Antagonist of human integrin α4β7

Abstract

To provide small molecule antagonists of α4β7 integrin, and methods of using them to treat a number of specific diseases or conditions.SOLUTION: The present invention provides a compound represented by formula (I). There is also provided a pharmaceutical composition comprising the compound for treating a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, graft versus host disease, a chronic inflammatory disease of the lung, HIV, and hematological tumor.SELECTED DRAWING: Figure 1-1

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 656,742, filed Apr. 12, 2018.

Background Art

[0002] The heterodimeric integrin family of receptors regulates cell shape and cell adhesion to the extracellular matrix in response to exogenous and endogenous cues.

[0003] Integrin signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.

[0004] Integrin receptors can signal exclusively to cells in both a "inside-out" and "outside-in" bidirectional manner. Thus, they mediate cell migration by transmitting force from the extracellular matrix to the cytoskeleton, and regulate cytoskeletal organization to achieve the shape changes necessary during cell migration.

[0005] Integrins are expressed on the surface of most human cells. Their pathologies contribute to a diverse range of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration, as well as various autoimmune and chronic inflammatory diseases.

[0006] Integrins form heterodimers of two different chains, an α (alpha) and a β (beta) subunit. α4β7 integrin is expressed on lymphocytes, is responsible for the recirculation of T cells to gut-associated lymphoid tissue via binding to mucosal addressin cell adhesion molecule (MAdCAM), and is present on the high endothelial venules of mucosal lymphoid organs.

[0007] Inhibitors of specific integrin-ligand interactions have been shown to be effective as anti-inflammatory agents for the treatment of various autoimmune diseases. For example, monoclonal antibodies that exhibit high binding affinity for α4β7 show therapeutic effects against gastrointestinal autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis.

[0008] The role of integrins as drug targets has long been recognized, and a total of six injectable integrin inhibitors have been approved by the Food and Drug Administration for various therapeutic indications, namely inflammatory bowel disease (Entyvio®, Tysabri®), multiple sclerosis (Tysabri®), psoriasis (Raptiva®), and acute coronary syndrome (Reopro®, Aggrastat®, Integrilin®). However, the success of treatment with orally bioavailable integrin inhibitors is notably lacking.

[0009] Of the 24 known integrin heterodimers, at least half are associated with inflammation, fibrosis, oncology, and vascular diseases. Therefore, a new class of integrin inhibitors is needed. SUMMARY OF THE INVENTION

[0010] In certain embodiments, the invention is a compound of formula I, wherein

Chemical formula

Chemical formula

[0011] In certain embodiments, the invention is a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, graft-versus-host disease, chronic inflammatory diseases of the lung, HIV, and hematological malignancies, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0012]

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BEST MODE FOR CARRYING OUT THE INVENTION

[0013] In certain embodiments, the present invention relates to compounds that antagonize α4β7 integrin. The compounds will be useful for treating inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, graft-versus-host disease, chronic inflammatory diseases of the lung, HIV, or hematological malignancies.

[0014] Definitions For convenience, before further describing the present invention, certain terms used in this specification, the examples, and the appended claims are collected herein. These definitions are to be read in view of the remainder of the disclosure and are to be understood by those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0015] To more readily understand the present invention, certain terms and phrases are defined below and throughout this specification.

[0016] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0017] As used herein in the specification and claims, the phrase "and / or" is to be understood to mean "either or both" of the elements so conjoined, i.e., elements that may be conjunctively present or disjunctively present. Multiple elements listed with "and / or" are to be construed in the same fashion, i.e., as "one or more" of the elements so conjoined. Other elements may optionally be present whether or not related to those specifically identified by the "and / or" clause, except for those elements specifically identified. Thus, by way of non-limiting example, reference to "A and / or B" when used in combination with open-ended language such as "comprising" may refer, in one embodiment, to only A (optionally including elements other than B), in another embodiment, to only B (optionally including elements other than A), and in yet another embodiment, to both A and B (optionally including other elements).

[0018] As used in the specification and claims herein, "or" is to be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one, and also including two or more, of the several elements or of the elements of the list, and optionally including additional items not in the list. In contrast, only terms such as "only one of" or "exactly one of", or when used in the claims, terms such as "consisting of", clearly indicate that only one of several elements or of a list of elements is included. In general, the term "or" as used herein shall be interpreted to indicate exclusive alternatives (i.e., "either one or the other but not both") only when preceded by terms such as "any", "one of", "only one of", or "exactly one of". As used in the claims, "consisting essentially of" shall have the ordinary meaning as used in the field of patent law.

[0019] As used in this specification and the claims, with respect to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more of the elements in the list of elements, provided that it is not necessarily required to include at least one of each element specifically listed within the list of elements, and combinations of elements within the list of elements are not excluded. Also, according to this definition, elements can optionally exist outside of the elements specifically identified within the list of elements referred to by the phrase "at least one", regardless of whether they are related to those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") can, in one embodiment, refer to at least one A that optionally includes two or more As and no B (and optionally includes elements other than B), in another embodiment, refer to at least one B that optionally includes two or more Bs and no A (and optionally includes elements other than A), and in yet another embodiment, can refer to at least one A that optionally includes two or more As, at least one B that optionally includes two or more Bs (and optionally includes other elements).

[0020] Also, conversely, it should be understood that unless explicitly indicated otherwise, in any method claimed in this specification that includes two or more steps or acts, the order of the steps or acts of the method is not necessarily limited to the order of the steps or acts of the recited method.

[0021] In the claims and the above specification, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "consisting of", etc. are to be understood as being non-limiting, i.e., meaning including but not limited to them. As described in Section 2111.03 of the United States Patent and Trademark Office's Manual of Patent Examining Procedure, only the transitional phrases "consisting of" and "consisting essentially of" are to be considered limiting (closed) or semi-limiting transitional phrases, respectively.

[0022] Specific compounds included in the compositions of the present invention may exist as specific geometric or stereoisomers. Further, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, their racemic mixtures, as well as other mixtures thereof, as being included within the scope of the present invention. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All such isomers, as well as their mixtures, are intended to be included in the present invention.

[0023] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary group to provide the pure enantiomer of interest. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomers formed are resolved by fractional crystallization or by chromatographic means well known in the art, and the subsequent pure enantiomer is recovered.

[0024] The structures shown herein also mean that they contain different compounds only in the presence of one or more isotope-enriched atoms. For example, by substituting hydrogen with deuterium or tritium, or by substituting carbon with 13 C- or 14 compounds produced by substituting with C-enriched carbon are within the scope of the present invention.

[0025] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refer to liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in transporting or delivering the subject chemical substance from one organ or part of the body to another organ or part of the body, and mean pharmaceutically acceptable materials, compositions, or vehicles such as these. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not harmful to the patient, and substantially nonpyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are nonpyrogenic, i.e., they do not cause a significant increase in temperature when administered to a patient.

[0026] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic acid addition salts and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0027] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and can thus form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases refers to relatively non-toxic inorganic base addition salts and organic base addition salts of the compound(s). These salts can similarly be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free acid form with a suitable base such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary amine, organic secondary amine, or organic tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, the above Berge et al.).

[0028] The "therapeutically effective amount" (or "effective amount") of a compound for use in therapy refers to the amount of the compound in a formulation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), alleviates symptoms, ameliorates a condition, or delays the onset of a disease state, according to clinically acceptable criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to medical treatment.

[0029] The term "preventive or therapeutic" treatment is recognized in the art and includes administration of one or more of such compositions to a host. When administered prior to the clinical symptoms of an undesirable state (e.g., a disease or other undesirable state of a host animal), the treatment is preventive (i.e., it protects the host against the onset of the undesirable state), and when administered after the manifestation of the undesirable state, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize the existing undesirable state or its side effects).

[0030] The term "patient" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0031] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl as defined below. Straight-chain aliphatic chains are limited to non-branched carbon chain moieties. As used herein, the term "aliphatic group" refers to a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, including saturated aliphatic groups such as alkyl groups, alkenyl groups, or alkynyl groups, and unsaturated aliphatic groups.

[0032] "Alkyl" refers to a fully saturated cyclic or fully saturated acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or up to 30 carbon atoms if not specified. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, the straight-chain or branched-chain alkyl has 30 or fewer (e.g., C1-C 30 for straight-chain and C3-C 30 ) carbon atoms in its backbone, more preferably 20 or fewer carbon atoms. The alkyl group may or may not be substituted.

[0033] As used herein, the term "alkylene" refers to an alkyl group having a specific number of carbons, e.g., 2 to 12 carbon atoms, including two attachment points to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. The alkylene group can be a cyclic or acyclic, branched or unbranched carbon chain moiety and may optionally be substituted with one or more substituents.

[0034] "Cycloalkyl" means a monocyclic or bicyclic, or bridged or spirocyclic or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyl has 3 to 10 carbon atoms in the ring structure, more preferably 3 to 6 carbons in the ring structure. The cycloalkyl group can be substituted or unsubstituted.

[0035] Unless otherwise specified, "lower alkyl" as used herein means an alkyl group as defined above, having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have a similar chain length. Throughout this application, a preferred alkyl group is lower alkyl. In certain embodiments, a substituent designated as alkyl herein is lower alkyl.

[0036] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having a specified number of carbon atoms, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified, and having one or more double bonds in the moiety. Alkenyls of 6 to 26 carbon atoms are exemplified in various isomers by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, and the unsaturated bond(s) can be located anywhere in the moiety and the double bond(s) can take either the (Z) or (E) configuration.

[0037] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but having one or more triple bonds in the moiety.

[0038] The term "alkylthio" refers to an alkyl group as defined above having a sulfur moiety attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2) m -R 1 and R 1is defined as follows. Representative alkylthio groups include methylthio, ethylthio, and the like. As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group defined below to which an oxygen moiety is attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently bonded by oxygen. Thus, the substituents of alkyl that form an ether can be -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m -R 10 such that it can be represented by one of the following alkoxyls, or is similar to an alkoxyl, where m and R 10 are described below.

[0039] The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines, for example, of the formula:

Chemical formula

[0040] The term "amide" as used herein refers to the following group

Chemical formula

[0041] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups where each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic systems having two or more cyclic rings where two or more carbons are common to two adjacent rings, with at least one of the rings being aromatic. For example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, and the ring structures contain 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0042] As used herein, the term "halo", "halide", or "halogen" means halogen and includes, for example, but not limited to, fluoro, chloro, bromo, iodo in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0043] The term "heterocyclyl" or "heterocyclic group" refers to a ring structure having 3 to 12 members, more preferably 5 to 12 members, more preferably 5 to 10 members, and the ring structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of the heterocyclyl group include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, phthalazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones such as azetidinone and pyrrolidinone, lactams such as sultam and sultone. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic, or heteroaromatic moieties, -CF3, -CN, etc.

[0044] The term "carbonyl" is recognized in the art and has the formula:

Chemical formula

[0045] As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. Exemplary substituents include, for example, those described above herein. Permissible substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent of the organic compound described herein and / or any permissible substituent that satisfies the valence of the heteroatom. The present invention is not intended to be limited in any way by the permissible substituents of the organic compound. It will be understood that "substituted" or "substituted with" includes the implicit conditions that such substitution follows the allowed valences of the substituting atom and the substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, etc.

[0046] As used herein, the term "nitro" means -NO2, the term "halogen" represents -F, -Cl, -Br, or -I, the term "sulfhydryl" means -SH, the term "hydroxyl" means -OH, the term "sulfonyl" means -SO2-, the term "azide" means -N3, the term "cyano" means -CN, the term "isocyanato" means -NCO, the term "thiocyanato" means -SCN, and the term "isothiocyanato" means -NCS, and the term "cyanato" means -OCN.

[0047] The term "sulfamoyl" is recognized in the art and has the formula:

Chemical formula

[0048] The term "sulfate" is recognized in the art and has the formula:

Chem.

[0049] The term "sulfonamide" is recognized in the art and has the formula:

Chem.

[0050] The term "sulfonic acid" is recognized in the art and has the formula:

Chem.

[0051] As used herein, the terms "sulfoxide" or "sulfinyl" refer to the formula:

Chem.

[0052] The term "urea" is recognized in the art and has the general formula

Chem.

[0053] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., is intended to be independent of its definition elsewhere in the same structure if it occurs more than once in any structure.

[0054] As used herein, the term "prodrug" encompasses compounds that are converted to a therapeutically active agent under physiological conditions. A common method for making a prodrug is to include a selected moiety that is hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

[0055] For the purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside front cover of the Handbook of Chemistry and Physics, 67th Edition, 1986 - 87.

[0056] Exemplary Compounds In certain embodiments, the invention is a compound of formula I,

Chemical formula

Chemical formula

[0057] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is alkyl. In certain embodiments, R 1 is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.

[0058] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is alkylene-cycloalkyl. In some embodiments, alkylene-cycloalkyl is methylene-cyclopropyl.

[0059] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is heterocyclyl. In some embodiments, R 1 is substituted heterocyclyl. In some embodiments, R 1 is N-containing heterocyclyl. In some embodiments, R 1 is substituted N-containing heterocyclyl.

[0060] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is - alkylene - O - alkyl. In some embodiments, R 1 is methylene - O - methyl.

[0061] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is aryl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is unsubstituted phenyl. In some embodiments, R 1 is substituted phenyl. In some embodiments, the substituted phenyl is substituted with one or more substituents selected from alkyl and halogen.

[0062] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 1 is alkylene - CF3. In some embodiments, R 1 is methylene - CF3.

[0063] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 2 is heterocyclyl. In certain embodiments, R 2 is substituted heterocyclyl. In certain embodiments, R 2 is N - containing heterocyclyl. In certain embodiments, the N - containing heterocyclyl is a 6 - to 12 - membered heterocyclyl. In some embodiments, R 2 is substituted with one or more substituents selected from amino, alkyl, and alkoxy, wherein the alkyl or alkoxy is substituted with morpholino, cyclic amino, or acyclic amino, and wherein the alkyl, alkoxy, morpholino, cyclic amino, or acyclic amino moieties are optionally substituted with one or more alkoxyls or fluorines.

[0064] In an embodiment, R 2is unsubstituted pyridinonyl. In certain embodiments, R 2 is substituted pyridinonyl. In some embodiments, the substituted pyridinonyl is substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, aryl, heteroaryl, and CF3.

[0065] In some embodiments, R 2 is

Chemical formula

[0066] In some embodiments, R 2 is

Chemical formula

[0067] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 3 is

Chemical formula

[0068] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 4 is H.

[0069] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 4 is (C1-C6)-alkyl. In one embodiment, R 4 is methyl, ethyl, isopropyl, n-propyl, iso-butyl, n-butyl, or tert-butyl.

[0070] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R a is H.

[0071] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R a is alkyl. In one embodiment, R a is methyl.

[0072] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R a is cyclopropyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R a is CN.

[0073] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R a is -O-alkyl. In some embodiments, R a is -OMe.

[0074] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is H.

[0075] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is alkyl. In one embodiment, R b is methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R b is t-butyl.

[0076] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is aryl. In some embodiments, R b is substituted aryl.

[0077] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R bRelates to any one of the aforementioned compounds wherein R is heteroaryl. In some embodiments, R b is substituted heteroaryl. In some embodiments, the substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from alkyl, halogen, OH, -O-alkyl, CN, cycloalkyl, or heterocycloalkyl. In some embodiments, R b is substituted aryl. In some embodiments, R b is

Chemical formula

[0078] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is heterocyclyl. In some embodiments, R b is substituted heterocyclyl. In some embodiments, the substituted heterocyclyl is substituted with one or more substituents selected from alkyl, OH, and -O-alkyl. In some embodiments, R b is

Chemical formula

Chemical formula

[0079] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is -O-cyclobutyl. In some embodiments, R b is -O-cyclobutyl.

[0080] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R b is -O-aryl. In some embodiments, R bis -O-phenyl.

[0081] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 3 is [Chemical formula] relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 3 is [Chemical formula] relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R 3 is [Chemical formula] relates to any one of the aforementioned compounds.

[0082] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R c is H.

[0083] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R c is alkyl. In some embodiments, R c is methyl or ethyl.

[0084] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R c is cycloalkyl.

[0085] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R c is heterocycloalkyl.

[0086] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein R c is halogen.

[0087] In certain embodiments, the present invention relates to an R c which is any one of the aforementioned compounds where R is CF3.

[0088] In certain embodiments, the present invention relates to an R d which is any one of the aforementioned compounds where R is aryl. In some embodiments, R d is a substituted aryl. In some embodiments, the substituted aryl is substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylalkyl, halogen, OH, OMe, CF3, and CN. In some embodiments, R d is

Chemical formula

[0089] In certain embodiments, the present invention relates to an R d which is any one of the aforementioned compounds where R is heterocyclyl. In some embodiments, R d is a substituted heterocyclyl.

[0090] In certain embodiments, the present invention relates to an R d which is any one of the aforementioned compounds where R is heteroaryl. In some embodiments, R d is a substituted heteroaryl. In some embodiments, the substituted heterocyclyl or substituted heteroaryl is substituted with one or more substituents selected from alkyl and cycloalkyl.

[0091] In certain embodiments, the present invention relates to an R d which is

Chemical formula

[0092] In certain embodiments, the present invention relates to an R d which is

Chemical formula

[0093] In certain embodiments, the present invention relates to R e Relates to any one of the aforementioned compounds wherein R is aryl. In some embodiments, R e is phenyl. In some embodiments, R e is substituted phenyl. In some embodiments, the substituted phenyl is alkyl-substituted phenyl. In some embodiments, R e is

Chemical formula

[0094] In certain embodiments, the present invention relates to R e Relates to any one of the aforementioned compounds wherein R is heteroaryl.

[0095] In certain embodiments, the present invention relates to R e Relates to any one of the aforementioned compounds wherein R is heterocyclyl.

[0096] In some embodiments, R e is substituted pyrrolidinyl. In some embodiments, R e is alkyl-substituted pyrrolidinyl. In some embodiments, R e is

Chemical formula

[0097] In certain embodiments, the present invention relates to any one of the aforementioned compounds wherein the compound is a pharmaceutically acceptable salt.

[0098] In certain embodiments, the present invention

Chemical formula

[0099] In certain embodiments, the present invention

Chemical formula

[0100] In certain embodiments, the present invention

Chemical formula

[0101] In certain embodiments, the present invention

Chemical formula

[0102] In certain embodiments, the present invention

Chemical formula

[0103] In certain embodiments, the present invention relates to

Chemical formula

[0104] In certain embodiments, the present invention relates to

Chemical formula

[0105] In certain embodiments, the present invention relates to

Chemical formula

[0106] In certain embodiments, the present invention relates to

Chemical formula

[0107] In certain embodiments, the present invention relates to

Chemical formula

[0108] In certain embodiments, the present invention relates to

Chemical formula

[0109] In certain embodiments, the present invention relates to [Chemical formula] compounds selected from the group consisting of JPEG0007700193000060.jpg231163 and JPEG0007700193000061.jpg139164.

[0110] In certain embodiments, the present invention relates to [Chemical formula] compounds selected from the group consisting of JPEG0007700193000063.jpg202167, JPEG0007700193000064.jpg235164, and JPEG0007700193000065.jpg144164.

[0111] Exemplary pharmaceutical compositions In certain embodiments, the present invention relates to a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable carrier.

[0112] Patients, including but not limited to humans, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active substance can be in liquid or solid form and can be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, rectally, or topically.

[0113] The concentration of the active compound in the pharmaceutical composition depends on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values also vary depending on the severity of the condition to be alleviated. Further, for any particular subject, it may be necessary to adjust the specific dosage regimen over time according to the individual needs and the professional judgment of the person managing or supervising the administration of the composition, and it is to be understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or divided into several smaller doses to be administered at various time intervals.

[0114] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant substances can be included as part of the composition.

[0115] Tablets, pills, capsules, troches, etc. can contain any of the following ingredients or compounds of similar nature, namely, excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch, lubricants such as magnesium stearate or Sterotes, glidants such as colloidal silicon dioxide, sweetening agents such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, orange flavor, etc. When the dosage unit form is a capsule, in addition to the substances of the above types, a liquid carrier such as a fatty oil can be included. Further, the unit dosage form can contain various other materials that modify the physical form of the dosage unit, such as, for example, coatings of sugar, shellac, or other enteric solvents.

[0116] The compound can be administered as a component in elixirs, suspensions, syrups, oblat, chewing gums, etc. The syrup can contain, in addition to the active compound(s), sucrose or a sweetener as a sweetening agent, certain preservatives, dyes and colorants, and flavorings.

[0117] The compound or its pharmaceutically acceptable salts thereof can also be mixed with substances that complement the desired action, such as other active substances that do not impair the desired action, or other antiviral agents including, but not limited to, antibiotics, antifungal agents, anti-inflammatory agents, or nucleoside compounds. Solutions or suspensions for parenteral, intradermal, subcutaneous, or topical administration contain the following components: sterile diluents such as water for injection, physiological saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffering agents such as acetate, citrate, or phosphate, and tonicity regulators such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0118] In the case of intravenous administration, the carrier includes physiological saline and phosphate-buffered saline (PBS).

[0119] In certain embodiments, the active compound is prepared with a carrier that protects the compound from rapid excretion from the body, such as controlled-release formulations including, but not limited to, implantable devices and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. For example, enteric-coated compounds can be used to protect against cleavage by gastric acid. The method for preparing such formulations will be apparent to those skilled in the art. Suitable materials are also commercially available.

[0120] Liposomal suspensions (including, but not limited to, liposomes targeting infected cells having monoclonal antibodies against viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (incorporated by reference). For example, liposomal formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidoyl phosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating the inorganic solvent to leave a thin film of dry lipid on the surface of the container. Next, an aqueous solution of the active compound is introduced into the container. Then, the container is rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposomal suspension.

[0121] Exemplary methods In certain embodiments, the invention relates to a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, graft-versus-host disease, chronic inflammatory diseases of the lung, HIV, and hematological malignancies, the method comprising administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

[0122] In certain embodiments, the disease or condition is inflammatory bowel disease. In certain embodiments, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, nontropical sprue, enteropathy associated with seronegative arthritis, gastroenteritis, or pouchitis.

[0123] In certain embodiments, the disease or condition is colitis, and the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis.

[0124] In certain embodiments, the disease or condition is pouchitis, and the pouchitis results from ileal pouch-anal anastomosis.

[0125] In certain embodiments, the disease or condition is gastroenteritis. In certain embodiments, the gastroenteritis is eosinophilic gastroenteritis.

[0126] In certain embodiments, the disease or condition is eosinophilic esophagitis.

[0127] In certain embodiments, the disease or condition is a chronic inflammatory disease of the lung. In certain embodiments, the chronic inflammatory disease of the lung is interstitial fibrosis. In certain embodiments, the interstitial fibrosis is hypersensitivity pneumonitis, collagen disease, or sarcoidosis.

[0128] In certain embodiments, the disease or condition is a hematological tumor. In certain embodiments, the hematological tumor is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma.

[0129] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the subject is a human.

Examples

[0130] The present invention generally described herein is included for the purpose of illustration of certain aspects and embodiments of the present invention only and is not intended to limit the present invention. It will be more readily understood by reference to the following examples.

[0131] Example 1. General Scheme for the Synthesis of α4β7 Inhibitors General Procedure Suzuki Coupling

Chemical Formula

[0132] Amide bond formation

Chem.

[0133] Ester hydrolysis

Chem.

[0134] Analytical methods LCMS analysis The final compound was analyzed using LC / MS conditions with a UV detector monitoring at 214 nm and 254 nm and mass spectrometry scanning from 110 - 800 amu in ESI+ ionization mode.

[0135] LC / MS A: Column: XBridge C18, 4.6×50 mm, 3.5 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN, Gradient: 5% - 95% B for 1.4 min, then hold for 1.6 min, Flow rate: 1.8 mL / min, Oven temperature 50 °C.

[0136] LC / MS B: Column: SunFire C18, 4.6×50 mm, 3.5 μm, Mobile phase: A water (0.01% TFA), B CH3CN, Gradient: 5% - 95% B for 1.5 minutes, then hold for 1.5 minutes, Flow rate: 2.0 mL / min, Oven temperature 50°C. LC / MS C: Column: XBridge C18, 4.6×50 mm, 3.5 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN, Gradient: 5% - 95% B for 1.5 minutes, then hold for 1.5 minutes, Flow rate: 1.8 mL / min, Oven temperature 50°C.

[0137] LC / MS D: Column: Poroshell 120 EC-C138, 4.6×30 mm, 2.7 μm, Mobile phase: A water (0.01% TFA), B CH3CN (0.01% TFA), Gradient: 5% - 95% B for 1.2 minutes, then hold for 1.8 minutes, Flow rate: 2.2 mL / min, Oven temperature 50°C.

[0138] Preparative HPLC method The crude sample was dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument at a detection wavelength of 214 nm.

[0139] Preparative HPLC A: Column: XBridge C18, 21.2*250 mm, 10 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN, Gradient elution as described in the text, Flow rate: 20 mL / min.

[0140] Preparative HPLC B: Column: XBridge C18, 21.2*250 mm, 10 μm, Mobile phase: A water (10 mM formic acid), B CH3CN, Gradient elution as described in the text, Flow rate: 20 mL / min.

[0141] Preparative chiral SFC method The racemic and / or diastereomeric products were separated into individual enantiomers by preparative chiral SFC using an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm.

[0142] Preparative Chiral SFC A: Column: (R,R)-Whelk-O1, 20*250mm, 5μm (Decial), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0143] Preparative Chiral SFC B: Column: AD 20*250mm, 10μm (Daicel), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0144] Preparative Chiral SFC C: Column: AS 20*250mm, 10μm (Daicel), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0145] Preparative Chiral SFC D: Column: OD 20*250mm, 5μm (Daicel), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0146] Preparative Chiral SFC E: Column: (S,S)-Whelk-O1, 20*250mm, 5μm (Decial), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0147] Preparative Chiral SFC F: Column: OZ 20*250mm, 5μm (Daicel), Column Temperature: 35°C, Mobile Phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow Rate: 80g / min, Back Pressure: 100 bar.

[0148] Analytical Preparative SFC Method The chiral product was analyzed by chiral SFC at a detection wavelength of 214 nm using an SFC-80 (Thar, Waters) instrument.

[0149] Chiral SFC A: Column: (R,R)-Whelk-O1, 4.6*100 mm, 5 μm (Decial), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution of the text, flow rate: 4 g / min, back pressure: 120 bar.

[0150] Chiral SFC B: Column: AD 4.6*100 mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution of the text, flow rate: 4 g / min, back pressure: 120 bar.

[0151] Chiral SFC C: Column: AS 4.6*100 mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution of the text, flow rate: 4 g / min, back pressure: 120 bar.

[0152] Example 2. Preparation of the intermediate (R)-2-Bromo-4-methylpentanoic acid

Chemical formula

[0153] (S)-4-Methyl-2-(2-oxopyrazin-1(2H)-yl)pentanoic acid [Chemical formula] A solution of compound pyrazin-2(1H)-one (11.0 g, 114 mmol), Mg(Ot-Bu)2 (39.0 g, 229 mmol), and t-BuOK (13.5 g, 120 mmol) in THF (220 mL) was stirred at 25 °C for 20 min under N2. Next, compound (R)-2-bromo-4-methylpentanoic acid (33.5 g, 172 mmol) was added dropwise to the mixture. The reaction mixture was stirred at 25 °C for 20 h. HCl (3.0 M, 153 mL) was added dropwise to the mixture. The organic phase was washed with brine (100 mL) and concentrated. The mixture was purified by SFC (equipment: Thar SFC80 preparative SFC; column: Chiralpak AD-H 250*30 mm i.d. 5u; mobile phase: A for CO2 and B for IPA (0.1% NH3H2O); gradient: B% = 35%; flow rate: 75 g / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 100 bar; cycle time: 13 min; injection volume: 105 mg per injection) to give (S)-4-methyl-2-(2-oxopyrazin-1(2H)-yl)pentanoic acid (15.0 g, 61.7% yield, 99.0% purity) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 4.4 Hz, 1H), 5.14 - 5.21 (m, 1H), 1.84 - 1.92 (m, 2H), 1.17 - 1.26 (m, 1H), 0.82 - 0.84 (m, 6H).

[0154] 4-Methyl-2-(2-oxopyridin-1(2H)-yl)pentanoic acid

Chem.

[0155] (S)-4-Methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanoic acid

Chem.

[0156] (S)-4-Methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid

Chemical Structure

[0157] Step 1: Methyl 3-methoxy-2-(4-methyl-2-oxopyridin-1(2H)-yl)propanoate

Chemical Structure

[0158] Step 2: 3-Methoxy-2-(4-methyl-2-oxopyridin-1(2H)-yl)propanoic acid

Chemical Structure

[0159] Synthesis of 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetic acid Step 1: Methyl 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetate [Chemical formula] A mixture of 5-methyl-2-pyridone (1.463 g, 13.40 mmol), methyl α-bromophenylacetate (2.291 g, 10.00 mmol), and potassium carbonate (1.852 g, 13.40 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by silica gel column (petroleum ether:EtOAc 1:1) to afford the desired product methyl 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetate as a light brown oil (2.5 g). Yield 68% (97% purity, UV = 214 nm, ESI 258 (M+H) + ).

[0160] Step 2: 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetic acid [Chemical formula] Methyl 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetate (2.5 g, 9.6 mmol) was treated with LiOH-H2O (2.3 g, 54 mmol) and water (27 mL) in methanol (134 mL) at room temperature for 16 h. The reaction mixture was acidified to pH = 3 with 1 N hydrochloric acid. The solvent was removed in vacuo, and the residue was purified by preparative HPLC B (30 - 65% MeCN) to give the desired product 2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetic acid as a white solid (2.32 g). Yield 84% (100% purity, UV = 254 nm, ESI 244 (M+H) + ).

[0161] Synthesis of Ethyl (S)-3-(2-bromopyridin-4-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chemical Structure

Chemical Structure

[0162] (R,E)-N-((2-Bromopyridin-4-yl)methylene)-2-methylpropan-2-sulfinamide.

Chem.

[0163] Ethyl (R)-3-(2-bromopyridin-4-yl)-3-(((S)-tert-butylsulfinyl)amino)propanoate

Chem.

[0164] Ethyl (S)-3-(2-bromopyridin-4-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

Chem.

[0165] Ethyl (R)-3-amino-3-(2-bromopyridin-4-yl)propanoate

Chem.

[0166] Ethyl (S)-3-amino-3-(2-bromopyridin-4-yl)propanoate

Chem.

[0167] Ethyl (R)-3-(2-bromopyridin-4-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0168] Ethyl (S)-3-(2-bromopyridin-4-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chem.

[0169] Methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chem.

[0170] Step 1: 3-Amino-3-(5-bromopyridin-3-yl)propanoic acid

Chem.

[0171] Synthesis of methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate

Chem.

[0172] Synthesis of methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0173] Compound A1 1 1H NMR δ 8.58 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 4.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 5.69 (s, 1H), 5.11 (s, 1H), 3.66 (s, 3H), 2.87 (d, J = 8.0 Hz, 2H), 1.43 (s, 9H). Compound A2 1 1H NMR δ 5.58 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 4.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 5.70 (s, 1H), 5.11 (s, 1H), 3.66 (s, 3H), 2.87 (d, J = 8.0 Hz, 2H), 1.43 (s, 9H).

[0174] Synthesis of (S)-methyl 3-amino-3-(2'-methylbiphenyl-3-yl)propanoate Step 1: (S)-methyl 3-amino-3-(3-bromophenyl)propanoate

Chemical formula

[0175] Step 2: (S)-methyl 3-amino-3-(2’-methylbiphenyl-3-yl)propanoate

Chemical formula

[0176] Example 3. Preparation of representative compounds of the present invention Preparation of ((3S)-3-(3’,5’-dimethyl-[3,4’-bipyridine]-5-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta namide)propanoic acid (Compound 1-D1 and Compound 1-D2)

[0177] Step 1: (S)-(5-(1-((tert-Butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)pyridin-3-yl)boronic acid

Chem.

[0178] Step 2: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)propanoate

Chem.

[0179] Step 3: Methyl (S)-3-amino-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)propanoate [Chemical formula] (S)-3-((tert-Butoxycarbonyl)amino)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)propanoate (300 mg, 0.77 mmol) was treated with 4N HCl / dioxane (3 mL) at room temperature for 2 h. The solvent was removed in vacuo to afford the desired product methyl (S)-3-amino-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)propanoate as a yellow oil (350 mg, crude). (64% purity, UV = 254 nm, ESI 286 (M+H) + ).

[0180] Step 4: Methyl (3S)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate [Chemical formula] A mixture of methyl (S)-3-amino-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl) propanoate (250 mg, 0.87 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl) pentanoic acid (196 mg, 0.87 mmol), EDCI (249 mg, 1.3 mmol), HOBt (176 mg, 1.3 mmol), and DIEA (335 mg, 2.6 mmol) in DMF (3 mL) was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give the desired product methyl (3S)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl) pentanamido) propanoate as a brown oil (300 mg). Yield 70% (94% purity, UV = 254 nm, ESI 491 (M+H) + ).

[0181] Step 5: ((3S)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl) pentanamido) propanoic acid [Chemical formula] Methyl (3S)-3-(3’,5’-dimethyl-[3,4’-bipyridin]-5-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl) pentanamido) propanoate (300 mg, 0.61 mmol) was treated with LiOH-H2O (72 mg, 1.83 mmol) and H2O (1 mL) in MeOH (3 mL) at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC A (30 - 80% MeCN) to give compounds B1 (50 mg) and B2 (55 mg) as yellow solids.

[0182] Compound B1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.40 min, ESI 477 (M+H) + 。

[0183] 1H-NMR (500 MHz, MeOD) δ 8.61 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 8.3 Hz, 2H), 8.24 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 7.3 Hz, 2H), 6.25 - 6.23 (m, 2H), 5.69 (dd, J = 9.6, 6.6 Hz, 1H), 5.40 (t, J = 7.0 Hz, 1H), 2.83 (d, J = 7.1 Hz, 2H), 2.19 (s, 3H), 2.05 (s, 3H), 1.94 - 1.92 (m, 5H), 1.51 - 1.40 (m, 1H), 0.98 - 0.95 (m, 6H).

[0184] Compound B2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.43 min, ESI 477 (M+H) + 。1H-NMR (500 MHz, MeOD) δ 8.67 (d, J = 1.7 Hz, 1H), 8.36 (s, 2H), 8.32 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 6.37 (s, 1H), 6.30 (dd, J = 7.2, 1.8 Hz, 1H), 5.69 (dd, J = 9.3, 6.8 Hz, 1H), 5.36 (t, J = 7.1 Hz, 1H), 2.88 - 2.84 (m, 2H), 2.23 (s, 3H), 2.08 (s, 6H), 1.85 - 1.81 (m, 2H), 1.32 - 1.31 (m, 1H), 0.91 - 0.88 (m, 6H).

[0185] (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaamide)propanoic acid preparation

[0186] Step 1: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaamide)propanoate [Chemical formula] A mixture of (S)-4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaanoic acid (150 mg, 0.54 mmol), (S)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (169 mg, 0.59 mmol), HATU (246 mg, 0.65 mmol), and DIEA (0.2 mL) in DMF (5 mL) was stirred overnight at room temperature. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give the desired product (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaanamide)propanoate as a yellow solid (200 mg). Yield 68% (100% purity, UV = 214 nm, ESI 544 (M+H) + )

[0187] Step 2: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaanamide)propanoic acid [Chemical formula] (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaamide)propanoate (200 mg, 0.37 mmol) was treated with LiOH-H2O (74 mg, 1.84 mmol) and H2O (1 mL) in MeOH (3 mL) at room temperature for 2 hours. The reaction mixture was acidified to pH 4 - 5 with 1N HCl. The solvent was removed in vacuo and the residue was purified by preparative HPLC A (30 - 60% MeCN) to give (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaamide)propanoic acid as a white solid (130 mg, 67% yield). The diastereomer mixture was separated by preparative chiral SFCA to give compound C1 (40 mg) and C2 (20 mg) as white solids.

[0188] Compound C1 LC / MS B: 100% purity, UV = 214 nm, Rt = 2.01 min, ESI 530 (M + H) + 。

[0189] 1H-NMR (500 MHz, MeOD) δ 8.59 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 1.9 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.83 (s, 1H), 6.57 (dd, J = 7.7, 2.0 Hz, 1H), 5.78 - 5.68 (m, 1H), 5.39 (t, J = 7.4 Hz, 1H), 2.91 - 2.80 (m, 2H), 2.02 (s, 6H), 1.90 - 1.80 (m, 2H), 1.38 - 1.33 (m, 1H), 0.98 - 0.88 (m, 6H). Chiral SFC A (15% MeOH): ee 100%, Rt = 2.49 min Compound C2 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.98 min, ESI 530 (M + H) +. 1H-NMR (500 MHz, MeOD) δ 8.55 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.59 (s, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.71 (s, 1H), 6.53 (dd, J = 7.3, 2.0 Hz, 1H), 5.72 (dd, J = 9.2, 6.9 Hz, 1H), 5.41 (t, J = 7.0 Hz, 1H), 2.85 (t, J = 15.6 Hz, 2H), 2.04 - 1.92 (m, 5H), 1.85 (s, 3H), 1.55 - 1.42 (m, 1H), 0.98 - 0.86 (m, 6H). Chiral SFC A (15% MeOH): ee 98%, Rt = 3.59 min

[0190] Preparation of Compound D1 and Compound D2 Step 1: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentaamide)propanoate

Chemical Structure

[0191] Step 2: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2R)-4-methyl-2-(2-oxo-4-(trifluoromethyl)piperidin-1-yl)pentanamido)propanoate

Chemical formula

[0192] Step 3: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((2R)-4-methyl-2-(2-oxo-4-(trifluoromethyl)piperidin-1-yl)pentanamide)propanoic acid

Chemical formula

[0193] Compound D1 LC / MS E: 98% purity, UV = 214 nm, Rt = 1.74 min, ESI 534 (M+H) +, 1H-NMR (500 MHz, MeOD) δ: 8.55 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.64 (t, J = 1.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 5.40 (t, J = 7.0 Hz, 1H), 5.23 (dd, J = 9.0, 6.5 Hz, 1H), 3.59 - 3.55 (m, 1H), 3.33 - 3.28 (m, 1H), 2.96 - 2.87 (m, 2H), 2.84 - 2.79 (m, 1H), 2.66 (ddd, J = 17.5, 6.0, 1.5 Hz, 1H), 2.50 (dd, J = 17.3, 10.8 Hz, 1H), 2.14 - 2.11 (m, 1H), 2.00 (d, J = 6.0 Hz, 6H), 1.86 (ddd, J = 26.0, 12.0, 5.0 Hz, 1H), 1.74 - 1.68 (m, 1H), 1.63 - 1.58 (m, 1H), 1.47 - 1.41 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H).

[0194] Compound D2 LC / MS E: 100% purity, UV = 214 nm, Rt = 1.76 min, ESI 534 (M + H) + , 1H-NMR (500 MHz, MeOD) δ: 8.55 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.64 (t, J = 1.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 5.40 (t, J = 7.0 Hz, 1H), 5.23 (dd, J = 9.0, 6.5 Hz, 1H), 3.46 - 3.42 (m, 1H), 3.39 - 3.34 (m, 1H), 2.90 - 2.85 (m, 3H), 2.71 - 2.66 (m, 1H), 2.46 (dd, J = 17.0, 10.3 Hz, 1H), 2.19 - 2.15 (m, 1H), 2.00 (d, J = 7.5 Hz, 6H), 1.83 - 1.76 (m, 1H), 1.72 - 1.66 (m, 1H), 1.61 - 1.55 (m, 1H), 1.43 - 1.37 (m, 1H), 0.91 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H).

[0195] Preparation of Compound E Step 1: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2S)-4-methyl-2-(2-oxo-4-(trifluoromethyl)piperidin-1-yl)pentaamide)propanoate

Chem.

[0196] Step 2: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2S)-4-methyl-2-(2-oxo-4-(trifluoromethyl)piperidin-1-yl)pentaamide)propanoic acid

Chem.

[0197] Compound E LC / MS E: 98% purity, UV = 214 nm, Rt = 1.72 min, ESI 534 (M+H) + ; 1 1H-NMR (500 MHz, MeOD) δ: 8.55 (d, J = 1.5 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.64 (t, J = 1.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 5.40 (t, J = 7.0 Hz, 1H), 5.23 (dd, J = 9.0, 6.5 Hz, 1H), 3.59 - 3.55 (m, 1H), 3.33 - 3.28 (m, 1H), 2.96 - 2.87 (m, 2H), 2.84 - 2.79 (m, 1H), 2.66 (ddd, J = 17.5, 6.0, 1.5 Hz, 1H), 2.50 (dd, J = 17.3, 10.8 Hz, 1H), 2.14 - 2.11 (m, 1H), 2.00 (d, J = 6.0 Hz, 6H), 1.86 (ddd, J1 = 26.0, 12.0, 5.0 Hz, 1H), 1.74 - 1.68 (m, 1H), 1.63 - 1.58 (m, 1H), 1.47 - 1.41 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H).

[0198] Preparation of Compound F Step 1: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoate

Chemical Structure

[0199] Step 2: (S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoic acid, and (S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((S)-2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoic acid [Chemical formula] (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoate (200 mg, 0.39 mmol) was treated with LiOH-H2O (394 mg, 9.4 mmol) and water (1 mL) in methanol (10 mL) at room temperature for 16 h. The reaction was acidified to pH = 3 with 1 N HCl. The solvent was removed in vacuo and the residue was purified by preparative HPLC A (30 - 65% MeCN) to give the desired product (S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((S)-2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoic acid (86 mg, 43% yield) (100% purity, UV = 254 nm, ESI 496 (M+H) + ), and (S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-2-(5-methyl-2-oxopyridin-1(2H)-yl)-2-phenylacetamido)propanoic acid (81 mg, 41% yield) (100% purity, UV = 254 nm, ESI 496 (M+H) + ) as white solids.

[0200] Step 3: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((2R)-2-(5-methyl-2-oxopiperidin-1-yl)-2-phenylacetamido)propanoic acid

Chemical Structure

[0201] Compound F LC / MS B: 100% purity, UV = 214 nm, Rt = 1.60 min, ESI 500 (M+H) + 。

[0202] 1H-NMR (500 MHz, MeOD) δ 8.53 (dd, J = 5.0, 2.0 Hz, 1H), 8.22 (t, J = 2.3 Hz, 1H), 7.56 (dt, J = 11.0, 2.0 Hz, 1H), 7.29 - 7.23 (m, 3H), 7.19 (t, J = 7.5 Hz, 1H), 7.14 - 7.11 (m, 4H), 6.28 (d, J = 30.0 Hz, 1H), 5.50 - 5.46 (m, 1H), 3.05 (dd, J = 12.0, 11.0 Hz, 1H), 2.94 - 2.78 (m, 3H), 2.54 - 2.41 (m, 2H), 1.97 (t, J = 2.8 Hz, 6H), 1.82 - 1.70 (m, 2H), 1.57 - 1.31 (m, 1H), 0.85 (dd, J = 21.3, 6.8 Hz, 3H).

[0203] Preparation of Compound G Step 1: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((2S)-2-(5-Methyl-2-oxopiperidin-1-yl)-2-phenylacetamido)propanoic acid

Chemical Structure

[0204] Compound G LC / MS B: 100% purity, UV = 214 nm, Rt = 1.57 min, ESI 500 (M+H) + 。

[0205] 1H-NMR (500 MHz, MeOD) δ 8.60 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.67 (t, J = 2.3 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.32 (t, J = 7.5 Hz, 2H), 7.19 (dd, J = 8.8, 1.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.32 (d, J = 14.5 Hz, 1H), 5.52 (t, J = 7.3 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.86 - 2.83 (m, 3H), 2.41 (q, J = 4.5 Hz, 2H), 2.00 (d, J = 4.5 Hz, 6H), 1.78 - 1.69 (m, 2H), 1.48 - 1.31 (m, 1H), 0.83 (dd, J = 16.8, 6.8 Hz, 3H).

[0206] Preparation of Compounds H1 and H2 Step 1: Methyl 3-(2’,6’-dimethylbiphenyl-3-yl)-3-(3-methoxy-2-(4-methyl-2-oxopyridin-1(2H)-yl)propanamide) propanoate

Chemical Structure

[0207] Step 2: 3-(2’,6’-dimethylbiphenyl-3-yl)-3-(3-methoxy-2-(4-methyl-2-oxopyridin-1(2H)-yl)propanamide)propanoic acid [Chemical formula] Methyl 3-(2’,6’-dimethylbiphenyl-3-yl)-3-(3-methoxy-2-(4-methyl-2-oxopyridin-1(2H)-yl)propanamido)propanoate (150 mg, 0.32 mmol) was treated with LiOH-H2O (66 mg, 1.6 mmol) and H2O (1 mL) in THF (8 mL) at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC B (30 - 70% MeCN) to give compound H1 (10 mg) and compound H2 (30 mg) as white solids.

[0208] Compound H1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.64 min, ESI 463 (M+H) + .

[0209] 11H NMR (500 MHz, MeOD) δ 7.60 (d, J = 7.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.05 (d, J = 7.8 Hz, 3H), 6.99 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 6.20 (dd, J = 7.2, 1.8 Hz, 1H), 5.71 (dd, J = 7.6, 5.1 Hz, 1H), 5.38 (t, J = 6.9 Hz, 1H), 3.92 (ddd, J = 16.0, 10.8, 6.4 Hz, 2H), 3.34 (s, 3H), 2.86 (d, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.97 (s, 3H), 1.93 (s, 3H).

[0210] Compound H2 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.66 min, ESI 463 (M + H) + 。 1 1H NMR (500 MHz, MeOD) δ 7.63 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.10 (dt, J = 16.6, 6.2 Hz, 3H), 7.01 (d, J = 7.4 Hz, 1H), 6.35 (s, 1H), 6.24 (dd, J = 7.2, 1.9 Hz, 1H), 5.73 (dd, J = 6.7, 4.9 Hz, 1H), 5.37 (t, J = 6.8 Hz, 1H), 3.92 (dd, J = 10.6, 6.8 Hz, 1H), 3.82 - 3.79 (m, 1H), 3.20 (s, 3H), 2.83 - 2.78 (m, 2H), 2.23 - 2.19 (m, 3H), 1.99 (d, J = 3.5 Hz, 6H).

[0211] Preparation of Compound I Step 1: (S)-Methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(2'-methylbiphenyl-3-yl)propanoate

Chemical Structure

[0212] Step 2: (S)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)-3-(2'-methylbiphenyl-3-yl)propanoic acid

Chemical Structure

[0213] Compound I LC / MS A: 100% purity, UV = 214 nm, Rt = 1.69 min, ESI 498.1 (M+H) +。

[0214] 1 H-NMR (500 MHz, MeOD) δ 8.45 (s, 1H), 8.28 - 8.26 (m, 1H), 7.88 - 7.86 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.43 (t, J = 15.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.34 (s, 1H), 5.29 - 7.19 (m, 5H), 5.74 (m, 1H), 5.77 - 5.74 (m, 1H), 5.41 (t, J = 15 Hz, 1H), 2.93 - 2.83 (m, 2H), 2.26 (s, 3H), 2.02 - 1.92 (m, 2H), 1.47 - 1.41 (m, 1H), 0.95 - 0.91 (m, 6H)

[0215] Preparation of Compound J1 Step 1: (S)-Methyl 3-((R)-2-hydroxy-4-methylpentanamido)-3-(2’-methylbiphenyl-3-yl)propanoate

Chemical Structure

[0216] Step 2: (S)-Methyl 3-((R)-4-methyl-2-(methylsulfonyloxy)pentaamide)-3-(2'-methylbiphenyl-3-yl)propanoate [Chemical formula] To (S)-methyl 3-((R)-2-hydroxy-4-methylpentanamide)-3-(2'-methylbiphenyl-3-yl)propanoate (130 mg, 0.34 mmol) in DCM (10 mL), TEA (101 mg, 1.0 mmol) and methanesulfonyl chloride (46 mg, 0.4 mmol) were added dropwise, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was added, and the solution was extracted with DCM (10 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product (S)-methyl 3-((R)-4-methyl-2-(methylsulfonyloxy)pentaamide)-3-(2'-methylbiphenyl-3-yl)propanoate as a colorless oil (323 mg). Yield 62% (100% purity, UV = 254 nm, ESI 462.1 (M+H) + ). The crude product was used directly in the next step.

[0217] Step 3: Methyl (3S)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)-3-(2'-methyl-[1,1'-biphenyl]-3-yl)propanoate [Chemical formula] To a solution of (S)-methyl 3-((R)-4-methyl-2-(methylsulfonyloxy)pentaamide)-3-(2'-methylbiphenyl-3-yl)propanoate (130 mg crude) in MeCN (10 mL), K2CO3 (69 mg, 0.5 mmol) and pyridin-2(1H)-one (38 mg, 0.4 mmol) were added. The mixture was stirred at 80 °C for 16 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC A (40 - 70% MeCN) to obtain compound J1a (30 mg) and J1b (40 mg) as white solids.

[0218] Compound J1a: (100% purity, UV = 254 nm, ESI 461.1 (M+H) + )。Compound J1b: (100% purity, UV = 254 nm, ESI 461.1 (M+H) + )。Step 4: Compound J1

Chem.

[0219] Compound J1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.62 min, ESI 447.1 (M+H) + 。

[0220] 1 1H NMR (500 MHz, MeOD) δ 7.76 (m, J = 7.0, 1.7 Hz, 1H), 7.51 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.24 - 7.18 (m, 5H), 6.56 (d, J = 9.2 Hz, 1H), 6.42 (t, J = 6.2 Hz, 1H), 5.78 - 5.75 (m, 1H), 5.37 (t, J = 7.3 Hz, 1H), 2.90 - 2.79 (m, 2H), 2.26 (s, 3H), 1.92 - 1.76 (m, 2H), 1.44 - 1.23 (m, 1H), 0.91 - 089 (m, 6H).

[0221] Step 5: Compound J2

Chem.

[0222] Compound J2 LC / MS A: 100% purity, UV=214nm, Rt=1.66min, ESI447.1(M+H) + .

[0223] 1 H NMR (500MHz, MeOD)δ 7.83-7.68(m, 1H), 7.63-7.55(m, 1H), 7.38(s, 1H), 7.31-7.09(m, 6H), 7.08-6.66(m, 3H), 5.41(t, J=6.7Hz, 1H), 5.33 -5.25(m, 1H), 2.92-2.72(m, 2H), 2.20(s, 1H), 2.13(s, 2H), 1.99-1.82(m, 2H), 1.73-1.66(m, 1H), 1.06-0.87(m, 6H).

[0224] Preparation of Compound K Step 1: (S)-Methyl 3-(2',6'-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentamido)propanoate [ka] A mixture of (S)-methyl 3-(3-bromophenyl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)propanoate (100 mg, 0.2 mmol), 2,6-difluorophenylboronic acid (47 mg, 0.3 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and K2CO3 (83 mg, 0.6 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) was stirred at 110 °C for 1 h in a microwave oven. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:3) to give the desired product (S)-methyl (S)-methyl 3-(2’,6’-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)propanoate as a colorless oil (60 g). Yield 58% (93% purity, UV = 214 nm, ESI 534 (M+H) + ).

[0225] Step 2: (S)-3-(2’,6’-Difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)propanoic acid [Chemical Structure] (S)-Methyl 3-(2’,6’-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)propanoate (60 mg, 0.11 mmol) in THF (5 mL) was treated with LiOH-H2O (14 mg, 0.33 mmol) and H2O (0.5 mL) at room temperature for 16 h. The mixture was acidified to pH = 5 with HCl (1 M). The solvent was removed in vacuo, and the residue was purified by preparative HPLC B (30 - 70% MeCN) to give the desired product (S)-3-(2’,6’-difluorobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)propanoic acid (15 mg) as a white solid.

[0226] Compound K LC / MS B: 100% purity, UV = 214 nm, Rt = 1.87 min, ESI520(M+H) + 。

[0227] 1 H NMR (500 MHz, MeOD) δ 8.45 (s, 1H), 8.27 (dd, J = 8.1, 1.2 Hz, 1H), 7.92 - 7.82 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.51 - 7.33 (m, 5H), 7.17 - 7.01 (m, 2H), 5.77 (dd, J = 10.0, 6.5 Hz, 1H), 5.47 - 5.39 (m, 1H), 2.92 - 2.78 (m, 2H), 2.12 - 1.89 (m, 2H), 1.46 - 1.41 (m, 1H), 0.95 - 0.93 (m, 6H).

[0228] Preparation of Compound L Step 1: (S)-Methyl 3-(3-bromophenyl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)propanoate

Chem.

[0229] Step 2: (S)-Methyl 3-(2'-cyanobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)yl)pentaamide)propanoate

Chem.

[0230] Step 3: (S)-3-(2'-cyanobiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)propanoic acid

Chem.

[0231] Compound L LC / MS B: 100% purity, UV = 214 nm, Rt = 1.81 min, ESI 509.3 (M+H) + 。

[0232] 1 1H NMR (500 MHz, MeOD) δ 8.44 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.87 - 7.85 (m, 2H), 7.78 - 7.75 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.64 - 7.47 (m, 7H), 5.77 (dd, J = 10.4, 6.0 Hz, 1H), 5.47 (t, J = 7.1 Hz, 1H), 3.07 - 2.72 (m, 2H), 2.09 - 1.88 (m, 2H), 1.53 - 1.28 (m, 1H), 0.96 - 0.92 (m, 6H).

[0233] Preparation of Compound M Step 1: (S)-Methyl 3-(2’-fluoro-6’-methoxybiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl))penta-namide)propanoate

Chemical formula

[0234] Step 2: (S)-3-(2'-Fluoro-6'-methoxybiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamido)propanoic acid [Chemical formula] (S)-Methyl 3-(2'-fluoro-6'-methoxybiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamide)propanoate (100 mg, 0.18 mmol) was treated with LiOH-H2O (23 mg, 0.54 mmol) and H2O (0.5 mL) in THF (10 mL) at room temperature for 16 h. The mixture was acidified to pH = 5 with HCl (1 M). The solvent was removed in vacuo and the residue was purified by preparative HPLC B (30 - 70% MeCN) to give the product (S)-3-(2'-fluoro-6'-methoxybiphenyl-3-yl)-3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanamide)propanoic acid (40 mg) as a white solid.

[0235] Compound M LC / MS B: 100% purity, UV = 214 nm, Rt = 1.86 min, ESI 532 (M+H) + 。

[0236] 1 H NMR (500 MHz, MeOD) δ 8.45 (s, 1H), 8.26 (dd, J = 8.1, 1.1 Hz, 1H), 7.93 - 7.79 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.44 - 7.25 (m, 5H), 6.92 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 8.6 Hz, 1H), 5.77 (dd, J = 10.1, 6.4 Hz, 1H), 5.47 - 5.32 (m, 1H), 3.79 (s, 3H), 2.95 - 2.71 (m, 2H), 2.13 - 1.85 (m, 2H), 1.58 - 1.33 (m, 1H), 0.94 - 0.92 (m, 6H).

[0237] Preparation of Compound M1 Step 1: (S)-Methyl 3-(3-bromophenyl)-3-(tert-butoxycarbonylamino)propanoate

Chemical Structure

[0238] Step 2: (S)-methyl 3-(tert-butoxycarbonylamino)-3-(3-(piperidin-1-yl)phenyl)propanoate

Chemical formula

[0239] Step 3: (S)-methyl 3-amino-3-(3-(piperidin-1-yl)phenyl)propanoate [Chem.] (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(3-(piperidin-1-yl)phenyl)propanoate (200 mg, 0.55 mmol) was treated with HCl (1 mL) in dioxane (5 mL) at room temperature for 1 hour. The solvent was removed in vacuo, and the crude product (S)-methyl 3-amino-3-(3-(piperidin-1-yl)phenyl)propanoate was obtained as a yellow oil (145 mg). Yield 100% (98% purity, UV = 254 nm, ESI 263 (M+H) + ). The crude product was used directly in the next step.

[0240] Step 4: (S)-Methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)penta-namide)-3-(3-(piperidin-1-yl)phenyl)propanoate [Chem.] A mixture of (S)-methyl 3-amino-3-(3-(piperidin-1-yl)phenyl)propanoate (145 mg, 0.55 mmol), (S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)penta-noic acid (144 mg, 0.55 mmol), EDCI (159 mg, 0.83 mmol), HOBt (112 mg, 0.83 mmol), and DIPEA (214 mg, 1.66 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours. The mixture was poured into 10 mL of water, and the solution was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc = 1:1) to give the desired product (S)-methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)penta-namide)-3-(3-(piperidin-1-yl)phenyl)propanoate as a pale orange oil (224 mg). Yield 80% (95% purity, UV = 254 nm, ESI 505 (M+H) + )。

[0241] Step 5: (S)-3-((S)-4-Methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(3-(piperidin-1-yl)phenyl)propanoic acid

Chem.

[0242] Compound M1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.62 min, ESI 491 (M + H) + 。

[0243] 1 1H NMR (500 MHz, MeOD) δ 8.43 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.85 (dd, J = 11.2, 4.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.92 - 6.81 (m, 2H), 5.75 (dd, J = 10.1, 6.3 Hz, 1H), 5.29 (t, J = 7.4 Hz, 1H), 3.20 - 3.11 (m, 4H), 2.75 - 2.79 (m, 2H), 1.98 - 2.03 (m, 2H), 1.78 - 1.67 (m, 4H), 1.60 - 1.62 (m, 2H), 1.50 - 1.37 (m, 1H), 0.99 - 0.91 (m, 6H).

[0244] Preparation of Compound M2 and Compound M2a Step 41: Methyl 3-(tert-butoxycarbonylamino)-3-(2-o-tolylpyridin-4-yl)propanoate [Chemical formula] A mixture of methyl 3-(2-bromopyridin-4-yl)-3-(tert-butoxycarbonylamino)propanoate (600 mg, 1.71 mmol), o-tolylboronic acid (267 mg, 1.97 mmol), Pd(dppf)Cl2 (63 mg, 0.086 mmol), and K2CO3 (692 mg, 5.13 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) under N2 atmosphere was stirred at 100 °C for 1.5 h in a microwave oven. It was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column (petroleum ether:EtOAc 1:3) to obtain the desired product methyl 3-(tert-butoxycarbonylamino)-3-(2-o-tolylpyridin-4-yl)propanoate as a colorless oil (500 mg). Yield 72% (74% purity, UV = 214 nm, ESI 371 (M+H) + ).

[0245] Step 2: Methyl 3-amino-3-(2-o-tolylpyridin-4-yl)propanoate [Chemical formula] To a solution of methyl 3-(tert-butoxycarbonylamino)-3-(2-o-tolylpyridin-4-yl)propanoate (500 mg, 1.35 mmol) in DCM (6 mL) was added HCl in 1,4-dioxane (4 M, 2 mL), and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo to obtain the crude product methyl 3-amino-3-(2-o-tolylpyridin-4-yl)propanoate hydrochloride as a yellow solid (400 mg). Yield 99% (83% purity, UV = 214 nm, ESI 271 (M+H) + ). The crude product was used directly in the next step.

[0246] Step 3: Methyl 3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)-3-(2-o-tolylpyridin-4-yl)propanoate

Chem.

[0247] Step 4: 3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)-3-(2-o-tolylpyridin-4-yl)propanoic acid

Chem.

[0248] Compound M2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.53 min, ESI 448 (M+H) + 。

[0249] 1 H NMR (500 MHz, MeOD) δ 8.57 (d, J = 5.2 Hz, 1H), 7.75 (dd, J = 6.9, 1.6 Hz, 1H), 7.55 - 7.27 (m, 7H), 6.57 (d, J = 8.8 Hz, 1H), 6.42 (t, J = 6.3 Hz, 1H), 5.78 (t, J = 8.1 Hz, 1H), 5.35 (t, J = 7.0 Hz, 1H), 2.97 - 2.79 (m, 2H), 2.30 (s, 3H), 1.89 (t, J = 7.6 Hz, 2H), 1.37 - 1.35 (m, 1H), 0.93 - 0.90 (m, 6H).

[0250] Step 5: Compound M2a Compound M2 (50 mg) was separated into M2a (6 mg) and M2b (12 mg) as white solids by preparative chiral SFC E.

[0251] M2a LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 448 (M+H) + 。

[0252] 11H NMR (500 MHz, MeOD) δ 8.57 (d, J = 5.1 Hz, 1H), 7.75 (dd, J = 7.0, 1.8 Hz, 1H), 7.60 - 7.25 (m, 7H), 6.57 (d, J = 9.0 Hz, 1H), 6.42 (m, 1H), 5.78 (t, J = 8.1 Hz, 1H), 5.35 (t, J = 7.1 Hz, 1H), 3.00 - 2.75 (m, 2H), 1.89 (t, J = 7.6 Hz, 2H), 1.37 - 1.35 (m, 1H), 0.93 - 0.90 (m, 6H).

[0253] Preparation of Compound N1 and Compound N2 Step 1: 3-Cyclobutoxybenzaldehyde

Chemical Structure

[0254] Step 2: 3-Amino-3-(3-cyclobutoxyphenyl)propanoic acid

Chemical Structure

[0255] Step 3: 3-(tert-Butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoic acid

Chem.

[0256] Step 4: Benzyl 3-(tert-butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoate

Chem.

[0257] 3-(tert-Butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoic acid in DMF (10 mL) (360 mg, 1.07 mmol), BnBr (183 mg, 1.07 mmol), and K2CO3 (298 mg, 2.14 mmol) were stirred at room temperature overnight. The mixture was diluted with DCM (18 mL) and water (5 mL). The organic layer was separated and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to give a brown oil, which was purified by silica gel flash (5% - 10% EtOAc in petroleum ether) to afford the desired product benzyl 3-(tert-butoxycarbonylamino)-3-(3-cyclobutoxyphenyl)propanoate as a colorless oil (386 mg). Yield 85% (91% purity, UV = 214 nm, ESI 326 (MH - Boc) + ).

[0258] Step 5: Benzyl 3-amino-3-(3-cyclobutoxyphenyl)propanoate

Chem.

[0259] Step 6: Benzyl 3-(3-cyclobutoxyphenyl)-3-((S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chem.

[0260] Step 7: Compound N1 and Compound N2

Chemical Structure

[0261] Compound N1 LC / MS B: 100% purity, UV = 214 nm, Rt = 9.01 min, ESI 45127 (M+H) + 。

[0262] 1H-NMR (500 MHz, MeOD) δ 7.74 (dd, J = 7.0, 1.5 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 6.74 (m, 1H), 6.68 (dd, J = 7.0, 1.5 Hz, 1H), 6.55 (dd, J = 9.5, 0.5 Hz, 1H), 6.41 - 6.39 (m, 1H), 5.78 (t, J = 8.0 Hz, 1H), 5.30 (t, J = 7.0 Hz, 1H), 4.62 (t, J = 7.5 Hz, 1H), 2.79 (d, J = 7.5 Hz, 2H), 2.44 - 2.40 (m, 2H), 2.09 - 2.04 (m, 2H), 2.09 - 2.04 (m, 2H), 1.95 - 1.92 (m, 2H), 1.82 (m, 1H), 1.70 (m, 1H), 1.48 - 1.44 (m, 1H), 1.03 - 0.96 (m, 6H).

[0263] Compound N1 LC / MS B: 100% purity, UV = 214 nm, Rt = 9.26 min, ESI 45127 (M + H) + 。 1H-NMR (500 MHz, MeOD) δ 7.74 (dd, J = 7.0, 1.5 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 6.74 (dd, J = 8.0, 1.5 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 6.41 - 6.39 (m, 1H), 5.76 (m, 1H), 5.28 (t, J = 8.0 Hz, 1H), 4.69 (t, J = 7.0 Hz, 1H), 2.78 (m, 2H), 2.50 - 2.45 (m, 2H), 2.15 - 2.11 (m, 2H), 1.88 - 1.84 (m, 3H), 1.76 - 1.74 (m, H), 1.36 - 1.34 (m, 1H), 1.03 - 0.96 (m, 6H).

[0264] Preparation of Compounds O2 and O4 (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

Chemical Structure

[0265] Step 2: (S)-methyl 3-(tert-butoxycarbonylamino)-3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoate

Chemical formula

[0266] Step 3: (S)-Methyl 3-amino-3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoate [Chemical formula] (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoate (112 mg, 0.3 mmol) was treated with TFA (0.5 mL) in DCM (2 mL) at room temperature for 1 h. The solvent was removed in vacuo and the crude product (S)-methyl 3-amino-3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)propanoate was obtained as a yellow oil (79 mg). Yield 96% (98% purity, UV = 254 nm, ESI 274 (M+H) + ). The crude product was used directly in the next step.

[0267] Step 4: (S)-Methyl 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-3-((S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical Structure

[0268] Step 5: Compound O2

Chemical Structure

[0269] Compound O2 LC / MS A: 100% purity, UV = 214 nm, Rt = 7.27 min, ESI 451 (M+H) + 。

[0270] 1H-NMR (500 MHz, MeOD) δ 7.75 (dd, J = 7.0, 1.5 Hz, 1H), 7.50 - 7.53 (m, 1H), 7.39 - 7.42 (m, 1H), 7.31 - 7.30 (m, 2H), 7.20 (d, J = 7.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 6.44 - 6.41 (m, 1H), 5.75 (dd, J = 7.0, 9.5 Hz, 1H), 5.35 (t, J = 7.0 Hz, 1H), 2.87 - 2.77 (m, 2H), 2.27 (s, 6H), 1.88 - 1.84 (m, 2H), 1.37 - 1.32 (m, 1H), 0.92 - 0.89 (m, 6H).

[0271] Step 6: Compound O4 [Chemical formula] Compound O2 (70 mg, 0.15 mmol) was treated with LiOH (1 M in H2O, 0.6 mL) in THF (2 mL) at room temperature overnight. The mixture was adjusted to pH = 5 - 6 with 1 M HCl and the solvent was removed in vacuo. The residue was purified by preparative HPLC A (30 - 64% MeCN) to afford Compound O3 (35 mg) and O4 (26 mg) as white solids.

[0272] Compound O4 LC / MS A: 100% purity, UV = 214 nm, Rt = 7.26 min, ESI 451 (M + H) + .

[0273] 1H-NMR (500 MHz, MeOD) δ 7.75 (dd, J = 7.0, 1.5 Hz, 1H), 7.50 - 7.53 (m, 1H), 7.38 - 7.42 (m, 1H), 7.31 - 7.30 (m, 2H), 7.21 (d, J = 6.5 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 6.44 - 6.41 (m, 1H), 5.75 (dd, J = 7.0, 9.5 Hz, 1H), 5.35 (t, J = 7.0 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.27 (s, 6H), 1.88 - 1.84 (m, 2H), 1.37 - 1.32 (m, 1H), 0.92 - 0.89 (m, 6H).

[0274] Preparation of Compound P2 Step 1: 6-Hydroxy-2'-methylbiphenyl-3-carbaldehyde

Chem.

[0275] Step 2: 5-Formyl-2'-methylbiphenyl-2-yl trifluoromethanesulfonate

Chem.

[0276] Step 3: 6-Cyclopropyl-2'-methylbiphenyl-3-carbaldehyde

Chem.

[0277] Step 4: 3-Amino-3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)propanoic acid

Chem.

[0278] Step 5: Methyl 3-amino-3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)propanoate

Chem.

[0279] Step 6: Methyl 3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)-3-((S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical formula

[0280] Step 7: 3-(6-cyclopropyl-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical formula

[0281] 1 H NMR (500 MHz, MeOD) δ 7.76 (dd, J = 9.0, 3.7 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.32 - 7.19 (m, 4H), 7.15 (dd, J = 10.2, 7.0 Hz, 1H), 7.09 - 7.03 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 9.1 Hz, 1H), 6.41 (t, J = 6.8 Hz, 1H), 5.76 - 5.72 (m, 1H), 5.30 (t, J = 7.2 Hz, 1H), 2.86 - 2.68 (m, 2H), 2.11 (d, J = 6.3 Hz, 3H), 1.94 - 1.77 (m, 2H), 1.60 - 1.46 (m, 1H), 1.41 - 1.24 (m, 1H), 0.92 - 0.86 (m, 6H), 0.83 - 0.71 (m, 2H), 0.69 - 0.59 (m, 2H).

[0282] Preparation of Compound Q2 Step 1: 3-Amino-3-(3-bromo-4-methylphenyl)propanoic acid

Chemical Structure

[0283] Step 2: Methyl 3-amino-3-(3-bromo-4-methylphenyl)propanoate [Chemical formula] To a solution of 3-amino-3-(3-bromo-4-methylphenyl)propanoic acid (7.4 g, 28.8 mmol) in MeOH (50 mL) at 0 °C was added dropwise SOCl2 (5 mL, 20.6 mmol), and the reaction mixture was stirred at 80 °C for 2 h. Water (50 mL) was added, and the solution was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated aqueous NaHCO3 (20 mL × 2) and brine (20 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column (EtOAc) to obtain a residue, and the desired product methyl 3-amino-3-(3-bromo-4-methylphenyl)propanoate was obtained as a colorless oil (2.5 g). Yield 33% over 2 steps (90% purity, UV = 214 nm, ESI 272 (M+H) + ).

[0284] Step 3: Methyl 3-amino-3-(2’,6-dimethyl-[1,1’-biphenyl]-3-yl)propanoate [Chemical formula] A mixture of methyl 3-amino-3-(3-bromo-4-methylphenyl)propanoate (350 mg, 1.29 mmol), o-tolylboronic acid (263 mg, 1.94 mmol), PdCl2(dppf) (94 mg, 0.13 mmol), and K2CO3 (535 mg, 3.87 mmol) in dioxane (3 mL) and H2O (0.6 mL) under N2 atmosphere was heated at 110 °C for 1 h in a microwave oven. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by silica gel column (petroleum ether:EtOAc 1:1) to afford the desired product methyl 3-amino-3-(2’,6-dimethyl-[1,1’-biphenyl]-3-yl)propanoate as a colorless oil (280 mg). Yield 77% (70% purity, UV = 254 nm, ESI 284 (M+H) + ).

[0285] Step 4: Methyl 3-(2’,6-dimethyl-[1,1’-biphenyl]-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)penta-namide)propanoate [Chemical formula] A mixture of methyl 3-amino-3-(2’,6-dimethyl-[1,1’-biphenyl]-3-yl)propanoate (130 mg, 0.46 mmol), (S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)penta-noic acid (96 mg, 0.46 mmol), HOBt (74 mg, 0.55 mmol), EDCI (105 mg, 0.55 mmol), and DIEA (178 mg, 1.38 mmol) in DCM (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative-TLC (petroleum ether:EtOAc 1:1) to afford the desired product methyl 3-(2’,6-dimethyl-[1,1’-biphenyl]-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)penta-namide)propanoate as a colorless oil (150 mg). Yield 63% (86.83% purity, UV = 214 nm, ESI 475 (M+H) + )。

[0286] Step 5: 3-(2’,6-Dimethyl-[1,1’-biphenyl]-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)penta-namide)propanoic acid

Chem.

[0287] Compound Q2 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.91 min, ESI 461 (M + H) + 。

[0288] 1 H NMR (500 MHz, MeOD-d4) δ 7.80 - 7.72 (m, 1H), 7.52 - 7.49 (m, 1H), 7.30 - 7.19 (m, 5H), 7.08 - 7.04 (m, 2H), 6.55 (d, J = 9.1 Hz, 1H), 6.41 (t, J = 10.0 Hz, 1H), 5.77 - 5.72 (m, 1H), 5.31 (t, J = 7.2 Hz, 1H), 2.84 - 2.70 (m, 2H), 2.07 - 1.98 (m, 6H), 1.88 - 1.75 (m, 2H), 1.37 - 1.32 (m, 1H), 0.90 - 0.88 (m, 6H).

[0289] Preparation of Compound R1 and Compound R2 Step 1: 3-Amino-3-(3-tert-butylphenyl)propanoic acid

Chem.

[0290] Step 2: 3-(3-tert-butylphenyl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical formula

[0291] Compound R1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 413 (M+H) + 。

[0292] 11H NMR (500 MHz, MeOD) δ 7.73 (dd, J = 6.9, 1.7 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.33 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 9.1 Hz, 1H), 6.39 - 6.36 (m, 1H), 5.79 (dd, J = 9.1, 7.0 Hz, 1H), 5.34 (t, J = 7.3 Hz, 1H), 2.79 (dd, J = 11.8, 5.1 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.54 - 1.37 (m, 1H), 1.27 (s, 9H), 1.03 - 0.89 (m, 6H).

[0293] Compound R2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.63 min, ESI 413 (M + H) + 。

[0294] 1 1H NMR (500 MHz, MeOD) δ 7.76 (dd, J = 7.0, 1.8 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.42 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.43 - 6.41 (m, 1H), 5.77 (dd, J = 9.2, 6.9 Hz, 1H), 5.33 (t, J = 7.3 Hz, 1H), 2.88 - 2.69 (m, 2H), 1.91 - 1.79 (m, 2H), 1.41 - 1.35 (m, 1H), 1.35 (s, 9H), 0.98 - 0.91 (m, 6H).

[0295] Preparation of Compound S1 and Compound S2 Step 1: 3 - Amino - 3-(3 - phenoxyphenyl)propanoic acid

Chemical Structure

[0296] Step 2: 3-(4-Methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)-3-(3-phenoxyphenyl)propanoic acid [Chemical formula] A solution of 3-amino-3-(3-phenoxyphenyl)propanoic acid (49 mg, 0.19 mmol), (S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaanoic acid (50 mg, 0.24 mmol), EDCI (92 mg, 0.48 mmol), HOBt (48 mg, 0.36 mmol), and DIEA (93 mg, 0.72 mmol) in DCM (10 mL) was stirred at room temperature for 1 h. The mixture was poured into 30 mL of water and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC A (30 - 70% MeCN) to give the desired compounds S1 (6.6 mg) and S2 (1 mg) as white solids.

[0297] Compound S1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 449 (M + H) + .

[0298] 11H NMR (500 MHz, MeOD) δ 7.69 (dd, J = 7.0, 1.6 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.99 - 6.91 (m, 3H), 6.82 (dd, J = 8.1, 1.7 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 6.37 (t, J = 6.8 Hz, 1H), 5.76 (t, J = 8.1 Hz, 1H), 5.31 (t, J = 7.2 Hz, 1H), 2.90 - 2.65 (m, 2H), 1.93 (t, J = 7.6 Hz, 2H), 1.46 - 1.41 (m, 1H), 0.97 - 0.93 (m, 6H).

[0299] Compound S2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.84 min, ESI 449 (M + H) + 。

[0300] 1 1H NMR (500 MHz, MeOD) δ 7.61 (dd, J = 7.0, 1.8 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.27 - 7.21 (m, 3H), 7.04 - 6.98 (m, 2H), 6.94 - 6.84 (m, 3H), 6.79 (dd, J = 8.2, 1.7 Hz, 1H), 6.44 (d, J = 9.1 Hz, 1H), 6.30 (t, J = 6.9, 1H), 5.62 (dd, J = 9.6, 6.6 Hz, 1H), 5.17 (t, J = 7.3 Hz, 1H), 2.74 - 2.32 (m, 2H), 1.77 - 1.55 (m, 2H), 1.33 - 1.03 (m, 1H), 0.80 - 0.77 (m, 6H).

[0301] Preparation of Compound T2 Step 1: 3 3 - Amino - 3 - (5 - bromopyridin - 3 - yl) propanoic acid

Chem.

[0302] Step 2: Methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate

Chem.

[0303] Step 3: Methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chem.

[0304] Step 4: Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate [Chemical Structure] A mixture of methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (100 mg, 0.35 mmol), (S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaanoic acid (88 mg, 0.42 mmol), EDCI (135 mg, 0.7 mmol), HOBt (71 mg, 0.53 mmol), and DIEA (136 mg, 1.06 mmol) in DCM (15 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column (petroleum ether:EtOAc = 1:1) to give the desired product methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate (100 mg) in 60% yield (97% purity, UV = 214 nm, ESI 476 (M+H) + ).

[0305] Step 5: 3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chem.

[0306] Compound T1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.57 min, ESI 462 (M+H) + 。

[0307] 1 H NMR (500 MHz, MeOD) δ 8.53 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 7.0, 1.6 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15 - 7.10 (m, 2H), 6.44 (d, J = 9.1 Hz, 1H), 5.79 - 5.65 (m, 1H), 5.42 (t, J = 7.2 Hz, 1H), 2.88 (d, J = 7.2 Hz, 2H), 1.98 (s, 3H), 1.94 (t, J = 7.4 Hz, 2H), 1.87 (s, 3H), 1.48 - 1.42 (m, 1H), 0.98 - 0.95 (m, 6H)

[0308] Compound T2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.59 min, ESI 462 (M+H) + 。

[0309] 11H NMR (500 MHz, MeOD) δ 8.59 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 7.0, 1.7 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.26 - 7.19 (m, 1H), 7.23 - 7.15 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 6.43 - 6.40 (m, 1H), 5.80 - 5.70 (m, 1H), 5.38 (t, J = 7.3 Hz, 1H), 2.96 - 2.85 (m, 2H), 2.02 (s, 6H), 1.91 - 1.75 (m, 2H), 1.35 - 1.30 (m, 1H), 0.91 - 0.88 (m, 6H).

[0310] Preparation of Compound T2a and Compound T2b The T2 mixture was further separated by preparative chiral SFC D to obtain diastereomeric compounds T2a (8 mg) and T2b (7.5 mg) as white solids.

[0311] Compound T2a LC / MS A: 99% purity, UV = 214 nm, Rt = 1.56 min, ESI 462 (M + H) + .

[0312] 1 1H NMR (500 MHz, MeOD) δ 8.59 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 6.9, 1.7 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.53 - 7.50 (m1H), 7.26 - 7.19 (m, 1H), 7.23 - 7.15 (m, 2H), 6.56 (d, J = 9.1 Hz, 1H), 6.43 - 6.40 (m, 1H), 5.75 (t, J = 8.1 Hz, 1H), 5.38 (t, J = 7.3 Hz, 1H), 2.97 - 2.86 (m, 2H), 2.02 (s, 6H), 1.83 (t, J = 7.4 Hz, 2H), 1.36 - 1.30 (m, 1H), 0.91 - 0.88 (m, 6H).

[0313] Compound T2b LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 462 (M + H) + .

[0314] 1 1H NMR (500 MHz, MeOD) δ 8.52 (s, 1H), 8.18 (s, 1H), 7.69 (dd, J = 7.0, 1.8 Hz, 1H), 7.50 (s, 1H), 7.43 - 7.39 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15 - 7.09 (m, 2H), 6.45 (d, J = 9.1 Hz, 1H), 6.36 - 6.33 (m, 1H), 5.73 (t, J = 8.0 Hz, 1H), 5.42 (t, J = 7.0 Hz, 1H), 2.91 (d, J = 7.1 Hz, 2H), 1.97 (s, 3H), 1.96 - 1.92 (m, 2H), 1.87 (s, 3H), 1.49 - 1.43 (m, 1H), 0.98 - 0.95 (m, 6H).

[0315] Preparation of Compound U2 Step 1: 2-Bromo-4,4,4-trifluorobutanoic acid

Chem.

[0316] Step 2: 4,4,4-Trifluoro-2-(2-oxopyridin-1(2H)-yl)butanoic acid

Chem.

[0317] Step 3: Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4,4,4-trifluoro-2-(2-oxopyridin-1(2H)-yl)butanamido)propanoate

Chemical Structure

[0318] Step 4: 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4,4,4-trifluoro-2-(2-oxopyridin-1(2H)-yl)butanamide)propanoic acid [Chemical formula] Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4,4,4-trifluoro-2-(2-oxopyridin-1(2H)-yl)butanamide)propanoate (160 mg, 0.32 mmol) was treated with LiOH-H2O (40 mg, 0.96 mmol) and H2O (1 mL) in THF (6 mL) at room temperature for 16 h. The mixture was acidified to pH = 5 with HCl (1 M). The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC B (30 - 70% MeCN) to afford Compound U1 (34 mg) and U2 (12 mg) as white solids.

[0319] Compound U2 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.50 min, ESI 488 (M+H) + 。

[0320] 1 1H NMR (500 MHz, MeOD) δ 8.58 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.68 (s, 1H), 7.59 - 7.51 (m, 1H), 7.23 - 7.14 (m, 3H), 6.58 (d, J = 9.1 Hz, 1H), 6.45 (t, J = 6.4 Hz, 1H), 5.71 (d, J = 5.3 Hz, 1H), 5.44 (t, J = 7.1 Hz, 1H), 3.15 (m, 1H), 3.06 - 2.93 (m, 1H), 2.88 (d, J = 6.8 Hz, 2H), 2.01 (s, 6H).

[0321] Preparation of Compound V2 Step 1: 2-Bromo-3-cyclopropylpropanoic acid

Chem.

[0322] Step 2: 3-Cyclopropyl-2-(2-oxopyridin-1(2H)-yl)propanoic acid

Chem.

[0323] Step 3: Methyl 3-(3-cyclopropyl-2-(2-oxopyridin-1(2H)-yl)propanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] A mixture of 3-cyclopropyl-2-(2-oxopyridin-1(2H)-yl)propanoic acid (83 mg, 0.40 mmol), methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (114 mg, 0.40 mmol), HATU (228 mg, 0.60 mmol), and DIEA (155 mg, 1.20 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The mixture was poured into 10 mL of water and the solution was extracted with DCM (30 mL×3). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a yellow oil, which was purified by silica gel column (petroleum ether:EtOAc = 1:1) to afford the desired product methyl 3-(3-cyclopropyl-2-(2-oxopyridin-1(2H)-yl)propanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a yellow oil (200 mg). Yield 88% (95% purity, UV = 254 nm, ESI 474 (M+H) + ).

[0324] Step 4: 3-((S)-3-Cyclopropyl-2-(2-oxopyridin-1(2H)-yl)propanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid

Chemical formula

[0325] Compound V2 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.52 min, ESI 460 (M+H) + .

[0326] 1 1H NMR (500 MHz, MeOD) δ 8.59 (s, 1H), 8.24 (s, 1H), 7.77 (dd, J = 7.0, 1.7 Hz, 1H), 7.67 (s, 1H), 7.51 (t, J = 8.8, 6.7, 1.9 Hz, 1H), 7.24 - 7.12 (m, 3H), 6.55 (d, J = 8.9 Hz, 1H), 6.41 (t, J = 6.8 Hz, 1H), 5.62 (t, J = 7.8 Hz, 1H), 5.41 (t, J = 7.3 Hz, 1H), 3.00 - 2.83 (m, 2H), 2.00 (s, 3H), 1.99 (s, 3H), 1.88 - 1.94 (m, 1H), 1.84 - 1.76 (m, 1H), 0.53 (s, 1H), 0.33 - 0.35 (m, 1H), 0.23 - 0.27 (m, 1H), 0.02 - 0.04 (m, 2H).

[0327] Preparation of Compounds W1 and W2 Step 1: Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical formula

[0328] Step 2: 3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chem.

[0329] Compound W1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 475.8 (M+H) + 。

[0330] 1 1H NMR (500 MHz, MeOD) δ 8.53 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.21 - 7.11 (m, 3H), 6.27 (s, 1H), 6.23 (dd, J = 7.1, 1.8 Hz, 1H), 5.70 (t, J = 8.0 Hz, 1H), 5.41 (t, J = 7.2 Hz, 1H), 2.87 (d, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.91 (dd, J = 18.5, 11.1 Hz, 2H), 1.86 (s, 3H), 1.46 - 1.43 (m, 1H), 0.98 - 0.94 (m, 6H).

[0331] Compound W2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.61 min, ESI 475.8 (M+H) + 。

[0332] 1 1H NMR (500 MHz, MeOD) δ 8.59 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.25 - 7.12 (m, 3H), 6.38 (s, 1H), 6.31 (dd, J = 7.1, 1.8 Hz, 1H), 5.70 (t, J = 8.1 Hz, 1H), 5.37 (t, J = 7.2 Hz, 1H), 2.88 - 2.85 (m, 2H), 2.24 (s, 3H), 2.02 (s, 6H), 1.81 (t, J = 7.6 Hz, 2H), 1.33 - 1.31 (m, 1H), 0.90 - 0.88 (m, 6H).

[0333] Preparation of Compound W1a and Compound W1b Step 1: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chemical formula

[0334] Step 2: Methyl (S)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (2.7 g, 7.03 mmol) in DCM (10 mL) was added HCl (4 M, 5 mL) in dioxane. The solution was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 (20 mL) was added and the solution was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product methyl (S)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a yellow oil (1.9 g). Yield 95% (68% purity, UV = 214 nm, ESI 285.1 (M+H) + ). The crude product was used directly in the next step.

[0335] Step 3: Methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate [Chemical formula] A mixture of methyl (S)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (1.5 g, 5.28 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanoic acid (1.4 g, 6.34 mmol), HOBt (1.06 g, 7.92 mmol), EDCI (1.5 g, 7.92 mmol), and DIEA (2.04 g, 15.85 mmol) in DCM (30 mL) was stirred at room temperature for 2 h. The mixture was poured into water and the solution was extracted with EtOAc (30 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate as a yellow oil (3.95 g). Yield 52% (52% purity, UV = 214 nm, ESI 490.1 (M+H) + ). The crude product was used directly in the next step.

[0336] Step 4: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical Structure

[0337] Compound W1a LC / MS B: 99% purity, UV = 214 nm, Rt = 1.59 min, ESI 476.2 (M+H) + 。

[0338] 1 H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 8.20 (s, 1H), 7.58 (d, J = 7.1 Hz, 1H), 7.54 (s, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 6.6 Hz, 2H), 6.32 - 6.15 (m, 2H), 5.70 (t, J = 8.0 Hz, 1H), 5.43 (t, J = 7.3 Hz, 1H), 2.94 (d, J = 7.3 Hz, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.92 (t, J = 7.4 Hz, 2H), 1.87 (s, 3H), 1.47 (t, J = 6.9 Hz, 1H), 1.40 - 1.40 (m, 1H), 0.95 - 0.92 (m, 6H).

[0339] Compound W1b LC / MS B: 100% purity, UV = 214 nm, Rt = 1.62 min, ESI 476.3 (M+H) + 。

[0340] 1 H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 8.22 (s, 1H), 7.62 (s, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.20 - 7.12 (m, 3H), 6.34 (s, 1H), 6.26 (dd, J = 7.1, 1.5 Hz, 1H), 5.65 (t, J = 8.1 Hz, 1H), 5.34 (t, J = 7.3 Hz, 1H), 2.89 (dd, J = 17.3, 7.4 Hz, 2H), 2.19 (s, 3H), 1.97 (s, 6H), 1.78 - 1.75 (m, 2H), 1.32 - 1.25 (m, 1H), 0.87 - 0.80 (m, 6H).

[0341] Preparation of Compound W2a and Compound W2b Step 1: (R)-Methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chemical Structure

[0342] Step 2: Methyl (R)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] To a solution of (R)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (2.7 g, 7 mmol) in DCM (10 mL) was added HCl / dioxane (4 M, 5 mL), and the solution was stirred at room temperature for 2 h. The mixture was poured into saturated aqueous NaHCO3 (20 mL), and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (R)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a yellow oil (1.9 g). Yield 95% (68.19% purity, UV = 214 nm, ESI 285 (M+H) +)。The crude product was used directly in the next step without further purification.

[0343] Step 3: (3R)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chem.

[0344] Step 4: (3R)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chem.

[0345] Compound W2a LC / MS A: 99% purity, UV = 214 nm, Rt = 1.57 min, ESI 476 (M+H) + 。

[0346] 1 H NMR (500 MHz, MeOD) δ 8.52 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.23 - 7.10 (m, 3H), 6.26 (d, J = 10.2 Hz, 1H), 6.23 (dd, J = 7.1, 1.9 Hz, 1H), 5.72 - 5.66 (m, 1H), 5.42 (t, J = 7.2 Hz, 1H), 2.93 (d, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.97 (s, 3H), 1.94 - 1.89 (m, 2H), 1.86 (s, 3H), 1.52 - 1.37 (m, 1H), 0.98 - 0.87 (m, 6H).

[0347] Compound W2b LC / MS A: 99% purity, UV = 214 nm, Rt = 1.60 min, ESI 476 (M+H) + 。

[0348] 11H NMR (500 MHz, MeOD) δ 8.58 (s, 1H), 8.26 (s, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.27 - 7.10 (m, 3H), 6.38 (s, 1H), 6.31 (dd, J = 7.2, 1.9 Hz, 1H), 5.70 (t, J = 8.1 Hz, 1H), 5.38 (t, J = 7.4 Hz, 1H), 2.99 - 2.83 (m, 2H), 2.24 (s, 3H), 2.02 (s, 5H), 1.89 - 1.74 (m, 2H), 1.35 - 1.30 (m, 1H), 0.90 - 0.87 (m, 6H).

[0349] Preparation of Compounds X1 and X2 Step 1: Methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate [Chemical formula] To a solution of methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate (300 mg, 1.16 mmol) and Et3N (351 mg, 3.48 mmol) in DCM (4 mL) at room temperature was added di-tert-butyl dicarbonate (278 mg, 1.27 mmol), and the solution was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative-TLC (EtOAc: petroleum ether 1:1) to afford the desired product methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate as a colorless oil (301 mg). Yield 72% (100% purity, UV = 214 nm, ESI 359 (M + H) + ).

[0350] Step 2: Methyl 3-(tert-butoxycarbonylamino)-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate [Chemical formula] A solution of methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate (260 mg, 0.73 mmol), (S)-3-methylmorpholine (147 mg, 1.46 mmol), Pd(OAc)2 (17 mg, 0.073 mmol), X-Phos (65 mg, 0.146 mmol), and Cs2CO3 (714 mg, 2.19 mmol) in toluene (3 mL) was stirred at 120 °C for 16 h under N2. The mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (0% - 60% EtOAc in petroleum) to give the desired product methyl 3-(tert-butoxycarbonylamino)-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate as a yellow oil (162 mg). Yield 52% (90% purity, UV = 214 nm, ESI 280 (M+H) + ).

[0351] Step 3: Methyl 3-amino-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate hydrochloride

Chemical formula

[0352] Step 4: (S)-Methyl 4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanoate

Chemical formula

[0353] Step 5: (S)-4-Methyl-2-(4-oxoquinazolin-3(4H)-yl)pentanoic acid

Chemical formula

[0354] Step 6: Methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate

Chem.

[0355] Step 7: 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(5-((S)-3-methylmorpholino)pyridin-3-yl)propanoic acid

Chem.

[0356] Compound X1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.40 min, ESI 508 (M+H) + 。

[0357] 1 H NMR (500 MHz, MeOD) δ 8.41 (d, J = 3.7 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.86 (dd, J = 11.1, 4.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.27 (s, 1H), 5.69 (dd, J = 10.0, 6.4 Hz, 1H), 5.37 (t, J = 7.2 Hz, 1H), 3.94 - 3.60 (m, 5H), 3.09 - 3.03 (m, 2H), 2.97 - 2.79 (m, 2H), 2.22 - 1.96 (m, 2H), 1.68 - 1.46 (m, 1H), 1.07 - 0.78 (m, 9H).

[0358] Compound X2 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.36 min, ESI 508 (M+H) + 。

[0359] 11H NMR (500 MHz, MeOD) δ 8.44 (s, 1H), 8.27 (d, J = 6.9 Hz, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.87 (t, J = 7.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.36 (s, 1H), 5.72 (dd, J = 10.4, 5.9 Hz, 1H), 5.36 (t, J = 6.8 Hz, 1H), 4.08 - 3.63 (m, 5H), 3.30 - 3.09 (m, 2H), 2.81 (s, 2H), 2.17 - 1.88 (m, 2H), 1.44 (s, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.07 - 0.78 (m, 9H).

[0360] Preparation of Compound Y1, Compound Y2, and Compound Y4 Step 1: 4,5-Dimethylpyridin-2-ol

Chemical formula

[0361] Step 2: (S)-2-(4,5-Dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid

Chemical formula

[0362] Step 3: (3R)-methyl 3-(2-(4,5-dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] (S)-2-(4,5-Dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (89 mg, 0.375 mmol), (R)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (70 mg, 0.25 mmol), HOBt (51 mg, 0.37 mmol), EDCI (72 mg, 0.37 mmol), and DIEA (97 mg, 0.75 mmol) in DMF (4 mL) were stirred at room temperature for 2 h. The mixture was poured into water and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (0% - 80% EtOAc in petroleum) to afford the desired product (3R)-methyl 3-(2-(4,5-dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a colorless oil (92 mg). Yield 74% (86.01% purity, UV = 214 nm, ESI 504 (M+H) + ).

[0363] Step 4: (3R)-3-(2-(4,5-Dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid

Chem.

[0364] Compound Y1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 490 (M+H) + 。

[0365] 1 H NMR (500 MHz, MeOD) δ 8.51 (s, 1H), 8.18 (s, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 6.30 (s, 1H), 5.68 (dd, J = 9.0, 7.0 Hz, 1H), 5.42 (t, J = 7.1 Hz, 1H), 2.91 (d, J = 7.1 Hz, 2H), 2.15 (s, 3H), 2.02 (s, 3H), 1.96 (d, J = 7.9 Hz, 3H), 1.95 - 1.87 (m, 2H), 1.85 (s, 3H), 1.47 - 1.40 (m, 1H), 0.97 - 0.94 (m, 6H).

[0366] Compound Y2 LC / MS A: 97% purity, UV = 214 nm, Rt = 1.60 min, ESI 490 (M+H) + 。

[0367] 1 H NMR (500 MHz, MeOD) δ 8.58 (s, 1H), 8.26 (s, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.46 (s, 1H), 7.27 - 7.18 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.41 (s, 1H), 5.67 (t, J = 8.0 Hz, 1H), 5.38 (t, J = 7.3 Hz, 1H), 2.97 - 2.86 (m, 2H), 2.20 (s, 3H), 2.09 (s, 3H), 2.02 (s, 6H), 1.82 (t, J = 7.5 Hz, 2H), 1.36 - 1.28 (m, 1H), 0.90 - 0.87 (m, 6H).

[0368] Step 5: (3S)-Methyl 3-(2-(4,5-dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chemical Structure

[0369] Step 6: (3S)-3-(2-(4,5-dimethyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid

Chemical Structure

[0370] Compound Y4 LC / MS A: 100% purity, UV=214nm, Rt=1.60min, ESI490(M+H) + .

[0371] 1 H NMR (500MHz, MeOD)δ 8.59(s, 1H), 8.26(s, 1H), 7.66(t, J=1.8Hz, 1H), 7.46(s, 1H), 7.28-7.11(m, 3H), 6.41(s, 1H), 5.67(t, J=8.0Hz, 1H), 5.38(t, J=7 .3Hz, 1H), 2.95-2.71(m, 2H), 2.20(s, 3H), 2.09(s, 3H), 2.02(s, 6H), 1.84(t, J=7.5Hz, 2H), 1.37-1.28(m, 1H), 0.90-0.87(m, 6H).

[0372] Preparation of Compound Z Step 1: Methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [ka] A mixture of (S)-methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate (1.0 g, 2.79 mmol), 2,6-dimethylphenylboronic acid (628 mg, 4.19 mmol), Pd(dppf)Cl2 (164 mg, 0.22 mmol), and K2CO3 (963 mg, 7.0 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred at 110 °C for 4 h in a microwave oven. The mixture was poured into water and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (0% - 45% EtOAc in petroleum ether) to afford the desired product methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a pale yellow oil (987 mg). Yield 82% (88% purity, UV = 214 nm, ESI 385 (M+H) + ).

[0373] Step 2: (S)-Methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride [Chemical formula] To a solution of methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (410 mg, 1.07 mmol) in DCM (4 mL) was added HCl / dioxane (4 M, 2 mL) and the solution was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the crude product (S)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride as a white solid (303 mg), which was used directly in the next step without further purification. Yield 99% (90.38% purity, UV = 214 nm, ESI 285 (M+H) + ).

[0374] Step 3: (S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-2-hydroxy-4-methylpentanamide)propanoate

Chem.

[0375] Step 4: (S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-4-methyl-2-(methylsulfonyloxy)pentanamide)propanoate

Chem.

[0376] Step 5: (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-iodo-4-methylpentanamide)propanoate

Chemical Structure

[0377] Step 6: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pentaamide)propanoic acid

Chem.

[0378] Compound Z LC / MS A: 100% purity, UV = 214 nm, Rt = 1.67 min, ESI 514 (M + H) + 。

[0379] 1 H NMR (500 MHz, MeOD) δ 8.59 - 8.56 (m, 1H), 8.25 - 8.18 (m, 1H), 7.97 - 7.84 (m, 1H), 7.73 - 7.58 (m, 1H), 7.49 (q, J = 7.7 Hz, 1H), 7.40 - 7.00 (m, 5H), 5.49 - 5.32 (m, 2H), 3.76 - 3.42 (m, 2H), 3.17 - 2.78 (m, 4H), 2.01 - 1.95 (m, 5H), 1.87 - 1.66 (m, 3H), 1.65 - 1.43 (m, 1H), 1.07 - 0.89 (m, 6H).

[0380] Preparation of Compound AA1 and Compound AA2 Step 1: Ethyl 4-methyl-2-(1-oxoisoindolin-2-yl)pentanoate

Chem.

[0381] Step 2: 4-Methyl-2-(1-oxoisoindolin-2-yl)pentanoic acid

Chem.

[0382] Step 3: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(1-oxoisoindolin-2-yl)pentaamide)propanoate

Chem.

[0383] Step 4: Compounds AA1 and AA2

Chem.

[0384] Compound AA1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.61 min, ESI 500.3 (M+H) + 。

[0385] 1 H NMR (500 MHz, MeOD) δ 8.55 (s, 1H), 8.14 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.59 - 7.45 (m, 3H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 5.42 (t, J = 7.3 Hz, 1H), 5.05 (t, J = 7.9 Hz, 1H), 4.64 (d, J = 17.7 Hz, 1H), 4.51 (d, J = 17.7 Hz, 1H), 2.92 (t, J = 8.0 Hz, 2H), 1.93 (s, 3H), 1.89 - 1.85 (m, 2H), 1.67 (s, 3H), 1.54 - 1.49 (m, 1H), 1.03 - 0.97 (m, 6H).

[0386] Compound AA2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.63 min, ESI 500.3 (M+H) + 。

[0387] 1 H NMR (500 MHz, MeOD) δ 8.59 (s, 1H), 8.26 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.71 - 7.56 (m, 3H), 7.52 (t, J = 7.3 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.16 (d, J = 7.5 Hz, 2H), 5.42 (t, J = 7.4 Hz, 1H), 5.06 (t, J = 7.9 Hz, 1H), 4.77 (d, J = 17.8 Hz, 1H), 4.52 (d, J = 17.7 Hz, 1H), 2.97 - 2.87 (m, 2H), 2.02 (s, 6H), 1.78 (t, J = 7.5 Hz, 2H), 1.39 - 1.34 (m, 1H), 0.95 - 0.93 (m, 6H).

[0388] Preparation of Compound AB2 Step 1: 2 - Bromo - 4 - formylbenzonitrile

Chemical Structure

[0389] Step 2: 5-Formyl-2'-methylbiphenyl-2-carbonitrile

Chemical formula

[0390] Step 3: 3-Amino-3-(6-cyano-2'-methylbiphenyl-3-yl)propanoic acid

Chemical formula

[0391] Step 4: Methyl 3-amino-3-(6-cyano-2'-methylbiphenyl-3-yl)propanoate

Chemical formula

[0392] Step 5: Methyl 3-(6-cyano-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical formula

[0393] Step 6: 3-(6-Cyano-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid [Chemical formula] Methyl 3-(6-cyano-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate (70 mg, 0.14 mmol) was treated with LiOH-H2O (18 mg, 0.43 mmol) in 3 mL of THF and 1 mL of H2O at room temperature for 1 h. The solution was adjusted to pH = 3-4 with TFA. The solvent was removed in vacuo and the residue was purified by preparative HPLC A (33-70% MeCN) to give compounds AB1 (8.8 mg) and AB2 (8.4 mg) as white solids.

[0394] Compound AB2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.59 min, ESI 472 (M+H) + .

[0395] 11H NMR (500 MHz, MeOD) δ 7.82 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.53 - 7.50 (m, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.31 (dd, J = 10.7, 5.3 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.43 - 6.40 (m, 1H), 5.75 (t, J = 8.1 Hz, 1H), 5.36 (t, J = 7.2 Hz, 1H), 2.93 - 2.73 (m, 2H), 2.18 (s, 3H), 1.85 (t, J = 7.5 Hz, 2H), 1.36 - 1.31 (m, 1H), 0.91 - 0.89 (m, 6H).

[0396] Preparation of Compound AC2 Step 1: 6-Methoxy-2'-methylbiphenyl-3-carbaldehyde [Chemical formula] A mixture of 3-bromo-4-methoxybenzaldehyde (200 mg, 0.93 mmol), o-tolylboronic acid (190 mg, 1.4 mmol), PdCl2(dppf) (34 mg, 0.05 mmol), and K2CO3 (386 mg, 2.79 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred at 110 °C for 1 hour in a microwave oven. Water was added, and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether:EtOAc = 5:1) to obtain the desired product 6-methoxy-2'-methylbiphenyl-3-carbaldehyde as a colorless solid (245 mg) in a yield of 99% (96% purity, UV = 214 nm, ESI 227 (M+H) + )

[0397] Step 2: 3-Amino-3-(6-methoxy-2'-methylbiphenyl-3-yl)propanoic acid [Chemical formula] A mixture of 6-methoxy-2'-methylbiphenyl-3-carbaldehyde (245 mg, 1.08 mmol), malonic acid (100 mg, 1.3 mmol), and ammonium acetate (563 mg, 5.41 mmol) in EtOH (10 mL) was stirred at 85 °C for 20 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product 3-amino-3-(6-methoxy-2'-methylbiphenyl-3-yl)propanoic acid as a brown solid (70 mg). Yield 23% (22% purity, UV = 214 nm, ESI 269 (M+H) + ). The crude product was used directly in the next step.

[0398] Step 3: Methyl 3-amino-3-(6-methoxy-2'-methylbiphenyl-3-yl)propanoate

Chem.

[0399] Step 4: Methyl 3-(6-methoxy-2'-methylbiphenyl-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chem.

[0400] Step 5: Compound AC2 [Chemical Structure] AC1 (30 mg, 0.06 mmol) was treated with LiOH-H2O (8 mg, 0.18 mmol) and 1 mL of H2O in 3 mL of THF at room temperature for 1 h. The solution was adjusted to pH = 3 - 4 with TFA. The solvent was removed in vacuo and the residue was purified by preparative HPLC A (33 - 70% MeCN) to give the desired product AC2 (10 mg) as a white solid.

[0401] Compound AC2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.60 min, ESI 477 (M+H) +

[0402] 1 ​1H NMR (500 MHz, MeOD) δ 7.64 (dd, J = 6.9, 1.6 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.26 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 - 7.03 (m, 3H), 7.00 - 6.99 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 8.6 Hz, 1H), 6.27 (dd, J = 6.8, 5.7 Hz, 1H), 5.62 (dd, J = 9.4, 6.8 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 3.61 (s, 3H), 2.54 (d, J = 6.8 Hz, 2H), 1.97 (s, 3H), 1.72 (d, J = 32.4 Hz, 2H), 1.22 (br, 1H), 0.78 - 0.76 (m, 6H).

[0403] Preparation of Compound AD1 and Compound AD2 Step 1: Methyl 3-(3-bromo-4-methylphenyl)-3-((tert-butoxycarbonyl)amino)propanoate

Chem.

[0404] Step 2: Methyl 3-((tert-butoxycarbonyl)amino)-3-(4-methyl-3-morpholinophenyl)propanoate

Chem.

[0405] Step 3: Methyl 3-amino-3-(4-methyl-3-morpholinophenyl)propanoate hydrochloride

Chemical formula

[0406] Step 4: 4-Methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(4-methyl-3-morpholinophenyl)propanoate

Chemical formula

[0407] Step 5: 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(4-methyl-3-morpholinophenyl)propanoic acid [Chemical formula] Methyl 3-((S)-4-methyl-2-(4-oxoquinazolin-3(4H)-yl)pentaamide)-3-(4-methyl-3-morpholinophenyl)propanoate (100 mg, 0.19 mmol) was treated with LiOH-H2O (24 mg, 0.57 mmol) and H2O (2 mL) in THF (5 mL) at room temperature for 1 h. The mixture was acidified to pH = 5 - 6 with HCl (1 M), and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC A (30 - 70% MeCN) to afford the desired compounds AD1 (29 mg) and AD2 (13 mg) as white solids.

[0408] Compound AD1 LC / MS C 100% purity, UV = 214 nm, Rt = 1.54 min, ESI 507 (M+H) + .

[0409] 11H NMR (500 MHz, MeOD) δ 8.41 (s, 1H), 8.28 (dd, J = 8.0, 1.2 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 5.75 (dd, J = 9.4, 6.9 Hz, 1H), 5.32 (t, J = 7.3 Hz, 1H), 3.76 - 3.69 (m, 4H), 2.77 (dd, J = 10.5, 6.0 Hz, 6H), 2.22 (s, 3H), 2.11 - 2.02 (m, 2H), 1.60 - 1.52 (m, 1H), 1.05 - 0.98 (m, 6H).

[0410] Compound AD2 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.76 min, ESI 507 (M + H) + 。

[0411] 1 1H NMR (500 MHz, MeOD) δ 8.45 (s, 1H), 8.28 (d, J = 7.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 5.75 (dd, J = 10.0, 6.4 Hz, 1H), 5.31 (t, J = 7.1 Hz, 1H), 3.88 - 3.81 (m, 4H), 2.95 - 2.89 (m, 4H), 2.79 - 2.74 (m, 2H), 2.30 (s, 3H), 2.07 - 1.92 (m, 2H), 1.48 - 1.43 (m, 1H), 0.98 - 0.95 (m, 6H).

[0412] Preparation of Compound AE1 and Compound AE2 Step 1: Methyl 6 - methyl - 5 - o - tolunitrate

Chemical Structure

[0413] Step 2: (6-Methyl-5-o-tolylpyridin-3-yl)methanol

Chem.

[0414] Step 3: 6-Methyl-5-o-tolylnicotinaldehyde

Chem.

[0415] Step 4: 3-Amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoic acid [Chemical formula] A mixture of 6-methyl-5-o-tolylnicotinaldehyde (254 mg, 1.2 mmol), malonic acid (187 mg, 1.8 mmol), and NH4OAc (185 mg, 2.4 mmol) in EtOH (16 mL) was heated to reflux overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH = 8:1~1:1) to give the crude product 3-amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoic acid as a brown solid (155 mg). Yield 31% (91% purity, UV = 254 nm, ESI 271 (M+H) + ).

[0416] Step 5: Methyl 3-amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate [Chemical formula] A mixture of 3-amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoic acid (128 mg, 0.31 mmol) in MeOH (5 mL) was added with SOCl2 (184 mg, 1.55 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was adjusted to pH = 7 - 8 with saturated NaHCO3 solution, and the solution was extracted with EtOAc (30 mL × 2). The organic layer was concentrated under reduced pressure to obtain an oil, which was purified by silica gel column (DCM:MeOH = 20:1 - 2:1) to obtain the desired product methyl 3-amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate as a green oil (41 mg). Yield 47% (99% purity, UV = 254 nm, ESI 284 (M+H) + ).

[0417] Step 6: Methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate [Chemical formula] A mixture of methyl 3-amino-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate (41 mg, 0.14 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaanoic acid (34 mg, 0.15 mmol), EDCI (41 mg, 0.21 mmol), HOBt (29 mg, 0.21 mmol), and DIEA (56 mg, 0.43 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 hour. The mixture was diluted with DCM (10 mL) and 5 mL of water. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oil, which was purified by silica gel column (petroleum ether:EtOAc 1:10) to obtain the desired methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate (53 mg) as a colorless oil. Yield 75% (99% purity, UV = 254 nm, ESI 490 (M+H) + )。

[0418] Step 5: Compound AE1 and Compound AE2 [Chemical formula] 3-(4-Methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(6-methyl-5-o-tolylpyridin-3-yl)propanoate (53 mg, 0.108 mmol) was treated with LiOH (1 M in H2O, 0.54 mL) in THF (2 mL) at room temperature for 1 hour. The mixture was adjusted to pH = 5 - 6 with 1 M HCl and the solvent was removed in vacuo. The residue was purified by preparative HPLC A (30 - 64% MeCN) to give Compound AE1 (14 mg) and Compound AE2 (11 mg) as white solids.

[0419] Compound AE1 LC / MS A: 100% purity, UV = 214 nm, Rt = 8.25 min, ESI 476 (M + H) + .

[0420] 1 H NMR (500 MHz, MeOD) δ 8.40 (s, 1H), 7.57 (t, J = 6.9 Hz, 1H), 7.45 (dd, J = 8.6, 2.2 Hz, 1H), 7.38 - 7.24 (m, 3H), 7.05 (dd, J = 26.6, 7.4 Hz, 1H), 6.29 (d, J = 8.8 Hz, 1H), 6.25 (dd, J = 7.1, 1.9 Hz, 1H), 5.70 - 5.65 (m, 1H), 5.38 (dd, J = 15.1, 7.7 Hz, 1H), 2.99 - 2.78 (m, 2H), 2.21 (dd, J = 13.4, 2.6 Hz, 6H), 2.10 - 1.89 (m, 5H), 1.45 - 1.42 (m, 1H), 0.97 - 0.94 (m, 6H).

[0421] Compound AE2 - P2 LC / MS A: 100% purity, UV = 214 nm, Rt = 8.44 min, ESI 476 (M + H) + .

[0422] 11H NMR (500 MHz, MeOD) δ 8.46 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 7.0, 5.5 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.42 - 7.23 (m, 3H), 7.12 (dd, J = 10.8, 7.3 Hz, 1H), 6.38 (s, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.69 (q, J = 7.7 Hz, 1H), 5.34 - 5.32 (m, 1H), 3.02 - 2.76 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.91 - 1.71 (m, 2H), 1.43 - 1.22 (m, 1H), 0.98 - 0.75 (m, 6H).

[0423] Preparation of Compound AF1 and Compound AF2 Step 1: Methyl 5-bromo-6-iodonicotinate

Chemical Structure

[0424] Step 2: Methyl 5-bromo-6-methylnicotinate

Chemical Structure

[0425] Step 3: Methyl (S)-6-methyl-5-(3-methylmorpholino)nicotinate

Chem.

[0426] Step 4: (S)-(6-Methyl-5-(3-methylmorpholino)pyridin-3-yl)methanol

Chem.

[0427] Step 5: (S)-6-Methyl-5-(3-methylmorpholino)nicotinaldehyde

Chemical formula

[0428] Step 6: 3-Amino-3-(6-methyl-5-((S)-3-methylmorpholino)pyridin-3-yl)propanoic acid

Chemical formula

[0429] Step 7: Methyl 3-amino-3-(6-methyl-5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate

Chemical Structure

[0430] Step 8: Methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(6-methyl-5-((S)-3-methylmorpholino)pyridin-3-yl)propanoate

Chemical Structure

[0431] Step 9: Compound AF1, Compound AF2, and Compound AF3

Chemical Structure

[0432] Compound AF1 LC / MS A: 97% purity, UV = 214 nm, Rt = 1.26 min, ESI 485 (M+H) + 。

[0433] 1 1H NMR (500 MHz, MeOD) δ 8.14 (s, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H), 6.43 (d, J = 12.6 Hz, 1H), 6.31 (d, J = 7.0 Hz, 1H), 5.68 - 5.66 (m, 1H), 5.32 (s, 1H), 3.92 - 3.71 (m, 3H), 3.42 - 3.35 (m, 1H), 3.20 - 3.15 (m, 1H), 2.89 - 2.73 (m, 3H), 2.69 - 2.66 (m, 0.5H), 2.58 - 2.55 (m, 0.5H), 2.47 (s, 3H), 2.24 (d, J = 4.1 Hz, 3H), 2.01 - 1.86 (m, 2H), 1.48 - 1.43 (m, 1H), 0.99 - 0.96 (m, 6H), 0.72 (d, J = 6.1 Hz, 1.5H), 0.63 (d, J = 6.1 Hz, 1.5H).

[0434] Compound AF2 LC / MS A 100% purity, UV = 214 nm, Rt = 1.27 min, ESI 485 (M + H) + 。

[0435] 1 1H NMR (500 MHz, MeOD) δ 8.21 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 7.3 Hz, 2H), 6.41 (s, 1H), 6.32 (d, J = 5.6 Hz, 1H), 5.70 - 5.65 (m, 1H), 5.30 (t, J = 7.1 Hz, 1H), 3.94 - 3.77 (m, 3H), 3.43 (m, 1H), 3.30 (m, 1H), 2.97 - 2.71 (m, 4H), 2.53 (s, 3H), 2.25 (s, 3H), 1.87 - 1.82 (m, 2H), 1.39 - 1.33 (m, 1H), 0.95 - 0.91 (m, 6H), 0.80 (d, J = 6.2 Hz, 3H).

[0436] Compound AF3 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.28 min, ESI 485 (M + H) + 。

[0437] 11H NMR (500 MHz, MeOD) δ 8.21 (s, 1H), 7.66 - 7.59 (m, 2H), 6.40 (s, 1H), 6.32 (d, J = 7.2 Hz, 1H), 5.72 - 5.69 (m, 1H), 5.29 (t, J = 7.1 Hz, 1H), 3.94 - 3.76 (m, 3H), 3.40 (m, 1H), 3.30 (m, 1H), 2.97 - 2.73 (m, 4H), 2.53 (s, 3H), 2.25 (s, 3H), 1.87 - 1.80 (m, 2H), 1.38 - 1.32 (m, 1H), 0.94 - 0.91 (m, 6H), 0.79 (d, J = 6.1 Hz, 3H).

[0438] Preparation of Compound AG1b Step 1: (S)-Methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate

Chemical Structure

[0439] Step 2: (S)-Methyl 3-amino-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoate

Chemical Structure

[0440] Step 3: (3S)-Methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(5-((S)-2-methylpiperidin-1-yl))pyridin-3-yl)propanoate [Chemical formula] A mixture of (S)-methyl 3-amino-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoate (37 mg, 0.13 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaanoic acid (29 mg, 0.13 mmol), HOBt (27 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and DIEA (52 mg, 0.40 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was poured into 10 mL of water, and the solution was extracted with DCM (30 mL × 3). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc = 1:1) to give the desired product (3S)-methyl 3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoate as a yellow oil (40 mg). Yield 63% (95% purity, UV = 254 nm, ESI 483 (M+H)+ )。

[0441] Step 4: (S)-3-((S)-4-Methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoic acid

Chem.

[0442] Compound AG1b LC / MS A: 98% purity, UV = 214 nm, Rt = 1.57 min, ESI 469 (M + H) + 。

[0443] 1 H NMR (500 MHz, MeOD) δ 8.09 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.35 (s, 1H), 6.38 (s, 1H), 6.30 (dd, J = 7.2, 1.8 Hz, 1H), 5.70 (dd, J = 9.3, 6.8 Hz, 1H), 5.26 (t, J = 7.3 Hz, 1H), 4.10 (s, 1H), 3.39 (d, J = 12.3 Hz, 1H), 3.00 - 3.04 (m, 1H), 2.76 - 2.89 (m, 2H), 2.23 (s, 3H), 1.95 - 1.57 (m, 9H), 1.42 - 1.28 (m, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.90 - 0.93 (m, 6H).

[0444] Preparation of Compound AG2b Step 1: (R)-Methyl 3-(5-bromopyridin-3-yl)-3-(tert-butoxycarbonylamino)propanoate

Chemical Structure

[0445] Step 2: (R)-Methyl 3-amino-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoate

Chemical Structure

[0446] Step 3: Methyl (3R)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoate

Chem.

[0447] Step 4: (3R)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)-3-(5-((S)-2-methylpiperidin-1-yl)pyridin-3-yl)propanoic acid

Chem.

[0448] Compound AG2b LC / MS A: 98% purity, UV = 214 nm, Rt = 1.58 min, ESI 469 (M + H) + 。

[0449] 1 H NMR (500 MHz, MeOD) δ 8.11 (d, J = 2.7 Hz, 1H), 7.95 (s, 1H), 7.64 (d, J = 7.1 Hz, 1H), 7.38 (s, 1H), 6.43 - 6.25 (m, 2H), 5.70 (t, J = 8.0 Hz, 1H), 5.29 (t, J = 7.3 Hz, 1H), 4.11 (s, 1H), 3.42 (d, J = 12.4 Hz, 1H), 3.04 (t, J = 11.7 Hz, 1H), 2.82 - 2.86 (m, 2H), 2.25 (s, 3H), 1.98 - 1.58 (m, 8H), 1.41 - 1.31 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.95 - 0.91 (m, 6H).

[0450] Preparation of compound AH1 Step 1: (R)-Benzyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride

Chemical formula

[0451] Step 2: (3R)-benzyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate [Chemical Structure] A mixture of (R)-benzyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride (117 mg, 0.325 mmol), (S)-4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaanoic acid (71 mg, 0.34 mmol), HOBt (66 mg, 0.49 mmol), EDCI (94 mg, 0.49 mmol), and DIEA (126 mg, 0.98 mmol) in DMF (4 mL) was stirred at room temperature for 3 h. The mixture was poured into water, and the solution was extracted with EtOAc (20 mL×2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative-TLC (EtOAc:petroleum ether = 1:1) to afford the desired product (3R)-benzyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate as a colorless oil (80 mg). Yield 44% (70% purity, UV = 214 nm, ESI 552 (M+H) + ).

[0452] Step 3: (3R)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopiperidin-1-yl)pentaamide)propanoic acid

Chem.

[0453] Compound AH1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 466 (M + H) + 。

[0454] 1 1H NMR (500 MHz, MeOD) δ 8.57 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.67 - 7.59 (m, 1H), 7.27 - 7.07 (m, 3H), 5.42 (t, J = 7.0 Hz, 1H), 5.31 - 5.19 (m, 1H), 3.32 - 3.09 (m, 2H), 2.98 - 2.86 (m, 2H), 2.56 - 2.21 (m, 2H), 2.06 - 1.95 (m, 6H), 1.91 - 1.36 (m, 7H), 1.09 - 0.83 (m, 6H).

[0455] Preparation of Compound AH2 Step 1: 3-Amino-3-(5-bromopyridin-3-yl)propanoic acid

Chem.

[0456] Step 2: Methyl 3-amino-3-(5-bromopyridin-3-yl)propanoate

Chemical formula

[0457] Step 3: Methyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0458] Step 4: 3-(5-Bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoic acid

Chemical formula

[0459] Step 5: Benzyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0460] Step 6: Benzyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] A mixture of benzyl 3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate (4.3 mg, 9.9 mmol), (2,6-dimethylphenyl)boronic acid (1.78 g, 11.9 mmol), PdCl2(dppf) (724 mg, 0.99 mmol), and K2CO3 (2.7 g, 19.8 mmol) in dioxane (10 mL) and H2O (2 mL) under N2 atmosphere was heated at 110 °C for 1 h in a microwave oven. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL×3). The combined organic phases were concentrated under reduced pressure to give a residue, which was purified by silica gel column (35% EtOAc in petroleum ether) to give the desired product benzyl 3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a brown oil (3.1 g). Yield 70% (94% purity, UV = 214 nm, ESI 461 (M+H) +)。The racemic product was separated as a white solid by preparative chiral HPLC into benzyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (1.3 g) and benzyl (R)-3-((tert-butoxycarbonyl)amino)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (1.3 g).

[0461] Step 7: (S)-Benzyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride

Chem.

[0462] Step 8: (3S)-Benzyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chem.

[0463] Step 9: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxopiperidin-1-yl)pentaamide)propanoic acid

Chemical Structure

[0464] Compound AH2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.58 min, ESI 466 (M+H) + 。

[0465] 1 H NMR (500 MHz, MeOD) δ 8.57 (dd, J = 6.2, 2.1 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.24 - 7.18 (m, 1H), 7.15 (d, J = 7.4 Hz, 2H), 5.41 (t, J = 6.9 Hz, 1H), 5.32 - 5.20 (m, 1H), 3.30 - 3.20 (m, 2H), 2.91 (dd, J = 7.0, 4.9 Hz, 2H), 2.52 - 2.23 (m, 2H), 2.02 (s, 3H), 2.01 (d, J = 3.0 Hz, 3H), 1.92 - 1.56 (m, 6H), 1.55 - 1.41 (m, 1H), 0.99 - 0.90 (m, 6H).

[0466] Preparation of Compound AI Step 1: (R)-2-Bromopentanoic acid

Chem.

[0467] Step 2: (S)-2-(4-Methyl-2-oxopyridin-1(2H)-yl)pentanoic acid

Chem.

[0468] Step 3: Methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanamido)propanoate

Chemical Structure

[0469] Step 4: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid [Chemical formula] Methyl (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate (70 mg, 0.15 mmol) was treated with LiOH-H2O (19 mg, 0.45 mmol) and H2O (2 mL) in THF (4 mL) at room temperature for 1 h. The mixture was acidified to pH = 5 - 6 with HCl (1 M). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC A (30 - 70% MeCN) to give Compound AI1 (16.7 mg) and Compound AI2 (16.8 mg) as white solids.

[0470] Compound AI1 LC / MS A 100% purity, UV = 214 nm, Rt = 1.54 min, ESI 462 (M+H) + 。

[0471] 1 1H NMR (500 MHz, MeOD) δ 8.53 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.54 (s, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 6.6 Hz, 2H), 6.26 (s, 1H), 6.23 (dd, J = 7.1, 1.8 Hz, 1H), 5.57 (dd, J = 8.8, 7.1 Hz, 1H), 5.42 (t, J = 7.2 Hz, 1H), 2.93 (d, J = 7.2 Hz, 2H), 2.19 (s, 3H), 2.14 - 2.04 (m, 1H), 1.97 (s, 3H), 1.96 - 1.88 (m, 1H), 1.87 (s, 3H), 1.37 - 1.27 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0472] Compound AI2 LC / MS A 100% purity, UV = 214 nm, Rt = 1.57 min, ESI 462 (M + H) + 。

[0473] 1 1H NMR (500 MHz, MeOD) δ 8.59 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.68 (t, J = 1.9 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.16 (d, J = 7.5 Hz, 2H), 6.38 (s, 1H), 6.31 (dd, J = 7.2, 1.8 Hz, 1H), 5.56 (dd, J = 8.9, 6.9 Hz, 1H), 5.39 (t, J = 7.3 Hz, 1H), 2.96 - 2.87 (m, 2H), 2.24 (s, 3H), 2.05 - 1.93 (m, 7H), 1.90 - 1.79 (m, 1H), 1.31 - 1.12 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H).

[0474] Preparation of Compound AJ1a and Compound AJ1b Step 1: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((2R)-4-methyl-2-(4-methyl-2-oxopiperidin-1-yl)pentaamide)propanoic acid

Chemical Structure

[0475] Compound AJ1a LC / MS A: 100% purity, UV = 214 nm, Rt = 1.64 min, ESI 480 (M + H) + 。

[0476] 1 H NMR (500 MHz, MeOD) δ 8.57 (s, 1H), 8.25 (s, 1H), 7.57 (dd, J = 3.9, 2.1 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.19 - 7.13 (m, 2H), 5.42 (t, J = 7.0 Hz, 1H), 5.26 (t, J = 7.9 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.16 (m, 1H), 2.94 (dd, J = 6.8, 1.9 Hz, 2H), 2.49 - 2.29 (m, 1H), 2.02 (s, 3H), 2.00 (d, J = 2.8 Hz, 3H), 1.98 - 1.61 (m, 5H), 1.56 - 1.13 (m, 2H), 0.96 - 0.91 (m, 9H).

[0477] Step 2: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((2S)-4-methyl-2-(4-methyl-2-oxopiperidin-1-yl)pentaamide)propanoic acid

Chemical Structure

[0478] Compound AJ1b LC / MS A: 100% purity, UV = 214 nm, Rt = 1.62 min, ESI 480 (M + H) + 。

[0479] 1 H NMR (500 MHz, MeOD) δ 8.58 (s, 1H), 8.25 (s, 1H), 7.66 (s, 1H), 7.25 - 7.19 (m, 1H), 7.16 (d, J = 7.5 Hz, 2H), 5.42 (t, J = 6.9 Hz, 1H), 5.27 - 5.23 (m, 1H), 3.50 - 3.36 (m, 1H), 3.31 - 3.20 (m, 1H), 2.98 - 2.88 (m, 2H), 2.14 - 2.04 (m, 1H), 2.01 (d, J = 6.9 Hz, 6H), 1.94 - 1.88 (m, 2H), 1.74 - 1.34 (m, 4H), 1.08 - 1.00 (m, 3H), 0.96 - 0.83 (m, 6H).

[0480] Preparation of Compound AK1 and Compound AK2 Step 1: (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)propanoate

Chemical Structure

[0481] Step 2: (S)-Methyl 3-amino-3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)propanoate hydrochloride [Chemical formula] To a solution of methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)propanoate (88 mg, 0.22 mmol) in DCM (3 mL) was added HCl / dioxane (4 M, 10 mL), and the solution was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the crude product (S)-methyl 3-amino-3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)propanoate hydrochloride as a pale yellow solid (80 mg), which was used directly in the next step without further purification. Yield 100% (79% purity, UV = 214 nm, ESI 294 (M+H) + ).

[0482] Step 3: (3S)-Methyl 3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chem.

[0483] Step 4: (3S)-3-(5-(2,2-dimethylmorpholino)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chem.

[0484] Compound AK1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 485 (M+H) + 。

[0485] 1 H NMR (500 MHz, MeOD) δ 8.08 (d, J = 2.3 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.28 (s, 1H), 6.36 (s, 1H), 6.28 (dd, J = 7.1, 1.8 Hz, 1H), 5.69 (dd, J = 9.3, 6.8 Hz, 1H), 5.33 (t, J = 7.2 Hz, 1H), 3.95 - 3.82 (m, 2H), 3.18 - 3.11 (m, 2H), 3.06 - 2.99 (m, 2H), 2.83 (d, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.98 - 1.83 (m, 2H), 1.49 - 1.43 (dtm, 1H), 1.32 (s, 6H), 0.99 - 0.96 (m, 6H).

[0486] Compound AK2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.52 min, ESI 485 (M+H) + 。

[0487] 11H NMR (500 MHz, MeOD) δ 8.14 (d, J = 2.5 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.37 (s, 1H), 6.40 (s, 1H), 6.31 (dd, J = 7.1, 1.8 Hz, 1H), 5.69 (dd, J = 9.1, 7.0 Hz, 1H), 5.28 (t, J = 7.3 Hz, 1H), 3.98 - 3.79 (m, 2H), 3.24 - 3.17 (m, 2H), 3.08 (s, 2H), 2.91 - 2.79 (m, 2H), 2.25 (s, 3H), 1.93 - 1.75 (m, 2H), 1.40 - 1.35 (m, 1H), 1.34 (s, 6H), 0.94 - 0.90 (m, 6H).

[0488] Preparation of Compound AL1 and Compound AL2 Step 1: 2-(5,5-Dimethyl-2-oxopiperidin-1-yl)-4-methylpentanoic acid [Chemical formula] To a solution of 5,5-dimethylpiperidin-2-one (100 mg, 0.79 mmol) in DMF (3 mL) was added NaH (60% in oil, 158 mg, 3.95 mmol), and the mixture was stirred at 120 °C for 2 hours. Next, ethyl 2-iodo-4-methylpentanoate (320 mg, 1.19 mmol) was added, and the solution was stirred at room temperature for 2 hours. The reaction was quenched with MeOH and concentrated under reduced pressure. The residue was purified by preparative HPLC B (20 - 50% MeCN) to give the desired product 2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanoic acid as a white solid (38 mg). Yield 20% (100% purity, UV = 254 nm, ESI 242 (M+H) + ).

[0489] Step 2: Methyl (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] A mixture of 2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanoic acid (38 mg, 0.16 mmol), methyl (S)-3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate hydrochloride (56 mg, 0.18 mmol), HOBt (26 mg, 0.19 mmol), EDCI (36 mg, 0.19 mmol), and DIEA (62 mg, 0.48 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative-TLC (petroleum ether:EtOAc 1:1) to afford the desired product methyl (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a colorless oil (50 mg). Yield 63% (94% purity, UV = 254 nm, ESI 508 (M+H) + ).

[0490] Step 3: (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid [Chemical formula] Methyl (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (50 mg, 0.1 mmol) was treated with LiOH-H2O (21 mg, 0.5 mmol) and H2O (1 mL) in THF (5 mL) at room temperature for 1 h. The mixture was acidified to pH = 5 - 6 with HCl (1 M), and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC A (30 - 70% MeCN) to give the product (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid as a white solid (35 mg). Yield 72% (100% purity, UV = 254 nm, ESI 494 (M+H) +)。The diastereomer (3S)-3-(2-(5,5-dimethyl-2-oxopiperidin-1-yl)-4-methylpentanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid was separated as a white solid into two compounds, compound AL1 (10 mg) and compound AL2 (11 mg), by preparative chiral SFC F.

[0491] Compound AL1, LC / MS, B 99% purity, UV = 214 nm, Rt = 1.66 min, ESI 494 (M+H) + 。

[0492] 1 H NMR (500 MHz, MeOD) δ 8.46 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 7.13 - 6.98 (m, 3H), 5.27 (t, J = 6.9 Hz, 1H), 5.18 - 5.08 (m, 1H), 3.02 (d, J = 12.2 Hz, 1H), 2.91 (dd, J = 25.8, 9.8 Hz, 1H), 2.84 - 2.70 (m, 2H), 2.46 - 2.25 (m, 2H), 1.90 (s, 3H), 1.89 (s, 3H), 1.62 - 1.45 (m, 3H), 1.45 - 1.34 (m, 1H), 1.35 - 1.27 (m, 1H), 0.91 (d, J = 1.2 Hz, 6H), 0.83 - 0.71 (m, 6H).

[0493] Compound AL2, LC / MS, B 99% purity, UV = 214 nm, Rt = 1.66 min, ESI 494 (M+H) + 。

[0494] 11H NMR (500 MHz, MeOD) δ 8.57 (s, 1H), 8.24 (s, 1H), 7.62 (s, 1H), 7.23 - 7.14 (m, 3H), 5.43 (t, J = 6.9 Hz, 1H), 5.25 (dd, J = 8.4, 7.1 Hz, 1H), 3.06 (dd, J = 19.3, 9.8 Hz, 1H), 2.97 (d, J = 12.2 Hz, 1H), 2.92 (d, J = 6.8 Hz, 2H), 2.42 - 2.25 (m, 2H), 2.02 (s, 3H), 2.01 (s, 3H), 1.76 - 1.66 (m, 1H), 1.64 - 1.58 (m, 1H), 1.58 - 1.47 (m, 2H), 1.46 - 1.41 (m, 1H), 1.05 - 0.86 (m, 9H), 0.77 (s, 3H).

[0495] Preparation of Compound AM Step 1: Ethyl 4 - methyl - 2 - (methylsulfonyloxy) pentanoate

Chemical Structure

[0496] Step 2: Ethyl 2 - iodo - 4 - methylpentanoate

Chemical Structure

[0497] Step 3: Ethyl 4-methyl-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)pentanoate

Chemical formula

[0498] Step 4: 4-Methyl-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)pentanoic acid

Chemical formula

[0499] Step 5: (S)-Methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chemical formula

[0500] Step 6: 3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)pentanamide)propanoate

Chemical formula

[0501] Step 7: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)pentanamide)propanoic acid

Chemical Structure

[0502] Compound AM LC / MS A: 100% purity, UV = 214 nm, Rt = 1.67 min, ESI 514 (M + H) + 。

[0503] 1 1H NMR (500 MHz, MeOD) δ 8.58 (s, 0.5H), 8.48 (s, 0.5H), 8.25 (s, 0.5H), 8.19 (s, 0.5H), 7.67 (s, 0.5H), 7.45 (s, 0.5H), 7.31 - 6.77 (m, 7H), 5.67 - 5.52 (m, 2H), 3.00 - 2.77 (m, 4H), 2.77 - 2.58 (m, 2H), 2.05 - 1.87 (m, 8H), 1.35 (s, 1H), 0.96 - 0.75 (m, 6H).

[0504] Preparation of Compound AN1 and Compound AN2 Step 1: (S)-5-(1-(tert-Butoxycarbonylamino)-3-methoxy-3-oxopropyl)pyridin-3-ylboronic acid

Chemical Structure

[0505] Step 2: (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)propanoate

Chem.

[0506] Step 3: (S)-Methyl 3-amino-3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)propanoate [Chemical formula] To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)propanoate (120 mg, 0.30 mmol) in DCM (4 mL) was added HCl in dioxane (4 M, 2 mL), and the mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the crude product (S)-methyl 3-amino-3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)propanoate as a white solid (110 mg). (82% purity, UV = 214 nm, ESI 305.1 (M+H) + ). The crude product was used directly in the next step. Step 4: (3S)-Methyl 3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta-namido)propanoate

Chem.

[0507] Step 5: (3S)-3-(5-(2-chloro-6-methylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta-namido)propanoic acid

Chem.

[0508] 1 1H NMR (500 MHz, MeOD) δ 8.56 (s, 1H), 8.24 (s, 1H), 7.65 - 7.47 (m, 2H), 7.42 - 7.21 (m, 3H), 6.28 (s, 1H), 6.25 - 6.19 (m, 1H), 5.74 - 5.64 (m, 1H), 5.45 - 5.41 (m, 1H), 2.91 (d, J = 7.0 Hz, 2H), 2.19 (d, J = 7.1 Hz, 3H), 1.94 - 1.86 (m, 4H), 1.48 - 1.42 (m, 1H), 0.978 - 0.88 (m, 6H).

[0509] Compound AN2 LC / MS 100% purity, UV = 214 nm, Rt = 1.82 min, ESI 496.3 (M+H) + 。

[0510] 11H NMR (500 MHz, MeOD) δ 8.65 - 8.56 (m, 1H), 8.34 - 8.25 (m, 1H), 7.80 - 7.70 (m, 1H), 7.64 - 7.62 (m, 1H), 7.41 - 7.38 (m, 1H), 7.30 (t, J = 19.1 Hz, 2H), 6.39 (s, 1H), 6.32 - 6.30 (m, 1H), 5.72 - 5.68 (m, 1H), 5.42 - 5.37 (m, 1H), 3.01 - 2.74 (m, 2H), 2.21 (d, J = 30.5 Hz, 3H), 2.10 (s, 3H), 1.88 - 1.72 (m, 2H), 1.35 - 1.30 (m, 1H), 0.91 - 0.88 (m, 6H).

[0511] Preparation of Compounds AO1 and AO2 Step 1: (4-Fluoro-2,6-dimethylphenyl)boronic acid [Chemical Structure] To a solution of 2-bromo-5-fluoro-1,3-dimethylbenzene (2 g, 9.9 mmol) in THF (20 mL) under N2 atmosphere, n-BuLi (2.5 M in hexane, 6 mL, 14.8 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes. Triisopropyl borate (5.58 g, 29.7 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. HCl (5 M, 20 mL) was added and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc (30 mL × 2). The aqueous phase was acidified with HCl (5 M) to pH = 1 and the solution was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (4-fluoro-2,6-dimethylphenyl)boronic acid (500 mg). Yield 30% (86% purity, UV = 214 nm, ESI 167.2 (M+H) + ). The crude product was used directly in the next step.

[0512] Step 2: Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical] A mixture of (4-fluoro-2,6-dimethylphenyl)boronic acid (171 mg, 1.02 mmol), methyl (S)-3-(5-bromopyridin-3-yl)-3-((tert-butoxycarbonyl)amino)propanoate (120 mg, 0.34 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and K2CO3 (117 mg, 0.85 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) under N2 atmosphere was stirred at 110 °C for 3 h in a microwave oven. The mixture was poured into water and the solution was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give the desired product methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)propanoate as a colorless oil (150 mg). Yield 76% (68% purity, UV = 214 nm, ESI 403.2 (M+H) + )

[0513] Step 3: Methyl (S)-3-amino-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical] To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)propanoate (150 mg, 0.37 mmol) in DCM (2 mL) was added HCl in dioxane (4 M, 1 mL). The solution was stirred at room temperature for 1 h. Saturated aqueous NaHCO3 (20 mL) was added and the solution was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over NaSO4 and filtered. The filtrate was concentrated under reduced pressure to afford the crude product methyl (S)-3-amino-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)propanoate as a colorless oil (110 mg). Yield 99% (81% purity, UV = 214 nm, ESI 303.2 (M+H) + ). The crude product was used directly in the next step.

[0514] Step 4: Methyl (3S)-3-(5-(4-fluoro-2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical Structure

[0515] Step 5: (S)-3-(5-(4-Fluoro-2,6-dimethylphenyl)pyridin-3-yl)-3-((R)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical formula

[0516] 1 H NMR (500 MHz, MeOD) δ 8.53 (s, 1H), 8.17 (s, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.49 (s, 1H), 6.96 - 6.84 (m, 2H), 6.29 (s, 1H), 6.25 (d, J = 7.1 Hz, 1H), 5.68 (t, J = 8.1 Hz, 1H), 5.40 (t, J = 7.0 Hz, 1H), 2.89 (s, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.93 (t, J = 7.5 Hz, 2H), 1.86 (s, 3H), 1.47 - 1.42 (m, 1H), 1.03 - 0.85 (m, 6H).

[0517] Compound AO2 LC / MS C: 100% purity, UV = 214 nm, Rt = 1.61 min, ESI 494.0 (M+H) + 。

[0518] 1 H NMR (500 MHz, MeOD) δ 8.60 (s, 1H), 8.25 (s, 1H), 7.72 - 7.57 (m, 2H), 6.93 (d, J = 9.6 Hz, 2H), 6.41 (s, 1H), 6.34 (d, J = 7.0 Hz, 1H), 5.71 - 5.61 (m, 1H), 5.37 (t, J = 6.9 Hz, 1H), 2.85 (s, 2H), 2.25 (s, 3H), 2.02 (s, 5H), 1.92 - 1.75 (m, 2H), 1.46 - 1.26 (m, 1H), 0.97 - 0.87 (m, 6H).

[0519] Preparation of Compound AP1 and Compound AP2 Step 1: 2 - Bromo - 1 - methoxy - 3 - methylbenzene

Chemical Structure

[0520] Step 2: (S)-Methyl 3-(tert-butoxycarbonylamino)-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate [Chemical formula] A mixture of 2-bromo-1-methoxy-3-methylbenzene (85 mg), (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propanoate (199 mg, 0.49 mmol), PdCl2(dppf) (30 mg, 0.04 mmol), and K2CO3 (138 mg, 1.0 mmol) in dioxane (3 mL) and H2O (0.4 mL) under N2 atmosphere was stirred at 80 °C for 50 minutes in a microwave oven. Water (20 mL) was added and the solution was extracted with EtOAc (10 mL × 3). The combined organic phases were concentrated under reduced pressure and the residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to afford the desired product (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate as a colorless oil (110 mg). Yield 44% (61% purity, UV = 214 nm, ESI 401.1 (M + H) + )

[0521] Step 3: (S)-Methyl 3-amino-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate [Chemical formula] To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate (110 mg, 0.27 mmol) in DCM (3 mL) was added HCl in dioxane (4 M, 2 mL), and the solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the crude product (S)-methyl 3-amino-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate was obtained as a white solid (90 mg). (74% purity, UV = 214 nm, ESI 301.1 (M+H) + ). The crude product was used directly in the next step.

[0522] Step 4: (3S)-Methyl 3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta-namide)propanoate [Chemical formula] A mixture of (S)-methyl 3-amino-3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)propanoate (90 mg, 0.36 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanoic acid (81 mg, 0.36 mmol), HOBt (81 mg, 0.6 mmol), EDCI (115 mg, 0.6 mmol), and DIEA (93 mg, 0.72 mmol) in DCM (10 mL) was stirred at room temperature for 5 h. The mixture was poured into water and the solution was extracted with DCM (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash column (10% - 50% EtOAc in petroleum) to afford the desired product (3S)-methyl 3-(5-(2-methoxy-6-methylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta-namido)propanoate as a colorless oil (72 mg). Yield 52% (67% purity, UV = 214 nm, ESI 506.2 (M + H) + ).

[0523] Step 5: (3S)-3-(5-(2-Methoxy-6-methylphenyl)pyridin-3-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)penta-namido)propanoic acid

Chem.

[0524] Compound AP1: LC / MS 100% purity, UV = 214 nm, Rt = 1.73 minutes, ESI 492.3 (M+H) + 。

[0525] 1 H NMR (500 MHz, MeOD) δ 8.46 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 1.7 Hz, 1H), 7.64 - 7.48 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 2H), 6.29 (s, 1H), 6.25 - 6.21 (m, 1H), 5.71 (t, J = 8.1 Hz, 1H), 5.42 (t, J = 7.3 Hz, 1H), 3.68 (s, 3H), 2.92 (d, J = 7.3 Hz, 2H), 2.18 (s, 3H), 2.03 - 1.73 (m, 5H), 1.47 - 1.42 (m, 1H), 1.01 - 0.83 (m, 6H). Compound AP2: LC / MS 100% purity, UV = 214 nm, Rt = 1.59 minutes, ESI 492.3 (M+H) + 。

[0526] 1 H NMR (500 MHz, MeOD) δ 8.52 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.38 (s, 1H), 6.32 - 6.30 (m, 1H), 5.72 - 5.69 (m, 1H), 5.39 (t, J = 7.3 Hz, 1H), 3.72 (s, 3H), 2.98 - 2.73 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H), 1.88 - 1.67 (m, 2H), 1.40 - 1.21 (m, 1H), 1.01 - 0.83 (m, 6H).

[0527] Preparation of Compound AQ1b (R)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate

Chemical Structure

[0528] Step 2: (R)-ethyl 3-amino-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate hydrochloride

Chem.

[0529] Step 3: (3R)-Ethyl 3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate [Chemical formula] A mixture of (R)-ethyl 3-amino-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate hydrochloride (200 mg, 0.67 mmol), (S)-4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaanoic acid (181 mg, 0.81 mmol), HOBt (135 mg, 1.0 mmol), EDCI (191 mg, 1.0 mmol), and DIEA (258 mg, 2.0 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The mixture was poured into water, and the solution was extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography (0% - 50% EtOAc in petroleum) to give the desired product (3R)-ethyl 3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate as a pale yellow oil (183 mg). Yield 54% 3 steps (93% purity, UV = 214 nm, ESI 504 (M + H) + )

[0530] Step 4: (3R)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid [Chemical formula] (3R)-Ethyl 3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate (183 mg, 0.36 mmol) was treated with LiOH-H2O (46 mg, 1.09 mmol) and H2O (1 mL) in THF (6 mL) at room temperature for 1.5 h. The mixture was acidified to pH = 5 with HCl (1 M). The solvent was removed in vacuo and the residue was purified by preparative HPLC A (30 - 70% MeCN) to give compound AQ1a (40.2 mg) and compound AQ1b (48.4 mg) as white solids. Compound AQ1b LC / MS A: 100% purity, UV = 214 nm, Rt = 1.56 min, ESI 476 (M+H) + 。

[0531] 1 H NMR (500 MHz, MeOD) δ 8.60 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.44 (dd, J = 5.3, 1.6 Hz, 1H), 7.33 (s, 1H), 7.29 - 7.20 (m, 1H), 7.15 (d, J = 7.6 Hz, 2H), 6.38 (s, 1H), 6.31 (dd, J = 7.1, 1.7 Hz, 1H), 5.71 (t, J = 8.1 Hz, 1H), 5.34 (t, J = 7.1 Hz, 1H), 2.99 - 2.80 (m, 2H), 2.24 (s, 3H), 2.01 (s, 6H), 1.84 (t, J = 7.6 Hz, 2H), 1.38 - 1.32 (m, 1H), 0.98 - 0.84 (m, 6H).

[0532] Preparation of compound AQ2b Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate

Chemical formula

[0533] Step 2: Ethyl (S)-3-amino-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate [Chemical formula] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate (265 mg, 0.67 mmol) in DCM (2 mL) was added HCl / dioxane (4 M, 1 mL). The solution was stirred at room temperature for 1 h. Saturated aqueous NaHCO3 (20 mL) was added and the solution was extracted with EtOAc (30 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product ethyl (S)-3-amino-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)propanoate as a yellow oil (240 mg). Yield 99% (72% purity, UV = 214 nm, ESI 299.0 (M+H) + ). The crude product was used directly in the next step.

[0534] Step 3: Ethyl (3S)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoate

Chemical formula

[0535] Step 4: (3S)-3-(2-(2,6-dimethylphenyl)pyridin-4-yl)-3-(4-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical formula

[0536] Compound AQ2b LC / MS A: 98% purity, UV = 214 nm, Rt = 1.55 min, ESI 476.2 (M + H) + 。

[0537] 1 1H NMR (500 MHz, MeOD) δ 8.59 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.44 (dd, J = 5.3, 1.5 Hz, 1H), 7.33 (s, 1H), 7.27 - 7.07 (m, 3H), 6.38 (s, 1H), 6.31 (dd, J = 7.1, 1.7 Hz, 1H), 5.70 (t, J = 8.0 Hz, 1H), 5.34 (t, J = 7.1 Hz, 1H), 3.00 - 2.74 (m, 2H), 2.24 (s, 3H), 2.01 (s, 6H), 1.84 (t, J = 7.5 Hz, 2H), 1.38 - 1.32 (m, 1H), 0.98 - 0.83 (m, 6H).

[0538] Preparation of Compound AR1 and Compound AR2 Step 1: Ethyl 2-(4-bromo-5-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate

Chemical formula

[0539] Step 2: Ethyl 2-(5-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate

Chem.

[0540] Step 3: 2-(5-Fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid

Chem.

[0541] Step 4: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(5-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoate [Chemical formula] A mixture of 2-(5-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (100 mg, 0.41 mmol), (S)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (118 mg, 0.41 mmol), HATU (189 mg, 0.5 mmol), and DIEA (107 mg, 0.83 mmol) in DMF (3 mL) was stirred at room temperature for 1 h. The mixture was poured into 30 mL of water and the solution was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. Filtered. The filtrate was concentrated under reduced pressure to give the crude product (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-(5-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoate (220 mg). Yield 100% (85% purity, UV = 214 nm, ESI 508.3 (M+H) + ).

[0542] Step 5: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-(2-(5-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid

Chem.

[0543] Compound AR1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.65 min, ESI 494.2 (M + H) + 。

[0544] 1 1H NMR (500 MHz, MeOD) δ 8.54 (s, 1H), 8.18 (s, 1H), 7.68 (d, J = 5.7 Hz, 1H), 7.55 (s, 1H), 7.20 - 7.18 (m, 1H), 7.14 - 7.11 (m, 2H), 6.32 (d, J = 7.2 Hz, 1H), 5.67 (t, J = 7.9 Hz, 1H), 5.41 (t, J = 7.2 Hz, 1H), 2.89 (d, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.94 - 1.89 (m, 2H), 1.88 (s, 3H), 1.47 - 1.44 (m, 1H), 0.99 - 095 (m, 6H).

[0545] Compound AR2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.68 min, ESI 494.2 (M + H) + 。

[0546] 1 1H NMR (500 MHz, MeOD) δ 8.59 (s, 1H), 8.25 (s, 1H), 7.74 (d, J = 5.8 Hz, 1H), 7.67 (s, 1H), 7.28 - 7.19 (m, 1H), 7.16 - 7.15 (m, 2H), 6.43 (d, J = 7.1 Hz, 1H), 5.74 - 5.58 (m, 1H), 5.38 (t, J = 7.3 Hz, 1H), 2.90 - 2.86 (m, 2H), 2.24 (s, 3H), 2.02 (s, 6H), 1.86 - 1.72 (m, 2H), 1.41 - 1.20 (m, 1H), 0.91 - 0.88 (m, 6H).

[0547] Preparation of Compound AS2 Step 1: Ethyl 3 - methyl - 2-(4 - methyl - 2 - oxopyridin - 1(2H)-yl)butanoate [Chemical formula] To a solution of ethyl 2 - bromo - 3 - methylbutanoate (200 mg, 0.96 mmol) and 4 - methylpyridin - 2 - ol (105 mg, 0.96 mmol) in toluene (2 mL), Cs2CO3 (626 mg, 1.92 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h. Saturated aqueous sodium carbonate solution (30 mL) was added to the mixture and the solution was extracted with EtOAc (20 mL × 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc = 2:1) to afford the desired product ethyl 3 - methyl - 2-(4 - methyl - 2 - oxopyridin - 1(2H)-yl)butanoate (200 mg) as a yellow oil. Yield 46% (98% purity, UV = 214 nm, ESI 238 (M + H) + ).

[0548] Step 2: 3 - Methyl - 2-(4 - methyl - 2 - oxopyridin - 1(2H)-yl)butanoic acid [Chemical formula] Ethyl 3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)butanoate (200 mg, 0.93 mmol) was treated with LiOH (1 M in H2O, 0.6 mL) in THF (5 mL) at room temperature for 2 h. The mixture was adjusted to pH = 5 - 6 with 1 M HCl. The solvent was removed in vacuo to afford the crude product 3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)butanoic acid (194 mg) as a white solid. Yield 100% (98% purity, UV = 214 nm, ESI 210 (M+H) + ). The crude product was used directly in the next step.

[0549] Step 3: (3S)-Methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)butanamido)propanoate

Chemical Structure

[0550] Step 4: (S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((S)-3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)butanamide)propanoic acid

Chem.

[0551] Compound AS2 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.55 min, ESI 462 (M + H) + 。

[0552] 1 1H NMR (500 MHz, MeOD) δ 8.63 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.71 (t, J = 2.0 Hz, 1H), 7.28 - 7.12 (m, 3H), 6.44 - 6.30 (m, 2H), 5.38 (t, J = 7.4 Hz, 1H), 5.23 (d, J = 11.1 Hz, 1H), 2.88 - 2.95 (m, 2H), 2.42 - 2.22 (m, 4H), 1.99 (s, 3H), 1.97 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H).

[0553] Preparation of compound AT1b Step 1: (2R,3S)-2-Bromo-3-methylpentanoic acid

Chem.

[0554] Step 2: (2S,3S)-3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanoic acid

Chemical formula

[0555] Step 3: (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanamide)propanoate

Chemical formula

[0556] Step 4: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical formula

[0557] Compound AT1b LC / MS A: 100% purity, UV = 214 nm, Rt = 1.69 min, ESI 476 (M+H) + 。

[0558] 1 H NMR (500 MHz, MeOD) δ 8.62 (s, 0.5H), 8.59 (s, 0.6H), 8.26 (s, 4H), 7.78 (d, J = 7.2 Hz, 0.6H), 7.70 (s, 0.6H), 7.67 (s, 0.4H), 7.63 (d, J = 7.2 Hz, 0.4H), 7.27 - 7.10 (m, 3H), 6.39 (s, 1H), 6.32 (d, J = 7.1 Hz, 1H), 5.72 - 5.29 (m, 2H), 3.02 - 2.74 (m, 2H), 2.24 (s, 3H), 2.18 - 1.85 (m, 1H), 2.01 (s, H), 1.99 (s, 3H), 1.43 - 1.07 (m, 1H), 1.02 - 0.95 (m, 1H), 0.91 - 0.57 (m, 6H).

[0559] Preparation of Compound AT2b Step 1: (2R,3R)-2-Bromo-3-methylpentanoic acid

Chemical formula

[0560] Step 2: (2S,3R)-3-Methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanoic acid

Chemical formula

[0561] Step 3: (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-((3R)-3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentanamide)propanoate

Chemical formula

[0562] Step 4: (3S)-3-(5-(2,6-Dimethylphenyl)pyridin-3-yl)-3-((3R)-3-methyl-2-(4-methyl-2-oxopyridin-1(2H)-yl)pentaamide)propanoic acid

Chemical Structure

[0563] 1 H NMR (500 MHz, MeOD) δ 8.62 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.38 (s, 1H), 6.31 (dd, J = 7.2, 1.8 Hz, 1H), 5.41 - 5.28 (m, 2H), 2.96 - 2.85 (m, 2H), 2.23 (s, 3H), 2.20 - 2.13 (m, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.20 - 1.15 (m, 1H), 1.02 - 0.96 (m, 1H), 0.88 - 0.76 (m, 6H).

[0564] Preparation of Compound AU1 and Compound AU2 Step 1: 5 - ((Dimethylamino)methyl)pyridin - 2(1H) - one

Chemical Structure

[0565] Step 2: Ethyl 2 - (5 - ((dimethylamino)methyl) - 2 - oxopyridin - 1(2H) - yl) - 4 - methylpentanoate [Chemical formula] A mixture of 5-((dimethylamino)methyl)pyridin-2(1H)-one (500 mg, 3.28 mmol), K2CO3 (1.36 g, 9.86 mmol), and ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (1.17 g, 4.93 mmol) in CH3CN (20 ml) was stirred at 70 °C overnight. The solvent was concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether:EtOAc 1:2) to give the desired product ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate as a yellow oil (300 mg). Yield 31% (ESI 295 (M+H) + ).

[0566] Step 3: 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid [Chemical formula] Ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (300 mg, 1.02 mmol) was treated with LiOH-H2O (120 mg, 3.02 mmol) and water (1 mL) in methanol (2 mL) at room temperature for 2 h. The reaction was acidified to pH = 3 with 1N hydrochloric acid. The solvent was removed in vacuo, and the residue was purified by preparative HPLC A (30 - 80% MeCN) to give the desired product 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid as a white solid (100 mg). Yield 37% (ESI 267 (M+H) + ).

[0567] Step 4: (3S)-methyl 3-(2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate [Chemical formula] A mixture of (2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (100 mg, 0.375 mmol), (S)-methyl 3-amino-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate (117 mg, 0.413 mmol), HATU (142.5 mg, 0.375 mmol), and DIEA (0.5 mL) in DMF (3 mL) was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by combiflash (eluent A: 10 mM NH4HCO in water 3、 eluent B: MeOH, gradient A->B 0-100%) to give the desired product (3S)-methyl 3-(2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate as a yellow solid (80 mg). Yield 41% (ESI 533 (M+H)+).

[0568] Step 5: (S)-3-((S)-2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoic acid

Chemical formula

[0569] Compound AU1 ESI519 (M+H) +

[0570] 1H NMR (500 MHz, MeOD) δ 8.57 (t, J = 13.2 Hz, 1H), 8.21 (t, J = 8.7 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.88 - 7.86 (m, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.53 (dd, J = 9.4, 2.5 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 9.3 Hz, 1H), 5.76 (t, J = 8.0 Hz, 1H), 5.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.86 (d, J = 13.3 Hz, 1H), 2.87 (dd, J = 14.9, 8.6 Hz, 1H), 2.77 (dd, J = 14.9, 5.8 Hz, 1H), 2.70 (s, 6H), 2.05 - 1.88 (m, 8H), 1.48 - 1.38 (m, 1H), 0.99 - 0.91 (m, 6H).

[0571] Compound AU2 ESI519 (M+H) +

[0572] 1H NMR (500 MHz, MeOD) δ 8.58 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 14.9, 1.9 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.64 (t, J = 1.9 Hz, 1H), 7.57 (dd, J = 9.3, 2.5 Hz, 1H), 7.22 (dd, J = 8.4, 6.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.60 (d, J = 9.3 Hz, 1H), 5.57 (ddd, J = 18.8, 9.4, 5.5 Hz, 2H), 4.23 (d, J = 13.3 Hz, 1H), 3.84 (d, J = 13.3 Hz, 1H), 2.81 (s, 6H), 2.73 (dd, J = 15.3, 4.4 Hz, 1H), 2.60 (dd, J = 15.3, 11.0 Hz, 1H), 2.07 - 2.00 (m, 7H), 1.58 (dt, J = 13.5, 6.8 Hz, 1H), 1.48 (td, J = 13.3, 6.6 Hz, 1H), 0.93 - 0.84 (m, 6H).

[0573] Preparation of Compound AV1 and Compound AV2 Step 1: 2-Oxo-2,3-dihydropyridine-4-carbaldehyde

Chemical Structure

[0574] Step 2: 4-((Dimethylamino)methyl)pyridin-2(1H)-one

Chemical Structure

[0575] Step 3: Ethyl 2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate

Chemical Structure

[0576] Step 4: 2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid

Chem.

[0577] Step 5: (S)-Methyl 3-((S)-2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)propanoate

Chem.

[0578] Step 6: (S)-3-((S)-2-(4-((dimethylamino)methyl)-2-oxopyrid...

Claims

1. A compound represented by formula (I), wherein 【Chemical 1】 in the formula,[[]] R １ is alkylene-cycloalkyl, heterocyclyl, alkylene-O-alkyl, aryl, or alkylene-CF ３ and R ２ is a heterocyclyl, R ３ is 【Chemical 2】 and R ４ is H, or (C １ -C ６ )-alkyl, and R ａ is H, alkyl, cycloalkyl, CN, or -O-alkyl, R ｂ is alkyl, heterocyclyl, -O-cycloalkyl, or -O-aryl, the compound, or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, wherein R is alkylene-cycloalkyl.

3. The compound according to claim 2, wherein the alkylene-cycloalkyl is methylene-cyclopropyl.

4. R １ The compound according to claim 1, wherein R is heterocyclyl.

5. The compound according to claim 4, wherein the heterocyclyl is an N-containing heterocyclyl.

6. R １ The compound according to claim 1, wherein R is -alkylene-O-alkyl.

7. R １ The compound according to claim 6, wherein R is -methylene-O-methyl.

8. R １ The compound according to claim 1, wherein R is aryl.

9. The compound according to claim 8, wherein the aryl is phenyl.

10. The compound according to claim 9, wherein the phenyl is unsubstituted phenyl or substituted phenyl.

11. R １ is alkylene-CF ３ The compound according to claim 1, wherein

12. alkylene-CF ３ wherein the alkylene-CF ３ is methylene-CF, the compound according to claim 11.

13. R ２ The compound according to claim 1, wherein R is a 6- to 12-membered N-containing heterocyclyl.

14. R ２ The compound according to claim 1, wherein R is substituted with one or more substituents selected from amino, alkyl, and alkoxy, the alkyl or alkoxy is substituted with morpholino, cyclic amino, or acyclic amino, and the alkyl, alkoxy, morpholino, cyclic amino, or acyclic amino moiety is optionally substituted with one or more alkoxyl or fluorine.

15. The compound according to claim 13, wherein the 6- to 12-membered N-containing heterocyclyl is unsubstituted pyridinonyl or substituted pyridinonyl.

16. R ２ is 【Chemical Formula 3-1】 [Chemical Formula 3-2] The compound according to claim 1, selected from

17. R ２ is 【Chemical Formula 4-1】 [Chemical Formula 4-2] The compound according to claim 1, selected from

18. R ａ The compound according to claim 1, wherein R is H or methyl.

19. R ｂ The compound according to claim 1, wherein R is alkyl.

20. The compound according to claim 19, wherein the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, or t-butyl.

21. The compound according to claim 20, wherein the alkyl is t-butyl.

22. R ｂ The compound according to claim 1, wherein R is heterocyclyl.

23. R ｂ The compound according to claim 22, wherein R is a substituted heterocyclyl.

24. R ｂ is 【Chemical Formula 5】 The compound according to claim 22, selected from

25. R ｂ The compound according to claim 1, wherein R is -O-cycloalkyl.

26. The compound according to claim 25, wherein -O-cycloalkyl is -O-cyclobutyl.

27. R ｂ The compound according to claim 1, wherein R is -O-aryl.

28. The compound according to claim 27, wherein -O-aryl is -O-phenyl.

29. R ４ The compound according to any one of claims 1 to 28, wherein R is H.

30. R ４ is (C １ -C ６ )-alkyl, the compound according to any one of claims 1 to 28.

31. (C １ -C ６ )-alkyl is methyl, ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, or tert-butyl, the compound according to claim 30.

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 and a pharmaceutically acceptable excipient.

33. The pharmaceutical composition according to claim 32, for treating a disease or condition selected from the group consisting of inflammatory bowel disease, ileoanal anastomosis, eosinophilic esophagitis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, graft-versus-host disease, chronic inflammatory diseases of the lung, HIV, and hematological malignancies.

34. The pharmaceutical composition according to claim 33, wherein the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, non-tropical sprue, enteropathy associated with seronegative arthritis, gastroenteritis, or cystitis.

35. The pharmaceutical composition according to claim 33, wherein the inflammatory bowel disease is colitis or Crohn's disease.

36. The pharmaceutical composition according to claim 35, wherein the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis.

37. The pharmaceutical composition according to claim 34, wherein the gastroenteritis is eosinophilic gastroenteritis.

38. The pharmaceutical composition according to claim 33, wherein the disease or condition is eosinophilic esophagitis.

39. The pharmaceutical composition according to claim 33, wherein the chronic inflammatory disease of the lung is interstitial fibrosis, hypersensitivity pneumonitis, collagen disease, or sarcoidosis.

40. The pharmaceutical composition according to claim 33, wherein the hematological tumor is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma.

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