, J = 4.0 Hz), 5.33 (0.4H, m), 3.77 (1.2H, m), 3.58 (0.8H, m), 3.14 (2H, m), 2.44 (1H, m), 2.38 (1.8H, s), 2.20 (1H, 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

(2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methylpyridine-4 -yl)[(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1 :1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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 (1H, m), 2.37 (2.1H, s), 2.21 (0.9H, s), 2.15 (1H, m), 1.98 (2H, m), 1.47 (3H, m). MS (ESI) M/Z: 489.3 [M+H] ⁺ .

Example 2.162

[2-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,1- Dioxylyl-1,2-thiazolidin-2-yl)pyridin-4-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -Methyl ketone (2E)-but-2-enedioate (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

N -(6-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[( 2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)methanesulfonamide (2E)-but-2-ene Diacid salt (1:1): MS (ESI) m/z: 285 [M+2H] ⁽²⁺⁾ /2.

Example 2.164

(4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-methoxypyridine- 2-()()-[( 2R )-2-(4,5-dimethyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]-methanone (2E)-but-2-ene Diacid salt (1:1): MS (ESI) m/z: 260.3 [M+2H] ⁽²⁺⁾ /2.

Example 2.165

[4-{5-[(2 R )-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-2-yl][(2 R )-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)- But-2-ene diacid salt (1:1): ¹ H NMR (400 MHz, CDCl ₃ ) 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, J = 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

1-(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-yl]carbonyl}pyridin-2-yl)pyrrolidin-2-one (2E)-but-2-ene Diacid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

3-(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-yl]carbonyl}pyridin-2-yl)-1,3-oxazolidin-2-one (2E) -but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

1-(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-yl]carbonyl}pyridin-2-yl)-5-methylpyrrolidin-2-one (2E)- But-2-ene diacid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, J = 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

1-(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-yl]carbonyl}pyridin-2-yl)piperidin-2-one (2E)-but-2-ene Diacid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-yl]carbonyl}pyridin-2-yl)-N-methylacetamide (2E)-butyl-2 - enedic acid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 2.071

1-(4-{5-[(2R)-2-amino-1-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)pyrrolidin-2-one (2E)-but-2-ene Diacid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-1,2 ,4-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E -but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-imidazole-1 -yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Diacid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-pyrazole- 1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2- Olelic acid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, m), 3.77-3.10 (6H, m), 2.70-1.86 (7H, m), 1.53-1.47 (3H, m). MS (ESI) m / z: 541 [M+H] ⁺ .

Example 2.175

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(2H-1,2 ,3-triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E -but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H-1,2 ,3-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E )-but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMS0-d ₆ ) 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E) -but-2-enedioate (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-(1,3-oxazol-2-yl)isonicotinamide (2E)-but-2-enedioate ( 1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 6-methylpyridin-3-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1) : MS (ESI) m/z: 510 [M+H] ⁺ .

Example 2.181

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[1-(1-A -1H-pyrazol-3-yl)ethyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1 ): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 6-methylpyridin-2-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate (1:1) : ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (1.8) H, 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

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 1-methyl-1H-pyrazol-4-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate ( 1:1): MS (ESI) m/z: 499 [M+H] ⁺ .

Example 2.184

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(1,5-di) Methyl-1H-pyrazol-4-yl)methyl]-N-methyl-6-(1,3-oxazol-2-yl)isonicotinamine amide (2E)-but-2-ene Acid salt (1:1): MS (ESI) m/z: 513 [M+H] ⁺ .

Example 2.185

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(1,3-di) Methyl-1H-pyrazol-5-yl)methyl]-N-methyl-6-(1,3-oxazol-2-yl)isonicotinamine amide (2E)-but-2-ene Acid salt (1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (0.7H, s), 8.42 (0.3H, s), 8.27 (0.7H, s), 8.25 (1H, s ), 8.19 (0.3H, s), 7.57 (1H, 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

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl-1H -pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

(2-Amino-6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}pyridine-4- ()((2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1:1 ): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.28-6.96 (8H, m), 6.73 (0.75H, s), 6.72 (0.75H, s), 6.62 (2H, s), 6.54 (0.25) H, 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

2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[( 1-methyl-1H-pyrazol-3-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamide amide (2E)-but-2-enedioate ( 1:1): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

(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-1-yl]methanone 2-hydroxypropane-1,2,3-tricarboxylate (1:1): MS (ESI) M/Z: 475 [M+H] ⁺ .

Example 2.190

(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-1-yl]methanone 2-hydroxypropane-1,2,3-tricarboxylate (1:1): MS (ESI) M/Z: 475 [M+H] ⁺ .

Example 2.191

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrrolidine-1- Pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-ene Acid salt (1:1): MS (ESI) M/Z: 544 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (0.4 H, 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

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-4-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): MS (ESI) M/Z: 505 [M+H] ⁺ .

Example 2.193

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(difluoromethoxy Pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioic acid Salt (1:1): MS (ES/) M/Z: 541 [M+H] ⁺ .

Example 2.194

4-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-6-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): MS (ESI) M/Z: 505 [M+H] ⁺ .

Example 2.195

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}pyridine-2(1H)-one (2E)-butyl- 2-Oledic acid salt (1:1): MS (ESI) M/Z: 545 [M+H] ⁺ .

Example 2.196

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-ethyl-4-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): MS (ESI) M/Z: 519 [M+H] ⁺ .

Example 2.197

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-ethoxypyridine-4 -yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-but-2-enedioate (1: 1): MS (ESI) M/Z: 519 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (1.8) H, 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

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-[(2-methoxy) Ethylethyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone (2E)-butyl -2-enedioic acid salt (1:1): MS (ESI) M/Z: 548 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, J = 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 (1H, 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

(2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-[(2-methoxy) (ethyl)amino(methyl)amino]pyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone 2E)-but-2-enedioate (1:1): MS (ESI) M/Z: 562 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 (1H, 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 (1H, 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

[2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-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): MS (ESI) M/Z: 518 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24-7.11 (5.3H, m), 7.05-6.98 (2.7 H, m), 6.73 (0.7H, br s), 6.62 (2H, s), 6.40 (0.3H, br s), 5.43 (0.7H, dd, J = 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, J = 7.2 Hz), 1.17 (0.9H, t, J = 7.2 Hz).

Example 2.201

3-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-5-{[ (2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioic acid Salt (1:1): MS (ESI) M/Z: 505 [M+H] ⁺ .

Example 2.202

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-yl]carbonyl}pyridine-2(1H)-one (2E)-but-2-enedioate (1:1 ): MS (ESI) M/Z: 491 [M+H] ⁺ .

Example 2.203

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 -Phenoxy-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 459 [M+H] ⁺ .

Example 2.204

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-oxooxy-1,2-dihydropyridine-4-carboxamide: MS (ESI) M/Z: 473 [M+H ] ⁺ .

Example 2.205

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-butyl-1-methyl -2-Alkyloxy-N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 501 [M+H] ⁺ .

Example 2.206

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-4-{[ 2-(3-Methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one: MS (ESI) m/z: 490 [ M+H] ⁺ .

Example 2.207

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-butyl-1-methyl -2-Sideoxy-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 501 [M+H] ⁺ .

Example 2.208

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 -Phenoxy-N-(1H-pyrazol-5-ylmethyl)-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 448 [M+H] ⁺ .

Example 2.209

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2 -Phenoxy-N-[1-(2-thienyl)ethyl]-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 478 [M+H] ⁺ .

Example 2.210

6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-[(2,5-di Methyl-1,3-oxazol-4-yl)methyl]-N,1-dimethyl-2-oxooxy-1,2-dihydropyridine-4-carboxamide: MS (ESI) m/z: 477 [M+H] ⁺ .

Example 2.211

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropane Base-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide. ¹ H NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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), 1.673 (s, 3 H), 0.666 (m, 2 H), 0.558 (m, 2H).

Example 2.212

(3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-bromophenyl)(( R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20-8.11 (m, 2H), 7.86 (m, 1H), 7.33-7.21 (m, 4H), 7.03-7.01 (m, 2H), 6.81-6.79 (m, 1H), 5.67-5.63 (m, 0.6H), 5.11 (m, 0.3H), 3.98- 3.70 (m, 2H), 3.59-3.54 (m, 1H), 3.29-3.21 (m, 1H), 3.11-3.07 (m, 1H), 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

(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-1-yl)methanone: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01-7.93 (m, 2H ), 7.73-7.72 (m, 1H), 7.29-7.22 (m, 4H), 7.04-7.01 (m, 2H), 6.85-6.84 (m, 1H), 5.85-5.85 (m, 1H), 5.54-5.23 (m, 2H), 4.06-3.63 (m, 4H), 3.29-3.24 (m, 1H), 3.11-3.07 (m, 1H), 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

(R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol -4-yl)methyl)-4,5-difluoro-N-methylbenzamide: LC/MS RT: 7.30, m/z 482.

Example 2.215

(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-1-yl)methanone: LC/MS RT: 7.08-7.45, m/z 494.

Example 2.216

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluoro Phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone: m/z: M ⁺ : 494.200.

Example 2.217

(R)-5-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol -4-yl)methyl)-2,4-difluoro-N-methylbenzamide: m/z: M ⁺ : 482.201.

Example 2.218

(R)-4-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-5-fluoro-N-methylpyridinecarhamamine. MS (ESI) RT 6.66, m / z: 465.204 [M + 1] +.

Example 2.219

(R)-4-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-di) Methyloxazol-4-yl)methyl)-5-methoxy-N-methylpyridinecarhamamine. MS (ESI) RT 6.57, m / z: 477.224 [M + 1] +.

Example 2.220

(R)-3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-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

(3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-4,5 (Difluorophenyl)((S)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone: LC/MS RT: 7.51, m/z 512.189.

Example 2.222

(5-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,4-difluorophenyl ((R)-2-(4- Methyloxazol -2-yl)pyrrolidin-1-yl)methanone: m/z: M ⁺ : 494.200.

Example 3: Inhibition of membrane aspartate 2β-secretase activity Example 3.1

The potency of the compounds was determined by measuring the inhibition of the activity of the membrane aspartic protease 2 against fluorescent receptors. Kinetic inhibition experiments were performed using the procedure described in Ermolieff et al. ( Biochemistry 39: 12450-12456 (2000), the teachings of which is incorporated herein by reference in its entirety). Briefly, the analysis was carried out by pre-incubating the membrane aspartame 2 enzyme with the compound for 20 minutes at pH 4, 37 °C. Activity measurements were initiated by the addition of fluorescent receptor FS-2 (Bachem Americas, Torrance, CA) MCA-SEVNLDAEFK-DNP (SEQ ID NO.: 2). The receptor is derived from 10 amino acids of human amyloid precursor protein (APP), and a Swedish-type variant amino acid is present at the β-secretase cleavage site. The terminal amino acid is modified from arginine to lysine to facilitate derivatization with functional groups for detection by spontaneous fluorescence. The amino acid sequence of the stressed "core" peptide is SEVNLDAEFK (SEQ ID NO.: 3). Derivatization of the amino terminus with (7-methoxycoumarin-4-yl)ethenyl (MCA) and derivatization of the terminal residue with 2,4-dinitrophenyl (DNP) (sequence SEVNLDAEFK (SEQ ID NO.: The ε amine of the amino acid side chain of K). The results are shown in Table 1 ("BACE1 K _i "). For example, using this procedure for (7-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) The BACE1 K _i determined by alk-5-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone was about 702 nM. In other examples, 3'-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'- (2-(5-Methylfuran-2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile is about 1562 nM, 3'-(5-((R) )-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'-((R)-2-(4-methylthiazole- 2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile is about 201 nM, (R)-3-(5-(2-amino-1-phenyl) Prop-2-yl)-1,3,4-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-1-phenylpropan-2-yl)-1,3,4- 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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-( Oxazol-2-yl]pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone fumarate is about 139 nM , (R)-3-(5-(2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-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-1-phenylpropan-2-yl)-1,3,4-oxa (oxazol-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidine -1-yl)methanone fumarate is about 124 nM, (R)-3-(5-(2-amino-1-(4-fluorophenyl)propan-2-yl)-1 ,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide The amine is about 29 nM, (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N- --N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide is about 30 nM, (R)-3-(5-(2) -amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((2,5-dimethyloxazole- 4-yl)methyl)-4-fluorobenzamide is about 18 nM, (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3, 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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole -2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone is about 101 nM, (R)- 3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((4-A) Thiazole-2-yl)methyl)-5-(oxazole- 2-yl)benzamide is about 20 nM, (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone is about 63 nM, (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-methylphenyl) ( (2R,4S)-4-fluoro-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone is about 438 nM, 1-(3-(5-((R)-) 2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2-(4-methylthiazol-2-yl) Pyrrolidine-1-carbonyl)phenyl)pyrrolidin-2-one is about 677 nM, and (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-) 1,3,4-oxadiazol-2-yl)-5-methylphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone About 473 nM.

Example 3.2

2 Protease enzyme measured as IC film aspartic acid _50, at pH 4.4, at room temperature, by the film 2 aspartic protease enzyme and compound were pre-incubated together for 15 minutes for analysis. Fluorescence intensity was measured 60 minutes after the addition of the fluorescent receptor MCA-SEVNLDAEFK-DNP (SEQ ID No: 2) (M-2485, Bachem Americas, Torrance, CA). The IC ₅₀ value is calculated by SAS version 8.2.

Example 3.3

3.2 as described in Example ₅₀ the measured values of IC, except calculated using Graphpad Prism version 5.

Example 3.4

BACE 1% inhibition was measured at 3 μM inhibitor concentration as described in Example 3.2.

N.I. = No inhibition of Aβ was observed using the cell assay described in Example 5.

*Measure using the analytical conditions described in Example 3.1;

** Use the analysis conditions described in Example 3.2 to measure inputs with plus (+) and no underscores. The entries with plus (+) and underscores were measured using the analytical conditions described in Example 3.3. The input condition with the ampersand (&) was measured using the analytical conditions described in Example 3.4, where &=26-50% inhibition %, &&=51-75% inhibition %, and &&&=76-100+% % inhibition.

N.I. = No inhibition of Aβ was observed using the cell assay described in Example 5.

** The input with plus (+) and underscore is measured using the analysis conditions described in Example 3.3.

Example 4: Inhibition of membrane aspartic protease 1 β-secretase activity and cathepsin D activity Inhibition of membrane aspartic acid protease 1 activity

The activity of the recombinant membrane aspartic acid protease 1 (R&D Systems) and the inhibition of the activity of the compounds were analyzed using the same procedure as outlined in Example 3 above.

Inhibition of cathepsin D activity

Fluorescent FRET peptide targeting cathepsin D activity (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 in DMSO at 75 μM. Cathepsin D protein was obtained from rat liver homogenate. Briefly, rat livers were homogenized in PBS. The extract was acidified to pH 4 with 2 M sodium acetate (pH 4) and incubated overnight at 4 °C. After adding Triton X-100 to a final concentration of 1%, the extract was centrifuged at 25,000 x g and stirred overnight with a gastric inhibitor A immobilized on agarose beads (Sigma-Aldrich). After washing with sodium acetate/1% Triton X-100 (pH 4), cathepsin D immobilized with aprotinin A was dissolved by adding 0.1 M Tris-HCl (pH 8.5). The eluent was immediately adjusted to pH 5 with 2 M sodium acetate. Cathepsin D activity was compared to tissue at pH 4, 37 ° C using the same analytical procedure as described for the membrane aspartate 2 activity and K _i outlined in Example 3 above, in the presence and absence of the compound. Protease D was analyzed for quality. For example, using this procedure for (7-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) The cathepsin DK _i determined by alk-5-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone was about 411 nM.

Example 5: Cellular AβIC ₅₀ Determination Example 5.1

The potency of the compounds against intracellular membrane aspartate 2 activity was determined in a cellular assay of A[beta] production. Compounds that successfully penetrate cell membranes have been shown to inhibit endomembranous aspartyl protease 2 activity by blocking A[beta] production upon secretion into culture medium. Human neuroblastoma cell line SK-N-BE (2) (ATCC No. CRL-2271) in complete medium [MEM + F12 (1:1 ratio) + 1% penicillin / streptomycin (pen / strep) + 10% fetal calf serum was seeded in 96-well plates at 10,000 cells per well and incubated at 37 ° C / 5% CO ₂ for 24 hours. The compound was diluted to 50 μM with DMSO, and then further diluted to 1 with a final DMSO concentration of 0.2% using serum-limited medium [MEM+F12 (1:1 ratio) + 1% penicillin/streptomycin + 5% fetal bovine serum] Final concentration range of μM-0.00002 μM. After incubation for 24 hours at 37 ° C / 5% CO ₂ , a portion (100 μl) of conditioned medium was removed to analyze Aβ ₄₀ using a sandwich ELISA (Invitrogen). The relative amount of the compound-free control of the cultivation of Aβ ₄₀ represents a 4-parameter fit model IC ₅₀ within a range of compound concentrations. The results are provided in Table 1 above ("Cell IC ₅₀ "). For example, using this procedure for (7-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) The cell Aβ IC ₅₀ determined by alk-5-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone was about 1.5 μM. In other examples, 3'-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'- (2-(5-Methylfuran-2-yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile showed no inhibition, 3'-(5-((R) 2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'-((R)-2-(4-methylthiazole-2 -yl)pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile is about 432 nM, (R)-3-(5-(2-amino-1-phenylpropane) -2-yl)-1,3,4-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-1-phenylpropan-2-yl)-1,3,4- Oxadiazol-2-yl)-6-(oxazol-2-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl) The ketone fumarate is about 75 nM, (R)-3-(5-(2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4- 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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-( 1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone The diacid salt is about 90 nM, (R)-3-(5-(2) -amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazole- 2-yl)methyl)-5-(oxazol-2-yl)benzamide is about 50 nM, (R)-3-(5-(2-amino-1-phenylprop-2- -1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl Benzoguanamine is about 56 nM, (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -N-cyclopropyl-N-((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide is about 20 nM, (R)-3-(5- (2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazole-4-yl) Methyl)-4,5-difluoro-N-methylbenzamide is about 78 nM, (3-(5-((R)-2-amino-1-phenylpropan-2-yl))) -1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazole-2 -yl)pyrrolidin-1-yl)methanone is about 21 nM, (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxa Diazol-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-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole- 2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyridinium The pyridin-1-yl) ketone is about 30 nM.

Example 5.2

The potency of compounds against BACE1 activity was determined in a cellular assay of A[beta] production. Human SK-N-BE(2) neuroblastoma cells were plated in 96-well plates per 100 μL per well of 96,000 cells in RPMI 1640/10% FBS/penicillin-streptomycin at 37 ° C, 5% CO Cultivate for 2 hours under ₂ hours. Test compounds were dissolved and diluted with Me ₂ SO and further with RPMI1640 / 5% FBS / penicillin - streptomycin was diluted (to give 0.5% final Me ₂ SO concentration). The medium in the 96-well plate was replaced with 125 μL of the medium containing the test compound per well. After 6 hours of incubation at 37 ° C, 5% CO ₂ , 50 μL of the medium was transferred to a fresh 96-well plate and used for Aβ40 analysis by ELISA kit (#27718, Immuno-Biological Laboratories, Japan). After the medium was removed 50 μL for analysis for Aβ, with viability CellTiter-Glo ^TM Luminescent Cell Analysis (# 7571, Promega) measuring cell viability. The CellTiter-Glo substrate was dissolved in CellTiter-Glo buffer and added to the plate at 75 μL per well. After shaking the plate for 2 minutes, the entire sample was transferred to a white 96-well plate and luminescence was measured for ATP quantification as cell viability. The Aβ concentration measured by ELISA was corrected by the viability of the corresponding cells.

Example 6: Determination of CYP3A4 inhibition

To assess the drug-potential interaction potential of the compounds, the efficacy of inhibiting the major metabolic cytochrome CYP450 isoform 3A4 was assessed. The inhibition constant K _i for inhibition of the metabolism of midazolam, a CYP3A4 receptor, was determined.

Analysis program

According to the latest published scheme, slightly modified (Di, L., Kerns, EH, Li, SQ and Carter, GT (2007) Comparison of cytochrome P450 inhibition assays for drug discovery using human liver microsomes with LC-MS, rhCYP450 isozymes with F1uorescence, and double cocktail with LC-MS. International Journal of Pharmaceutics 335: 1-11) for CYP3A4 K _i analysis. P450 inhibition assays were performed in 96-well plates at 37.2 °C in a shaking incubator. Compounds were diluted from 5 mM stocks with 100% DMSO and human liver microsomes (HLM) with a final protein concentration of 0.1 mg/mL protein at seven final concentrations of 0.078 to 10 μM (0.1% DMSO in each final incubation) ) and cultured with a concentration range of 1.25 to 10 mM (midazolam).

The assay was normalized to phosphate buffer (100 mM, pH 7.4) and NADPH regeneration system (MgCl ₂ , 3.3 mM; G6P, 3.3 mM; G6PD, 1 U/ml; NADP+, 1.3 mM). Eight parallel assay control samples (0.1% DMSO, no compound) were prepared. An analysis (200 μL) was established by mixing HLM+ substrate, 2% DMSO containing 10 mL of test article, and substrate, and then the reaction was initiated by adding a regeneration system mixture. The reaction was quenched after 20, 30 and 40 minutes of incubation as described below.

Reactant quenching and MS-Prep

After incubation for a specified period of time in a humidified shaker incubator, 20 mL of the reaction mixture was removed and the reaction was stopped by the addition of 200 μL of cold acetonitrile. The samples were centrifuged at 1000 x g for 15 minutes in a Solvinert filter plate. The receiver disk was dried by high speed vacuum at 40 °C. The sample was reconstituted with a recovery buffer consisting of 10% acetonitrile, 10% DMSO, 90% H ₂ O supplemented with an internal standard at a concentration of 100 ng/ml. MS analysis was performed using LC-MS/MS. The formation of 1 '-hydroxymidazolam was measured by monitoring the specific SRM (342 > 203) transition of the CYP3A4 metabolite.

Determination of K _i

Data are expressed as the amount of midazolam metabolites incubated relative to controls. The initial velocity is obtained by multiplying the relative amount by the initial substrate concentration and dividing by the incubation duration. By the Dixon method (Dixon, M. (1953) Biochemical Journal 55: 170-171), the data is converted to the reciprocal of the initial velocity by measuring where the intercept [I] = -K _i at various substrate concentrations And expressed relative to the inhibitor concentration [I] to determine K _i .

Example 7: In vivo test Example 7.1 Aβ40 reduction in rats

Formulation

Test compounds were prepared using a vehicle of 35% HPβCD in H ₂ O. Test compounds were formulated on the day of oral administration. Dosage and concentration are based on the free base equivalent. I need to use sonic processing to help with the deployment.

Test species

Male Sprague-Dawley rats (200-400 grams) were obtained from Taconic Farms (Hudson, NY) and experiments were performed approximately one week after adaptation. Animals were fasted overnight before oral administration; and food was returned 2 hours after administration. Drink water freely throughout the study. Animals were visually inspected for health prior to inclusion in the study group and randomly assigned to treatment and control groups to achieve similar group mean body weight. Dosing is done in the morning. Dosing solution (dose volume) using a 3-inch metal rodent feeding needle 10 mL/kg) was directly administered to the stomach. Control animals received oral administration of an equal volume of vehicle.

Sampling method

Blood samples were collected from the saphenous vein (approximately 150 μl in volume). Alternatively, the blood is finally sampled by cardiac puncture (see final procedure 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 minutes at 4 °C and then stored at -70 °C.

Final procedure

The animals were euthanized using an excess of isoflurane for a fixed period of time after administration (e.g., 3 hours). Blood is collected by cardiac puncture. After rapid dissection and exposure to the occipital occipital membrane, CSF was carefully removed from the cisterna magna using a 29 gauge needle. CSF samples were centrifuged at 6000 rpm (3,300 rcf) for 10 minutes to confirm no blood contamination and stored at -70 °C. The brain hemispheres were collected immediately after collection of CSF, dissected into sections (cortex, hippocampus, cerebellum), snap frozen in liquid nitrogen, and subsequently stored at -70 °C.

Brain Aβ extraction

Fragments of the hemisphere (about 100 mg) or hippocampus (from 1 hemisphere) were weighed at the time of freezing. Add 10 volumes (w:v) of 0.2% diethylamine (DEA) containing 50 mM NaCl (pH 10), followed by 100-fold dilution (v:v) of protease inhibitor cocktail 1 (containing AEBSF, inhibiting Peptidase, E-64 protease inhibitor, EDTA and leupeptin; catalog number 539131, Calbiochem). The brain was homogenized by sonicating on ice for 35 seconds in a microcentrifuge tube (level 10 of the XL-2000 Microson Cell Crusher). The resulting homogenate was centrifuged at 14,000 x g for 30 minutes at 4 °C in a freezer bench centrifuge. The supernatant was collected and stored at -70 °C.

Determination of Aβ

Aβ40 in brain homogenate, plasma and CSF was analyzed by ELISA (human/rat Aβ40 ELISA II, catalog number 294-64701, WAKO Chemicals, Inc., USA). The amount of Aβ40 reduction was determined by dividing the average concentration of Aβ40 obtained from the animals treated with the test article by the average Aβ40 from the animals receiving only the vehicle (control group).

Example 7.2 Cognitive function of mice

animal:

Tg2576 mouse is a hemizygous transgenic mouse (K670N/M671L) that overexpresses human mutant APP (Hsiao K et al. Correlative memory deficits, Ab elevation, and amyloid plaques in transgenic mice. Science 1996; 274:99-102) It was mated with normal C57BL6/SJL mice in Charles River Japan (Atsugi, Japan). Female Tg2576 mice and age-matched wild-type (Wt) littermates were studied in Japan (including Tsukuba, Japan). The genotype of the mouse was analyzed by PCR using DNA from the tail.

Drug treatment:

The compound of the formula (I) was dissolved in distilled water and orally administered in a volume of 10 mL/kg. The compound of formula (I) was administered 3 hours prior to the 6-month-old Y-maze of Tg2576 or the Morris water maze task.

Y Labyrinth Test (YM):

Working memory performance was examined by recording the spontaneous transformation behavior in the Y-maze test. The mice were placed at the end of one arm and the number of arms entering and changing was counted for 8 minutes. The transformation is defined as continuously entering all three arms. Calculate the conversion rate (%) as follows:

Conversion rate (%) = (transformation / total number of entries - 2) × 100

Morris Water Maze Mission (MWM):

Space memory was tested using the Morris Water Maze mission, which consisted of three parts: visible platform training (Day 1), hidden platform training (Day 2-4), and probe test (Day 4). A circular cell (100 cm in diameter) was filled with opaque water at a temperature of 21 ± 1 ° C, and a transparent acrylic platform (9 cm in diameter) immersed 1.5 cm below the surface of the water was placed in the cell. The escape platform is maintained at a constant position at the center of one of the four quadrants of the pool. During visible platform training, the platform position is indicated by a marker that rises above the water. In the first part of the test (visible), the mice were tested for their ability to determine the position of the platform to rule out differences in vision and motivation for the four trials. In the second part of the test (hidden), the mice were trained to determine the position of the hidden platform, and each training consisted of three consecutive experiments (1 minute each) (represented by H1-H3). When the mouse finds the platform, it is kept on the platform for 30 seconds. If the mouse does not find the platform within 60 seconds, it is removed from the water and placed on the platform for 30 seconds. In the third part of the test (exploration), it was checked whether the mouse was looking for a quadrant for the platform (target quadrant) to spend more time than the other quadrants of the pool (moving out of the platform). This test was performed immediately after H6 and the assumed measure of reserved spatial memory was obtained. Record the escape latency of each trial (the time to find the hidden platform) and the time spent swimming in the target quadrant. The cumulative latency of the 3-day hidden platform test for each treatment group was calculated.

Claims (327)

a compound of formula (I), Wherein R ¹ is A ¹ -L ¹ - or and R together with the attached nitrogen form a ² together with A ¹ -L ¹ -, substituents of ^{R. 6A} and R ^6B 5 or 6-membered heterocycloalkyl ring; R ² is Hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, Optionally substituted portion of a heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl group, or together with R ¹ and the nitrogen to which it is attached, form A ¹ -L ¹ - a 5 or 6 membered heterocycloalkyl ring substituted with R ^6A and R ^6B ; A ¹ is optionally substituted heteroaryl; L ¹ is a bond, -N(R ¹⁷ )-, -S-, -S (O)-, -S(O) ₂ - or optionally substituted alkyl; R ^6A and R ^{6B are} independently hydrogen, halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or selected from alkyl, cycloalkyl, cycloalkyl- Alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycloalkyl, heterocycloalkyl _- alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion substituted as the case may be; A ² is selected from the group consisting of a cycloalkyl group, a heterocycloalkyl group, an exoaryl group and a heteroaryl group. a portion substituted; X ¹ and X ^{2 are} independently N or CH; R ³ is hydrogen, -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ , -C(O)R ¹² , or Substituted from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl Part; R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaryl a portion of the alkyl group which is optionally substituted; R ^7A is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ , heterocycle Optionally substituted portion of alkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl, or together with R ^7B and the carbon to which it is attached, form R ⁴ - L ⁴ -substituted cycloalkyl ring; R ^7B is R ⁴ -L ⁴ - or together with R ^7A and the carbon to which they are attached form an R ⁴ -L ⁴ -substituted cycloalkyl ring; R ⁴ is hydrogen, Halogen, -OH, -NO ₂ , -N(R ⁸ )R ⁹ , -OR ¹⁰ , -SH, -SR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O ) R ^12, or selected from alkyl, cycloalkyl, cycloalkyl - Group, - alkyl -OR ^10, - alkyl -N (R ⁸⁾ R ^9, heterocycloalkyl, heterocycloalkyl-alkyl - alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl of a portion substituted as appropriate; L ⁴ is a bond or an optionally substituted alkyl; R ^{8 is} independently hydrogen, -C(O)R ¹³ , -S(O) ₂ R ¹⁴ , or is selected from an alkane Optionally substituted portion of a group, a cycloalkyl group, a cycloalkyl-alkyl group, a heterocycloalkyl group, a heterocycloalkyl-alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; ⁹ independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl a moiety substituted as appropriate; R ^{10 is} independently -C(O)R ¹³ or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkane Optionally substituted as a base, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{11 is} independently selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl a heterocyclic alkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl group optionally substituted, wherein if attached to S(O) ₂ , then R ¹¹ may also be -NR ¹⁵ R ¹⁶ ; R ¹² and R ^{13 are} each independently hydrogen, -N(R ¹⁸ )R ¹⁹ , -OR ¹⁹ , or selected from alkyl, cycloalkyl, or ring. Optionally substituted for alkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ^{14 is} independently hydrogen, - N(R ¹⁸ )R ¹⁹ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl or hetero a substituted portion of the aralkyl group; and R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ^{19 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hetero a optionally substituted portion of a cycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl group; the restriction is that when both R ³ and R ⁵ are hydrogen, One of R ^7A and R ^7B is a methyl group and the other is a benzyl group, X ¹ and X ^{2 are} each N, and A ² is a substituted 1,3-phenylene group at the 5-position and R ¹ together 5 heterocycloalkyl ring formed R ² together with the nitrogen and are attached, the heterocyclic ring of R ^{5. 1} is formed together with the nitrogen connected to R ² and the alkyl ring is divided by 2 a moiety other than the substituted pyrrolidinyl group, which is substituted with 5-chlorofuran-2-yl, 5-methylfuran-2-yl, 3-pyridyl or 5-bromo-3-pyridyl; or a pharmaceutical thereof A salt or solvate that is acceptable in the art. The compound of claim 1, wherein A ¹ is optionally substituted 5 to 7 membered heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 2, wherein A ¹ is optionally substituted 5-membered heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 3, wherein A ¹ is an optionally substituted 5-membered heteroaryl group, comprising at least one ring nitrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1 to 2, wherein A ¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazole , pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, oxazolyl, benzimidazolyl, benzene And thienyl, benzofuranyl, fluorenyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, fluorene Pyridyl, benzoisoxazolyl, pyrazinyl, pyrrolinyl, indolyl and benzodiazepine; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted moiety selected from the group consisting of thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, thienyl, pyridyl, Pyrimidinyl, oxadiazolyl and piperidyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted moiety selected from the group consisting of thiazolyl, oxadiazolyl and oxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted oxazolyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted oxadiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted imidazolyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is optionally substituted pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted isoxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is optionally substituted thienyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted pyridyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted pyrazinyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted pyrimidinyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is an optionally substituted 2-thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 5, wherein A ¹ is optionally substituted 2-oxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 19, wherein L ¹ is a bond or an optionally substituted alkylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is a bond; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is an optionally substituted alkylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is an optionally substituted C ₁ -C ₆ alkylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is an optionally substituted methylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is methylmethylene; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is a C ₁ -C ₆ alkylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 20, wherein L ¹ is a methylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 27, which has the formula (II): Or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 28, wherein R ² is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aromatic a substituted portion of a aryl group, an aralkyl group, a heteroaryl group, and a heteroarylalkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is hydrogen, or an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof . The compound of claim 29, wherein R ² is hydrogen or optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is hydrogen or optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is optionally substituted C ₁ -C ₃ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is 2-fluoroethyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is optionally substituted C ₃ -C ₆ cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is cyclobutyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is ethyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 29, wherein R ² is butyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 27, which has the formula (III): Wherein W is -CH ₂ -, -O-, -N(R ¹⁷ )-, -S-, -S(O)- or -S(O) ₂ -, or wherein W is -CH- or -N- And substituted by R ^6A or R ^6B , or wherein W is -C- and substituted by R ^6A and R ^6B ; and m is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, wherein W is -O-; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 44, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, wherein W is -S-, -S(O)- or -S(O) ₂ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, wherein W is -S-; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 47, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, wherein W is -N(R ¹⁷ )-; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, wherein W is -CH ₂ -; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 50, wherein m is 1; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 43, which has the formula (IIIa): Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 52, wherein the A ¹ -L ¹ - moiety is substituted on the pyrrolidine heterocycloalkyl ring according to the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 53, wherein A ¹ is an optionally substituted moiety selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrimidine , pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, oxazolyl, benzimidazolyl, benzothienyl, benzofuranyl, fluorenyl , quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzisoxazolyl, pyrazine a pyrroline group, a thiol group, and a benzodiazepine group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 53, wherein L ¹ is a bond; A ¹ is a substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 55, wherein A ¹ is 4-methylthiazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof. 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(R ⁸ )R ⁹ , -OR ¹⁰ or selected from alkane a substituted portion of a group, a cycloalkyl group, a cycloalkyl-alkyl group, a heterocycloalkyl group, a heterocycloalkyl-alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; A pharmaceutically acceptable salt or solvate thereof. The compound of claim 57, wherein R ^6B is hydrogen, or an optionally substituted moiety selected from the group consisting of aryl, aralkyl, heteroaryl and heteroarylalkyl; or a pharmaceutically acceptable salt or solvent thereof Compound. The compound of claim 57, wherein R ^6B is hydrogen, halogen, optionally substituted alkyl or -OR ¹⁰ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 57, wherein R ^6B is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 60, wherein R ^6B is a fluoro group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 57, wherein R ^6B is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 58 to 62, wherein R ^6A is hydrogen, halogen or an optionally substituted alkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 58 to 62, wherein R ^6A is hydrogen or halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 58 to 62, wherein R ^6A is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 58 to 62, wherein R ^6A is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 66, wherein R ^6A is a fluoro group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 57, wherein each of R ^6A and R ^6B is a fluoro group; 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 pyrrolidinylcycloalkyl 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 ^{6B are} substituted on the pyrrolidinylcycloalkyl ring according to the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 1 to 70, wherein A ² is an optionally substituted extended aryl group, optionally substituted aryl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 71, wherein A ² is selected from the group consisting of phenylene, pyridyl, oxazolyl, thiazolyl, thiazole, piperidyl, oxadiazole, and imidazolyl, An optionally substituted portion of a group of furanyl and pyridone groups; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 71, wherein A ² has the formula: Wherein L ² and L ^{3 are} independently a bond or optionally substituted C ₁ -C ₅ alkyl; R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen, halogen, -N(R ²⁴ )R ²⁵ , Or optionally selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a portion; each R ^{23 is} independently hydrogen, halogen, cyano, -NO ₂ , -N(R ²⁴ )R ²⁵ , -OR ²⁶ , -SR ²⁷ , -S(O)R ²⁷ , -S(O) ₂ R ²⁷ or -C(O)R ²⁸ , or selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, hetero a portion of the aryl and heteroarylalkyl which is optionally substituted; and Y is -N= or -C(R ²³ )=; wherein R ²⁴ and R ^{25 are} each independently hydrogen, -C(O)R ²⁹ or -S(O) ₂ R ³⁰ , or selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and a substituted portion of a heteroaralkyl group; wherein R ^{29 is} independently hydrogen, -N(R ³¹ )R ³² or -OR ³³ , selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hetero Cycloalkyl, heterocycloalkyl-alkyl, aryl, Optionally substituted according to aralkyl, heteroaryl and heteroarylalkyl; wherein R ³¹ , R ³² and R ^{33 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkane Optionally substituted moieties, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; and R ^{30 is} independently selected from alkyl, halo Optionally substituted for alkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; R ²⁶ independently Is hydrogen, or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl a substituted portion; R ^{27 is} independently -N(R ³⁴ )R ³⁵ , or is selected from alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, Optionally substituted for aryl, aralkyl, heteroaryl and heteroarylalkyl; wherein R ³⁴ and R ^{35 are} each independently hydrogen or selected from alkyl, cycloalkyl, cycloalkyl-alkane Base, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and Optionally substituted aralkyl group of the moiety; and R ²⁸ is independently ^{-OR 36, -N (R 37)} R 38, or selected from alkyl, cycloalkyl, cycloalkyl - alkyl, heterocycloalkyl Optionally substituted as a heterocyclic alkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl group; wherein R ³⁶ , R ³⁷ and R ^{38 are} each independently hydrogen, or Optionally substituted for alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 73, wherein A ² has the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 73, wherein A ² has the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 73, wherein A ² has the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 76, wherein Y is -C(R ²³ )=; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 76, wherein Y is -N=; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, wherein R ²³ is hydrogen, halogen, -N(R ²⁴ )R ²⁵ , -OR ²⁶ , -SR ²⁷ , -S(O)R ²⁷ , -S(O ₂ R ²⁷ , -C(O)R ²⁸ or optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 79, wherein R ²³ is cyano or -NO ₂ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 79, wherein R ²³ is hydrogen, halogen, -N(R ²⁴ )R ²⁵ or optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 81, wherein R ²³ is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 81, wherein R ²³ is hydrogen or -N(R ²⁴ )R ²⁵ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 83, wherein R ²³ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 83, wherein R ²³ is -N(R ²⁴ )R ²⁵ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 85, wherein R ²³ is -N(alkyl)alkylsulfonylamino; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 86, wherein R ²³ is -N-methyl-methanesulfonylamino; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 79, wherein R ²³ is -OR ²⁶ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 88, wherein R ²⁶ is hydrogen or optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 89, wherein R ²⁶ is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 90, wherein R ²⁶ is difluoromethyl or trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 90, wherein R ²⁶ is methyl or ethyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 79, wherein R ²³ is -SR ²⁷ , -S(O)R ²⁷ or -S(O) ₂ R ²⁷ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 79, wherein R ²³ is -C(O)R ²⁸ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 94, wherein R ²⁸ is -OR ³⁶ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 95, wherein R ³⁶ is C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 94, wherein R ²⁸ is -N(R ³⁷ )R ³⁸ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 97, wherein each of R ³⁷ and R ^{38 is} independently hydrogen or methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, wherein R ²³ is hydrogen, selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl a substituted portion of an aralkyl group, a heteroaryl group, and a heteroarylalkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl and heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is C ₁ -C ₆ alkyl substituted with one or more halogens; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 103, wherein R ²³ is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, and 2,2,2-trifluoroethyl; or a pharmaceutical thereof A salt or solvate that is acceptable in the art. The compound of claim 99, wherein R ²³ is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is optionally substituted cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 106, wherein R ²³ is cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 99, wherein R ²³ is optionally substituted heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 79, 81, 99, 100 or 108, wherein the optionally substituted heterocycloalkyl group is an optionally substituted cyclic sulfonamide group; or it is pharmaceutically acceptable a salt or solvate. The compound of claim 109, wherein the optionally substituted cyclic sulfonamide group is optionally substituted or Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 109, wherein R ²³ is Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 109, wherein R ²³ is Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 109, wherein R ²³ is optionally substituted pyrrolidinyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 113, wherein R ²³ is 2-sided oxypyrrolidin-1-yl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 109, wherein R ²³ is optionally substituted piperidinyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 115, wherein R ²³ is 2-sided oxypiperidin-1-yl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 109, wherein R ²³ is oxazolidinyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 117, wherein R ²³ is 2-sided oxy-3-oxazolidinyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, wherein R ²³ is selected from the group consisting of cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, a substituted portion of a heteroaryl or heteroarylalkyl group; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 119, wherein R ²³ is an optionally substituted moiety selected from the group consisting of aryl, aralkyl, heteroaryl and heteroarylalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 119, wherein R ²³ is an optionally substituted moiety selected from the group consisting of aryl and heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 119, wherein R ²³ is an optionally substituted aryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 119, wherein R ²³ is optionally substituted heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 119, wherein R ²³ is selected from the group consisting of pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl, pyrimidinyl, The optionally substituted portion of the piperidyl, pyrazinyl and furyl groups; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted with a thiazolyl, oxadiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl and pyrazinyl group; or a pharmaceutical thereof An acceptable salt or solvate. The compound of claim 124, wherein R ²³ is optionally substituted phenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted pyridyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted oxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is an optionally substituted oxadiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is an optionally substituted imidazolyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted pyrazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is an optionally substituted isoxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is an optionally substituted pyrimidinyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 124, wherein R ²³ is optionally substituted furanyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 124, wherein R ²³ is optionally substituted triazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 137, wherein R ²³ is an optionally substituted 1,2,3-triazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 137, wherein R ²³ is an optionally substituted 1,2,4-triazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 128, wherein R ²³ is optionally substituted 2-thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 129, wherein R ²³ is optionally substituted 2-oxazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 129, wherein R ²³ is optionally substituted 5-oxazolyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 135, wherein R ²³ is optionally substituted 2-pyrazinyl; or a pharmaceutically acceptable salt or solvate thereof. 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 the group consisting of alkyl and heteroalkyl; or a pharmaceutical thereof A salt or solvate that is acceptable in the art. 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 optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof Things. 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 hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 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. The compound according to any one of claims 73 to 77, 79 to 83 and 85, wherein at least one of R ²⁴ and R ²⁵ is an optionally substituted alkyl group; or a pharmaceutically acceptable salt or solvent thereof Compound. 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 group; or a pharmaceutically acceptable salt or solvate thereof. 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 a methyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein R ²⁴ and R ^{25 are} independently hydrogen, optionally substituted alkyl, -C(O)R ²⁹ or -S(O ₂ R ³⁰ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R ²⁴ and R ²⁵ is -C(O)R ²⁹ or -S(O) ₂ R ³⁰ ; or a pharmaceutical thereof A salt or solvate that is acceptable in the art. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R ²⁴ and R ²⁵ is -C(O)R ²⁹ ; or a pharmaceutically acceptable salt or solvate thereof Things. The compound of any one of claims 73 to 77, 79 to 83 and 85, wherein one of R ²⁴ and R ²⁵ is -S(O) ₂ R ³⁰ ; or a pharmaceutically acceptable salt or solvent thereof Compound. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein R ^{29 is} independently hydrogen, optionally substituted alkyl, -N(R ³¹ )R ³² or -OR ³³ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein R ^{29 is} independently hydrogen or optionally substituted alkyl; or a pharmaceutically acceptable salt or solvent thereof Compound. A compound according to any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein R ²⁹ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. A compound according to any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein R ²⁹ is an optionally substituted alkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 77, 79 to 83, 85 and 151 to 153, wherein R ²⁹ is a methyl group; or a pharmaceutically acceptable salt or solvate thereof. 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 pharmaceutically acceptable Salt or solvate. A compound according to 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. A compound according to 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. 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 optionally substituted alkyl Or a pharmaceutically acceptable salt or solvate thereof. 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 group; or a pharmaceutically acceptable salt or solvate thereof . The compound of any one of claims 73 to 77, 79 to 83, 85, 151, 152, and 154, wherein R ³⁰ is a methyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 73, wherein A ² has the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein L ² is optionally substituted C ₂ -C ₅ alkylene; and L ³ is a bond; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein L ² is a bond; and L ³ is optionally substituted C ₂ -C ₅ alkylene; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein L ² and L ^{3 are,} independently, optionally substituted C ₁ -C ₂ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein L ² is optionally substituted C ₁ -C ₄ alkyl; and L ³ is optionally substituted methylene; or a pharmaceutically acceptable salt or solvate thereof Things. The compound of claim 166, wherein L ² is optionally substituted C ₂ -C ₄ alkyl; and L ³ is a bond or optionally substituted methylene; or a pharmaceutically acceptable salt thereof Or a solvate. The compound of any one of claims 73 to 171, wherein R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen or optionally substituted C ₁ -C ₁₀ alkyl; or a pharmaceutically acceptable salt thereof or Solvate. The compound of any one of claims 73 to 171, wherein R ²⁰ , R ²¹ and R ^{22 are} independently hydrogen or optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt thereof or Solvate. 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. 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. The compound according to any one of claims 73 to 171, wherein at least one of R ²⁰ , R ²¹ and R ²² is -N(R ²⁴ )R ²⁵ ; or a pharmaceutically acceptable salt or solvate thereof . 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. The compound of any one of claims 73 to 171, wherein R ²¹ is -N(R ²⁴ )R ²⁵ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 171, wherein R ²² is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 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 optionally substituted C ₁ -C ₆ alkyl; or pharmaceutically acceptable Salt or solvate. 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. 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. The compound of claim 166, wherein A ² is a moiety selected from the group consisting of: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein A ² is part of the formula: Or a pharmaceutically acceptable salt or solvate thereof. A compound of claim 183 or 184, wherein R ²⁰ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein A ² is a moiety selected from the group consisting of: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 166, wherein A ² is part of the formula: Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 186 or 187, wherein R ²¹ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 73 to 188, wherein R ²² is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 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. The compound of claim 71, wherein A ² has the formula: Wherein each R ^{39 is} independently hydrogen or optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 191, wherein R ³⁹ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 191, wherein R ³⁹ is an optionally substituted alkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 191, wherein R ³⁹ is C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 194, wherein R ³⁹ is methyl or ethyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 195, wherein X ¹ is N; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 195, wherein X ² is N; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 195, wherein X ¹ and X ² are each N; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 195, wherein X ¹ and X ² are both CH; or a pharmaceutically acceptable salt or solvate thereof. 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. 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. The compound of any one of claims 1 to 201, wherein R ³ is -N(R ⁸ )R ⁹ , -S(O) ₂ R ¹¹ or -C(O)R ¹² ; or pharmaceutically acceptable a salt or solvate. The compound according to any one of claims 1 to 201, wherein R ³ is hydrogen, -C(O) ^t Bu, or an optionally substituted portion selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 202, wherein R ³ is -C(O)R ¹² ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 204, wherein R ¹² is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 201, wherein R ³ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aromatic a substituted portion of a aryl group, an aralkyl group, a heteroaryl group, and a heteroarylalkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 206, wherein R ³ is hydrogen, or an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof . A compound according to claim 206, wherein R ³ is hydrogen or optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 206, wherein R ³ is hydrogen or optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 206, wherein R ³ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 206, wherein R ³ is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 206, wherein R ³ is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 212, wherein R ⁴ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 212, wherein R ⁴ is an optionally substituted moiety selected from the group consisting of alkyl and heteroalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 212, wherein R ⁴ is optionally substituted from cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or pharmaceutically acceptable Salt or solvate. The compound of claim 215, wherein R ⁴ is an optionally substituted moiety selected from the group consisting of cycloalkyl and heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 215, wherein R ⁴ is an optionally substituted moiety selected from the group consisting of aryl and heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 215, wherein R ⁴ is an optionally substituted aryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 215, wherein R ⁴ is optionally substituted heteroaryl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 218, wherein R ⁴ is phenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 218, wherein R ⁴ is phenyl, optionally substituted with one or more halogens; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 221, wherein R ⁴ is 3,5-difluorophenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 221, wherein R ⁴ is 4-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 221, wherein R ⁴ is 3-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 224, wherein L ⁴ is a bond or an optionally substituted alkylene group; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 225, wherein L ⁴ is a bond; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 225, wherein L ⁴ is an optionally substituted alkylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 225, wherein L ⁴ is optionally substituted C ₁ -C ₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 225, wherein L ⁴ is C ₁ -C ₆ alkylene; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 225, wherein L ⁴ is methylene; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 230, wherein R ⁵ is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aromatic a substituted portion of a aryl group, an aralkyl group, a heteroaryl group, and a heteroarylalkyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 231, wherein R ⁵ is hydrogen, or an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof . The compound of claim 231, wherein R ⁵ is hydrogen or an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 231, wherein R ⁵ is hydrogen or optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 231, wherein R ⁵ is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 231, wherein R ⁵ is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 231, wherein R ⁵ is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 237, which has the formula (IV): Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 238, wherein R ^7A is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, -alkyl-OR ¹⁰ , -alkyl-N(R ⁸ )R ⁹ ,heterocycloalkyl a optionally substituted moiety of a heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 239, wherein R ^7A is an optionally substituted moiety selected from the group consisting of alkyl, cycloalkyl and cycloalkyl-alkyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is an optionally substituted alkyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 239, wherein R ^7A is optionally substituted C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 239, wherein R ^7A is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is an optionally substituted moiety selected from the group consisting of -alkyl-OR ¹⁰ and -alkyl-N(R ⁸ )R ⁹ ; or a pharmaceutically acceptable salt or solvent thereof Compound. The compound of claim 239, wherein R ^7A is optionally substituted alkyl-OR ¹⁰ ; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 245, wherein R ^7A is -CH ₂ OCH ₃ ; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is an optionally substituted moiety selected from the group consisting of heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl; A pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is an optionally substituted aralkyl group; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 239, wherein R ^7A is optionally substituted alkyl-phenyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 249, wherein R ^7A is benzyl or 3-phenylpropyl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 239, wherein R ^7A is an optionally substituted moiety selected from the group consisting of phenyl, pyrazolyl, furyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrole , pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, thienyl, dihydrothienopyrazolyl, thioxyl, carbazolyl, benzimidazolyl, benzothienyl, benzo Furanyl, fluorenyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isodecyl, acridinyl, benzopyrene Oxazolyl, dimethylhydantoin, pyrazinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, fluorenyl, diazenium, aziridine, thioxyl, piperidine And an oxo group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is selected from the group consisting of pyridyl, phenyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyrimidinyl, pyrazinyl and A substituted portion of a furanyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 239, wherein R ^7A is an optionally substituted moiety selected from the group consisting of pyridyl and imidazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 1, wherein the compound is selected from the group consisting of: (2-(5-(3-(methyl((4-methylthiazol-2-yl)methyl)))) Phenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2-yl)carbamic acid tert-butyl ester; (R)-3-(5-(2-amine) 1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl) Benzalamine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl -N-((4-methylthiazol-2-yl)methyl)-5-(pyridin-3-yl)benzamide; (3-(5-((R)-2-amino)-1 -Phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methyl) Thiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxa) (oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-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-1-yl)methanone; (3-methyl-5-(5-((R)-2-)methylamino) )-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidine -1- Methyl ketone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl) (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-(pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; N-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole-2 -yl)-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-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-1-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-1-yl)methanone; (3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Pyrazin-2-yl)phenyl)((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)phenyl)((2R,4S)-4-fluoro-2-(4-methyl Thiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amino-1-(4-fluorophenyl)) -2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazole-2- Pyrrolidin-1-yl)methanone; 1-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole) 2-yl)-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-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-1-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-1-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-1-yl)methanone; 3'-(5-((R)-2 -amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5'-((R)-2-(4-methylthiazol-2-yl Pyrrolidine-1-carbonyl)-[1,1'-biphenyl]-2-carbonitrile; (7-(5-((R)-2-amino-1-phenylpropan-2-yl)) -1,3,4-oxadiazol-2-yl) (5-(5-((R)-2-yl)-) 1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrrol-1-yl)phenyl)((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)-2-hydroxyphenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3- (5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-(( 4-methylthiazol-2-yl)methyl)benzamide; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4 -oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-4,4-difluoro-2-(4-methylthiazol-2-yl)pyrrolidine -1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N -cyclopropyl-N-((4-methylthiazol-2-yl)methyl)benzamide; (R)-3-(5-(2-amino-1-phenylprop-2- -1,3,4-oxadiazol-2-yl)-N-methyl-5-(N-methylmethanesulfonylamino)-N-((4-methylthiazol-2-yl) )methyl)benzamide; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -5-(oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazole-2- Pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl -N-cyclopentyl-N-((4-methylthiazol-2-yl)methyl)benzamide; (4-(5-((R))-2-amino-1-phenyl) Prop-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1- Methyl ketone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( 1-methyl-1H-pyrazol-4-yl)phenyl)((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-(1H-imidazol-1-yl)phenyl ((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amino-1-phenylpropane) -2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-5-yl)phenyl)((R)-2-(4-methylthiazole-2- (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole-2) -yl)-5-methylphenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (5-(5 -((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)((R)-2-( 4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino)-1- Propion-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-(fluoromethyl) (thiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4- Oxadiazol-2-yl)-5-(1H-imidazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone (5-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) (7)-()-(5)-(5-((R)-2-yl)-- 1-phenylpropan-2-yl)oxazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrole (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -5-(pyridin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (2-(5-(3- (Methyl((4-methylthiazol-2-yl)methyl)amine-methyl)phenyl)-1,3,4-oxadiazol-2-yl)-1-phenylpropan-2- Tert-butyl carbamic acid; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -5-(1-Methyl-1H-pyrrol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; R)-3-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-(( 4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide; (3-(5-((R))-2-amino-1-(4-) Fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((2R,4S)-4-fluoro- 2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amino-1-(4-fluorophenyl)-propene- 2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyrazin-2-yl)benzene ((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R)-2-)yl) -1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)piperidine- 1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5 -(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)- Ketone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-isopropyl-N -((4-methylthiazol-2-yl)methyl)benzamide; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)oxazole- 2-yl)-5-(oxazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl) Ketone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide; (2-(5-((R))-2-amino-1-phenylpropanyl) -2-yl)-1,3,4-oxadiazol-2-yl)-6-(dimethylamino)pyridin-4-yl)((R)-2-(4-methylthiazole- 2-yl)pyrrolidin-1-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-[(1R,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-1-methoxy-3-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-(4 -methylthiazol-2-yl)methyl)benzamide; 3-(5-(rel-(1S,2R)-1-amino-2-phenylcyclobutyl)-1,3,4 -oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)benzamide; 3-(5-(rel-(1R,2R) -1-amino-2-phenylcyclobutyl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)- Benzomethane; 3-{5-[(4E)-2-amino-1,5-diphenylpent-4-en-2-yl]-1,3,4-oxadiazole- 2-yl}-N-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]benzamide; 3-[5-(2-amino-1, 5-diphenylpentan-2-yl)-1,3,4-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]benzene Indoleamine; 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-1-phenylpropan-2) -yl)-1,3,4-oxadiazol-2-yl)-N-methyl-5-(oxazol-2-yl)-N-(pyrazin-2-ylmethyl)benzamide Amine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N- ((2-methylthiazol-4-yl)methyl)-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenyl) Prop-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((2-methyloxazol-4-yl)methyl)-5- (evil Oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl -N-methyl-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)-N-((R)-1-(4-methylthiazol-2-yl) Ethyl)-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-(4-fluorophenyl)propan-2-yl) -1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzene Methionine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N -methyl-N-((5-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amine) 1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methyloxazol-2-yl)methyl -5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxa Diazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(oxazol-2-yl)benzamide; (3-(5-((R)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazole-2- Phenyl)((R)-4-(4-methylthiazol-2-yl)oxazolidine-3-yl)methanone; (R)-3-(5-(2-amino-1) -(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl -N-methyl-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1, 3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl) Benzalamine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl -N-((4-methylthiazol-2-yl)methyl)-5-(pyrazin-2-yl)benzamide; (R)-3-(5-(2-amino-1) -Phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((3-methyl-1,2,4-oxo) -5-yl)methyl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole-2 -yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyridin-2-yl)benzamide; (R)-3 -(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-chloro-N-((2,5-dimethyl) (3-(5-((R))-2-amino-1-phenylpropan-2-yl)-1, 3,4-oxadiazol-2-yl)-4-chlorophenyl)((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)-4-chlorophenyl)((2R,4S) -4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropene- 2-yl)-1,3,4-oxadiazol-2-yl)-N-(t-butyl)-N-((4-methylthiazol-2-yl)methyl)-5-( Oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2- (N-((4-((R))))) Benzyl-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(fluoromethyl)phenyl)((2R,4S)-4-fluoro-2 -(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-benzene) Propion-2-yl)-1,3,4-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-oxadiazole-2 -yl)-5-(difluoromethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-( 5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclobutyl-N-((4-methylthiazole- 2-yl)methyl)-5-(oxazol-2-yl)benzamide; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-) 1,3,4-oxadiazol-2-yl)-5-(1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazole-2 -yl)pyrrolidin-1-yl)methanone; 5-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxan Zin-2-yl)-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-1,3,4-oxadiazole-2 ( 3H)-keto; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( 1-fluoroethyl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; 1-(3-(5-((R)-) 2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R)-2-(4-methylthiazol-2-yl) Pyrrolidine-1-carbonyl)phenyl)ethanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4- Oxadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl) Ketone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(isoxazole -5-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amine) -1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1,1-difluoroethyl)phenyl)((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-(isoxazol-3-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1- Methyl ketone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( 1H-pyrazol-3-yl)phenyl)((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-((R)-2-(4-methylthiazol-2-yl) Pyrrolidine-1-carbonyl)benzonitrile; 5-(3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole) -2-yl)-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-1,3,4-oxo Oxazol-2(3H)-one; 3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadi -2-yl)-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid ethyl ester; (3-(5-((R)-2) -amino-1-cyclohexylpropan-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino-1-cyclohexylpropan-2-yl)-1,3,4-oxadiazol-2-yl) -5-(oxazol-2-yl)phenyl)((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-(thiazol-2-yl)phenyl)((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)-N-methyl-5-((R)-2-(4.-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzene Formamide; 3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-((R -2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzamide; 3-(5-((R)-2-amino-1-phenylprop-2-) -1,3,4-oxadiazol-2-yl)-N,N-dimethyl-5-((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1 -carbonyl)benzamide;(R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N -methyl-N-((4-methylthiazol-2-yl)methyl)-5-(thiazole-2- Benzomidine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N- (2-fluoroethyl)-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)-N-ethyl-5-((R)-2-(4-A (thiazol-2-yl)pyrrolidin-1-carbonyl)benzamide; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3, 4-oxadiazol-2-yl)-5-(thiazol-2-yl)phenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl)pyrrolidine- 1-yl)methanone; (3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazole-2 -yl)-5-(thiazol-2-yl)phenyl)((2R,4S)-4-fluoro-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-((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-1-yl)methanone; (3- (5-((S)-2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)benzene ((S)-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-(oxazol-2-yl)phenyl)(( S)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((S)-2-amino-1-phenylprop-2-) -1,3,4-oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrole (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)- 5-(Dimethylamino)-N-methyl-N-((4-methylthiazol-2-yl)methyl)benzamide; (R)-3-(5-(2-amine) 1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(N-methylmethanesulfonylamino)-N-((4-methyl) Thiazol-2-yl)methyl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 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-1-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-1-yl Ketone; (R)-5-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4- Oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-6-methoxy-N-methylnicotinium amide; (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-1-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-methylthiazole- 2-(yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole- 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-(1-methyl-1H-imidazole- 2-(yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (5-(5-((R)-2-amino) -1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-3-yl)((R)-2-(4) -methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (5-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3, 4-oxadiazol-2-yl)-3'-methoxy-[1,1'-biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; (5-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3 , 4-oxadiazol-2-yl)-2'-methoxy-[1,1'-biphenyl]-3-yl)((R)-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole-2- -5-(furan-2-yl)phenyl)((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-iodophenyl)((R)-2-(4 -methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4 -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-1-yl)methanone; (3-(5-((R))-2-amino-1-phenylpropane) -2-yl)-1,3,4-oxadiazol-2-yl)-5-nitrophenyl)((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- (furan-3-yl)phenyl)((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-(pyrimidin-5-yl)benzene ((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amino-1-phenylpropane) -2-yl)-1,3,4-oxadiazol-2-yl)-5-(pyridin-3-yl)phenyl)((R)-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl -N-methyl-5-(N-methylaminesulfonyl)-N-((4-methylthiazol-2-yl)methyl)benzamide; (R)-3-(5 -(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazole-2- (meth)methyl)-5-(pyridin-2-yl)benzamide; (3-(5-((R))-2-amino-1-(2-fluorophenyl)propan-2-yl) )-1,3,4-oxadiazol-2-yl)-5-(pyrazin-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidine -1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)- 5-(2-methylthiazol-4-yl)phenyl)((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-(4,5-dimethylthiazole-2- ()phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1- Phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((3-fluoropyridin-2-yl) -N-methyl-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1 ,3,4-oxadiazol-2-yl)-N-methyl-5-(oxazol-2-yl)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl Benzoguanamine; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluoro -N-methyl-N-((4-methylthiazol-2-yl)methyl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2) -yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-4-fluoro-N-methylbenzene Methionamine; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluorobenzene ((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R))-2-amino-1-phenyl) Prop-2-yl)-1,3,4-oxadiazol-2-yl)-4-fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidine- 1-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-1-yl)methanone; (R)-3-(5-(2) -amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-N-((2,5-dimethyloxazole- 4-yl)methyl)-4-fluorobenzamide; (2-{5-[(2R)-2-amino-1-phenylprop-2- 1,],3,4-oxadiazol-2-yl}-6-cyclopropylpyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazole-2- Pyrrolidin-1-yl]methanone; 2-(6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole -2-yl}-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)benzonitrile [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1,3- Oxazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-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-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; N-(6-{5-[(2R)-2-amino- 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[(2R)-2-(4-methyl-1,3-thiazole-2- Pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-N-methylmethanesulfonamide; N-(4-{5-[(2R)-2-amino-1-phenylpropane) -2-yl]-1,3,4-oxadiazol-2-yl}-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine- 1-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-A -1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1, 3,4-oxadiazol-2-yl}-6-(1,3-oxazol-2-yl)pyridin-4-yl][(2R)-2-(4-ethyl-1,3- Thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxa Diazol-2-yl}-6-(1,3-oxazol-2-yl)pyridin-4-yl][(2R)-2-(4-cyclopropyl-1,3-thiazole-2- Pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2 -yl}-6-(1,3-oxazol-2-yl)pyridin-4-yl]{(2R)-2-[4-(methoxymethyl)-1,3-thiazole-2- (pyrrolidin-1-yl}methanone; (6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2 -yl}-2,3'-bipyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone;6-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-2,4'-bipyridine-4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amine 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrimidin-5-yl)pyridin-4-yl][(2R)-2- (4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; (2-{5-[(2R)-2-amino-1-phenylpropene- 2-yl]-1,3,4-oxadiazol-2-yl}-6-methylpyridin-4-yl)[(2R)-2-(4-methyl-1,3-thiazole-2 -yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole- 2-yl}-6-(1,1-dioxoindol-1,2-thiazolidin-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3 -thiazol-2-yl)pyrrolidin-1-yl]methanone; 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-yl]carbonyl}pyridine-2- 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-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [4-{ 5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl)-6-(1,3-oxazole-2- Pyridin-2-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; 1-(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-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-1, 3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1,3-oxazolidin-2-one; 1-(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-yl]carbonyl}pyridin-2-yl)-5-methylpyrrolidin-2-one; 1-(6-{5-[(2R)-2-amino) -1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-4-{[(2R)-2-(4-methyl-1,3-thiazole-2 -yl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)piperidin-2-one; N-(6-{5-[(2R)-2 phenyl-1-phenylprop-2- -1,3,4-oxadiazol-2-yl}-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl ]carbonyl}pyridin-2-yl)-N-methylacetamide; 1-(4-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3 , 4-oxadiazol-2-yl}-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2 -yl)pyrrolidin-2-one; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl }-6-(1H-1,2,4-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole [1-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl} -6-(1H-imidazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl Pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2- -6--6-(1H-pyrazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl Methyl ketone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(2H -1,2,3-triazol-2-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Methyl ketone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1H- 1,2,3-triazol-1-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]- Ketone; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-A -1H-pyrazol-4-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1-methyl- 1H-pyrazol-5-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; 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-(1,3-oxazol-2-yl)isonicotinamine; 2-{5-[(2R)-2-amino -1-benzene Propion-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[(6-methylpyridin-3-yl)methyl]-6-(1 , 3-oxazol-2-yl)isonicotinamine; 2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadi Zin-2-yl}-N-[1-(1-methyl-1H-pyrazol-3-yl)ethyl]-6-(1,3-oxazol-2-yl)isonicotinamide ;2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[ (6-methylpyridin-2-yl)methyl]-6-(1,3-oxazol-2-yl)isonicotinamine; 2-{5-[(2R)-2-amino- 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[(1-methyl-1H-pyrazol-4-yl)- -6-(1,3-oxazol-2-yl)isonicotinamine; 2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1 ,3,4-oxadiazol-2-yl}-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-N-methyl-6-(1,3 -oxazol-2-yl)isonicotinamine; 2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole- 2-yl}-N-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-N-methyl-6-(1,3-oxazol-2-yl)iso Nicotinamide; 2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(1 -methyl-1H-pyrazol-3-yl)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl] Methyl ketone; (2-amino-6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}pyridine -4-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; 2-{5-[(2R)-2- Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-[(1-methyl-1H-pyrazole-3- Methyl]-6-(1,3-oxazol-2-yl)isonicotinamide; (6-{5-[(2R)-2-amino-1-phenylprop-2- -1,3,4-oxadiazol-2-yl}pyridin-2-yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1 -yl]methanone; (2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}pyridine-4 -yl)[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amine 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(pyrrolidin-1-yl)pyridin-4-yl][(2R)-2 -(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; 6-{5-[(2R)-2-amino-1-phenylprop-2- -1,3,4-oxadiazol-2-yl}-1-methyl-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrole Aridin-1-yl]carbonyl}pyridine-2(1H)-one; [2-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4- Oxadiazol-2-yl}-6-(difluoromethoxy)pyridin-4-yl][(2R)-2-(4-methyl-1,3-thiazole-2 -yl)pyrrolidin-1-yl]methanone; 4-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2 -yl}-1-methyl-6-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H) -ketone; 6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-(cyclopropyl Methyl)-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one; 6- {5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-ethyl-4-{[(2R 2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one; (2-{5-[(2R)-2) -amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-ethoxypyridin-4-yl)[(2R)-2-(4 -methyl-1,3-thiazol-2-yl)pyrrolidin-1-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- 1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; (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- 1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; [2-{5-[(2R)-2-amino- 1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-6-(ethylamino)pyridin-4-yl][(2R)-2-(4- Methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone; 3-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1 ,3,4-oxadiazol-2-yl}-1-methyl-5-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1- Carbonyl}pyridine-2(1H)-one; 6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazole-2 -yl}-4-{[(2R)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]carbonyl}pyridine-2(1H)-one; 6- {5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2- side oxy-N-(pyridin-3-ylmethyl)-1,2-dihydropyridine-4-carboxamide; 6-{5-[(2R)-2-amino-1-phenylpropene- 2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-N-[(6-methylpyridin-2-yl)methyl]-2-oxanoxy 1,2-dihydropyridine-4-carboxamide; 6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxo Zin-2-yl}-N-butyl-1-methyl-2-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydropyridine-4-carboxamide; -{5-[(2R)-2-Amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-1-methyl-4-{[2 -(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]carbonyl}pyridyl -2(1H)-one; 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)-1,2-dihydropyridine-4-carboxamide; 6-{5-[(2R) 2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}-N,1-dimethyl-2-oxo-N-(1H -pyrazol-5-ylmethyl)-1,2-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-di Hydropyridine-4-carbamide; 6-{5-[(2R)-2-amino-1-phenylpropan-2-yl]-1,3,4-oxadiazol-2-yl}- N-[(2,5-Dimethyl-1,3-oxazol-4-yl)methyl]-N,1-dimethyl-2-oxooxy-1,2-dihydropyridine-4 -carbamamine; (R)-3-(5-(2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-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-methyl) Thiazol-2-yl)pyrrolidin-1-yl)methanone; (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxa) (oxazol-2-yl)-5-chlorophenyl)((2R,4S)-4-fluoro-2-(4-methylthiazol-2-yl) Pyrrolidin-1-yl)methanone; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-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-1-yl)methanone; (3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)) -1,3,4-oxadiazol-2-yl)-4-fluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone (R)-5-(5-(2-Amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5- Dimethyloxazol-4-yl)methyl)-2,4-difluoro-N-methylbenzamide; (R)-4-(5-(2-amino-1-phenylpropane) -2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-5-fluoro-N-A Pyridinecarbamide; (R)-4-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-( (2,5-Dimethyloxazol-4-yl)methyl)-5-methoxy-N-methylpyridinecarboxamide; (R)-3-(5-(2-amino-1) -(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl -4,5-difluoro-N-methylbenzamide; (3-(5-((R))-2-amino-1-(4-fluorobenzene) )propan-2-yl)-1,3,4-oxadiazol-2-yl)-4,5-difluorophenyl)((S)-2-(4-methyloxazol-2-yl) Pyrrolidin-1-yl)methanone; and (5-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazole-2 -yl)-2,4-difluorophenyl)((R)-2-(4-methyloxazol-2-yl)pyrrolidin-1-yl)methanone; or pharmaceutically acceptable Salt or solvate. The compound of claim 1, wherein the compound is selected from the group consisting of: (3-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4 -oxadiazol-2-yl)-5-(oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone (3-(5-((R)-2-amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-5- (oxazol-2-yl)phenyl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5-(2) -amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl -N-methyl-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1, 3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)-N-methyl-5-(pyrazin-2-yl) Benzylamine; (2-(5-((R)-2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-( Oxazol-2-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)-3-(5- (2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazole) 4-(4-(methyl)-2-yl)benzamide -2-yl)-1,3,4-oxadiazol-2-yl)-6-(1- Methyl-1H-pyrazol-4-yl)pyridin-4-yl)((R)-2-(4-methylthiazol-2-yl)pyrrolidin-1-yl)methanone; (R)- 3-(5-(2-Amino-1-(4-fluorophenyl)propan-2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-( (4-methylthiazol-2-yl)methyl)-5-(oxazol-2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropane) -2-yl)-1,3,4-oxadiazol-2-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)-5-(oxazole- 2-yl)benzamide; (R)-3-(5-(2-amino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)- N-cyclopropyl-N-((2,5-dimethyloxazol-4-yl)methyl)-4-fluorobenzamide; and (R)-3-(5-(2-amine) 1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-N-((2,5-dimethyloxazol-4-yl)methyl)- 4,5-difluoro-N-methylbenzamide; or a pharmaceutically acceptable salt or solvate thereof. a compound of formula (V), Where applicable, A ¹ , A ² , X ¹ , X ² , R ⁶ A, R ^6B , R ^7A and R ^{7B are} as defined in any one of the preceding claims; or a pharmaceutically acceptable salt or solvent thereof Compound. The compound of claim 256, wherein the compound has the formula (Va): Or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 256, wherein the compound has the formula (Vb): Where applicable, L ⁴ and R ^{4 are} as defined in any one of the preceding claims; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 258, wherein the compound has the formula (Vc): Where applicable, Y, R ²⁰ , R ²¹ and R ^{22 are} as defined in any one of claims 73 and 77 to 190; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 258, wherein the compound has the formula (Vd): Where applicable, Y, R ²⁰ , R ²¹ and R ^{22 are} as defined in any one of claims 73 and 77 to 190; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 258, wherein the compound has the formula (Ve): Wherein R ^{23 is} as defined in any one of claims 73 and 79 to 165; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 258, wherein the compound has the formula (Vf): Wherein Y is N or CH, and R ⁴⁰ is halogen or an optionally substituted alkoxy group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 262, wherein Y is CH; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 262 or 263, wherein R ⁴⁰ is optionally substituted methoxy; or a pharmaceutically acceptable salt or solvate thereof. A compound of claim 262 or 263, wherein R ⁴⁰ is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 265, wherein R ⁴⁰ is fluoro or chloro; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 266, wherein R ^6B is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 266, wherein R ^6B is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 268, wherein R ^6B is a fluoro group; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 269, wherein R ^6A is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 269, wherein R ^6A is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 271, wherein R ^6A is a fluoro group; or a pharmaceutically acceptable salt or solvate thereof. a compound of formula (VI), Where applicable, A ¹ , A ² , X ¹ , X ² , L ¹ , R ² , R ^7A and R ^{7B are} as defined in any one of the preceding claims; or a pharmaceutically acceptable salt or solvent thereof Things. The compound of claim 273, wherein the compound has the formula (VIa): Where applicable, L ⁴ and R ^{4 are} as defined in any one of the preceding claims; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 274, wherein the compound has the formula (VII): Where applicable, Y, R ²⁰ , R ²¹ and R ^{22 are} as defined in any one of claims 73 and 77 to 190; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 274, wherein the compound has the formula (VIII): Where applicable, Y, R ²⁰ , R ²¹ and R ^{22 are} as defined in any one of claims 73 and 77 to 190; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 274, wherein the compound has the formula (IX): Wherein R ^{23 is} as defined in any one of claims 73 and 79 to 165; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 274, wherein the compound has the formula (X): Wherein Y is N or CH, and R ⁴⁰ is halogen or an optionally substituted alkoxy group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 278, wherein Y is CH; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 278 or 279, wherein R ⁴⁰ is halogen; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 278 or 279, wherein R ⁴⁰ is an optionally substituted alkoxy group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 281, wherein R ⁴⁰ is trifluoromethoxy; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 273 to 282, wherein L ¹ is a methylene group; or a pharmaceutically acceptable salt or solvate thereof. 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 Things. The compound of claim 284, wherein R ^7A is methyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 285, wherein L ⁴ is a methylene group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 286, wherein R ⁴ is substituted or unsubstituted aryl; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 287, wherein R ⁴ is phenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 287, wherein R ⁴ is 4-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 289, wherein A ¹ is an optionally substituted thiazolyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 290, wherein A ¹ is 4-methylthiazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 290, wherein A ¹ is 4-(fluoromethyl)thiazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 289, wherein A ¹ is an optionally substituted oxazolyl group; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 293, wherein A ¹ is 4-methyloxazol-2-yl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 266 and 267 to 285, wherein A ¹ is an optionally substituted thiazolyl group; and R ⁴ is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof Or a solvate. The compound of claim 295, wherein A ¹ is 4-methylthiazol-2-yl, 4-(fluoromethyl)thiazol-2-yl or 4-methyloxazol-2-yl; and R ⁴ is benzene Or 4-fluorophenyl; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 296, wherein X ¹ is N; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 297, wherein X ² is N; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 297, wherein X ² is CH; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 256 to 296, wherein X ¹ is CH; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 300, wherein X ² is CH; or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 300, wherein X ² is N; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 302, wherein the compound has a membrane aspartic acid protease 2K _{i of} less than about 300 nM; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 302, wherein the compound has an apparent membrane aspartic acid protease 2 K _{i of} less than about 300 nM, such as by a membrane aspartic acid protease 2 versus a fluorescent receptor FS- The inhibition of the catalytic activity of 2 (MCA-SEVNLDAEFK-DNP; SEQ ID NO.: 2); or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 304, wherein the compound is capable of inhibiting cellular Aβ production with an IC ₅₀ of less than about 500 nM; or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 305, wherein the compound is capable of selectively reducing the catalytic activity of the membrane aspartic protease 2 relative to the catalytic activity of the membrane aspartic acid protease 1 or cathepsin D; or a pharmaceutical thereof An acceptable salt or solvate. The compound of claim 306, wherein the compound is capable of selectively reducing membrane catalytic aspartic protease 2 catalytic activity by more than about 5-fold relative to membrane aspartic acid protease 1 or cathepsin D catalytic activity; or pharmaceutically acceptable a salt or solvate. The compound of claim 307, wherein the compound is capable of selectively reducing membrane catalytic aspartic protease 2 catalytic activity by more than about 5 times relative to membrane aspartic acid protease 1 catalytic activity; or a pharmaceutically acceptable salt or solvent thereof Compound. The compound of any one of claims 1 to 308, wherein the compound (a) membrane aspartic acid protease 2 K _{i is} less than about 300 nM; (b) capable of inhibiting cellular Aβ production with an IC ₅₀ of less than about 500 nM; And (c) capable of selectively reducing membrane catalytic aspartic protease 2 catalytic activity by more than about 5-fold relative to membrane aspartic acid protease 1 or cathepsin D catalytic activity; 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. A formulation comprising a compound according to 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 a 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 according to any one of claims 1 to 309 or a pharmaceutically acceptable compound thereof a salt or solvate. A method of treating a condition mediated by membrane aspartic acid protease 2 catalytic activity in a subject 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. A method for reducing the catalytic activity of the membrane aspartic acid protease 2, the method comprising the step of the membrane aspartic acid protease 2 and an effective amount of a compound according to any one of claims 1 to 309, or a pharmaceutically acceptable salt thereof Or solvate contact. The method of claim 315, wherein the membrane aspartic acid protease 2 is contacted in the cell. A method for selectively reducing the catalytic activity of membrane aspartic protease 2 relative to the catalytic activity of membrane aspartic acid protease 1, which comprises potting aspartic protease 2 in the presence of membrane aspartic acid protease 1 The compound of any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof, is contacted. A method for selectively reducing the catalytic activity of membrane aspartic protease 2 relative to cathepsin D catalytic activity, the method comprising the step of treating the membrane aspartic protease 2 protein with a therapeutically effective amount in the presence of cathepsin D The compound of any one of 309 or a pharmaceutically acceptable salt or solvate thereof is contacted. A method for selectively reducing the catalytic activity of membrane aspartic protease 2 relative to membrane aspartic acid protease 1 catalytic activity and cathepsin D catalytic activity, the method comprising the presence of membrane aspartic acid protease 1 and cathepsin D The membrane aspartic acid protease 2 is contacted with a therapeutically effective amount of a compound according to any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof. The compound of any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament. Use of a compound according to any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture or prevention of catalysis by membrane aspartic protease 2 An agent that mediated the activity. Use of a compound according to any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prevention of catalytic activity by membrane aspartate 2 Guided by the condition. The use of claim 321 or 322, wherein the condition is Alzheimer's disease. A kit for treating or preventing an individual suffering from Alzheimer's disease, comprising: (a) a compound according to any one of claims 1 to 309, or a pharmaceutically acceptable salt or solvent thereof And (b) packaging. A kit for treating or preventing a subject having a condition mediated by the membrane aspartic acid protease 2 catalytic activity, comprising: (a) a compound according to any one of claims 1 to 309 or a medicament thereof a salt or solvate that is acceptable; and (b) a package. A kit for treating or preventing an individual suffering from Alzheimer's disease, comprising: (a) a formulation as claimed in claim 311 or 312; and (b) a package. A kit for treating or preventing an individual having a condition mediated by membrane aspartic protease 2 catalytic activity, comprising: (a) a formulation as claimed in claim 311 or 312; and (b) packaging .