Inhibition of αvβ6 integrin

Abstract

To provide small molecule inhibitors of αvβ6 integrin suitable for oral administration to treat diseases associated with αvβ6 integrin.SOLUTION: For example, a compound represented by the following formula, or a pharmaceutically acceptable salt thereof, are provided.SELECTED DRAWING: Figure 1-1

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application 62 / 724,423 filed on 29 August 2018; and U.S. Provisional Patent Application 62 / 859,457 filed on 10 June 2019.

[0002] This disclosure relates to novel compounds and methods useful for inhibiting αvβ6 integrin. [Background technology]

[0003] Receptors of the heterodimeric integrin family regulate cell morphology and cell adhesion to the extracellular matrix in response to exogenous and endogenous signals.

[0004] Integrin signaling regulates cell survival, cell cycle progression, cell differentiation, and cell migration.

[0005] Integrin receptors can transmit signals to cells primarily in both "inside to outside" and "outside to inside" directions. Therefore, integrin receptors mediate cell migration and regulate cytoskeletal mechanisms by transmitting force from the extracellular matrix to the cytoskeleton, thereby achieving the shape changes required during cell migration. RGD-binding integrins can bind to and activate TGF-β, and have recently been suggested to be involved in fibrous diseases.

[0006] Integrins are expressed on the surface of most human cells. Their pathologies are responsible for a diverse range of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidneys, macular degeneration, and various autoimmune and chronic inflammatory diseases.

[0007] The role of integrins as drug targets has long been recognized, and a total of six injectable integrin inhibitors—for inflammatory bowel disease (Entyvio®, Tysabri®), multiple sclerosis (Tysabri®), psoriasis (Raptiva®), and acute coronary insufficiency syndrome (Reopro®, Aggrastat®, Integrilin®)—have been approved by the Food and Drug Administration for the treatment of various indications. Of the 24 known integrin heterodimers, at least half are associated with inflammation, fibrosis, tumors, and vascular diseases. [Overview of the project] [Problems that the invention aims to solve]

[0008] A new type of integrin inhibitor is needed. Therapeutic responses with orally administered integrin inhibitors have been remarkably lacking. Therefore, small molecule αvβ6 integrin inhibitors suitable for oral administration are still needed. The oral route is preferable for small molecule delivery because it allows for a wide range of doses, enables convenient self-administration by patients, can be adapted to various administration methods, and requires no special equipment. Therefore, it is important to identify αvβ6 integrin inhibitor compounds that are not only potent at the intended biological target but also exhibit other characteristics related to the ability of the compound to be absorbed into the body in a therapeutically effective manner (e.g., after oral administration). For example, αvβ6 integrin inhibitor compounds can be selected based on both potency and results from in vitro permeability assays (e.g., evaluating the ability of the compound to traverse a layer of Maidin-Derby canine kidney (MDCK) cells from apical to basolateral (A→B)). [Means for solving the problem]

[0009] The applicants discovered novel αvβ6 integrin inhibitor compounds and evaluated the retention, performance, and usefulness of representative examples of such compounds in terms of both biochemical capabilities (e.g., evaluation of the αvβ6 binding fluorescence polarization assay of the compounds using the assay of Example 35) and in vitro permeability characteristics (e.g., evaluation of MDCK permeability using the assay of Example 36).

[0010] In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0011] [ka] During the ceremony, A is

[0012] [ka] and; B is alkylene, -alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-, or -alkylene-O-alkylene-; C is

[0013] [ka] and; R1 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; R2 is

[0014] [ka] The file is TIFF0007829635000005.tif19166; R3 and R5 are independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-O-C(O)O(C1-C6)alkyl; n is independently 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0015] In certain embodiments, the present invention relates to a compound of formula I below or a pharmaceutically acceptable salt of the compound.

[0016]

Chemical formula

[0017]

Chemical formula

[0018]

Chemical formula

[0019] [Chemical formula] and; in each case of R1, it is H; R2 is

[0020] [Chemical formula] and; R3 is H, halide, Me, OMe, or Ph; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R5 is F; R a is H; n is independently 0 or 1; m is 0 or 1; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0021] In certain embodiments, the present invention relates to a compound of formula I below or a pharmaceutically acceptable salt of the compound.

[0022] [Chemical formula] wherein A is

[0023] [Chemical formula] and; B is

[0024] [Chemical formula] selected from the group consisting of; q is 0, 1, 2, or 3; p is 0, 1, or 2; C is,

[0025] [Chemical formula] and; In any case of R1, it is H; R2 is,

[0026] [Chemical formula] and; R3 is H, halide, Me, OMe, or Ph; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R5 is F; R a is H; n is 0 or 1; m is 0 or 1; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0027] In certain embodiments, the present invention relates to a method of treating a disease or condition selected from the group consisting of idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplantation, Alport syndrome, interstitial lung disease radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, the method comprising administering to a subject in need of treatment a therapeutically effective amount of any one of the compounds described herein. [Brief Description of the Drawings]

[0028] [Figure 1-1] This table summarizes the inhibition of αvβ6 integrin by exemplary compounds, as measured by fluorescence polarization assay. [Figure 1-2] This table summarizes the inhibition of αvβ6 integrin by exemplary compounds, as measured by fluorescence polarization assay. [Figure 2] This table summarizes the inhibition of αvβ6 integrin by exemplary compounds, as measured by fluorescence polarization assay. [Figure 3-1] This table summarizes the permeability characteristics of the exemplary compounds shown in Figures 1-1 and 1-2, as measured by the MDCK in vitro assay in Example 36. [Figure 3-2] This table summarizes the permeability characteristics of the exemplary compounds shown in Figures 1-1 and 1-2, as measured by the MDCK in vitro assay in Example 36. [Figure 4] This table summarizes the permeability characteristics of the exemplary compounds shown in Figure 2, as measured by the MDCK in vitro assay in Example 36. [Modes for carrying out the invention]

[0029] In certain embodiments, the present invention relates to compounds that inhibit αvβ6 integrin. In certain embodiments, the compounds are selective for αvβ6 integrin.

[0030] This compound is useful for the treatment of idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological malignancies, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, or cardiac fibrosis.

[0031] <Definition> For convenience, before further description of the present invention, certain terms used in this specification, the examples, and the accompanying claims are hereby compiled. These definitions should be read in consideration of the remainder of this disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0032] To make the present invention easier to understand, certain terms and phrases are defined below and throughout the specification.

[0033] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0034] When used in this specification and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements thus combined, that is, elements that may sometimes exist together and, on the other hand, may exist separately. Multiple elements listed using "and / or" should be interpreted as being of the same form, that is, "one or more" elements thus combined. Other elements other than those specifically identified by the "and / or" clause may exist, whether or not they are related to the specifically identified elements. Thus, as a non-restrictive example, when "A and / or B" is used in conjunction with open-ended language such as "includes," in one embodiment it may refer only to A (optionally including elements other than B); in another embodiment it may refer only to B (optionally including elements other than A); and in yet another embodiment it may refer to both A and B (optionally including other elements), and so on.

[0035] Where used herein in this specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, where items in a list are separated, “or” or “and / or” should be interpreted as inclusive, that is, including at least one of several elements or lists of elements, and optionally including additional items not listed. Only terms with conflicting and explicit designations, such as “only one of ~” or “exactly one of ~” or, as used in the claims, “consisting of ~,” refer to including exactly one element of several elements or lists of elements. Generally, where used herein, the term “or” should be interpreted to indicate an exclusive choice (i.e., “either one of ~, but not both”) only when preceded by terms of exclusivity, such as “either of ~,” “one of ~,” “only one of ~,” or “exactly one of ~,” or “essentially consisting of ~,” and where used in the claims, it should have its usual meaning as used in the field of patent law.

[0036] When used herein in this specification and in the claims, the phrase “at least one” in relation to a list of one or more elements means at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically enumerated in the list of elements, nor excluding any combination of elements in the list of elements. This definition also allows for the possibility that there may be other elements in the list of elements other than those specifically identified, whether or not they are related to these specifically identified elements. Therefore, as a non-restrictive 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”) could, in one embodiment, refer to at least one A that includes any multiple elements and B is absent (and optionally includes elements other than B); in another embodiment, refer to B that includes any multiple elements and A is absent (and optionally includes elements other than A); and in yet another embodiment, refer to at least one A that includes any multiple elements and at least one B that includes any multiple elements (and optionally includes other elements), and so on.

[0037] It should be understood that, unless otherwise explicitly stated, in any method claimed herein that includes multiple steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed.

[0038] In the claims and the specification, all transitional clauses, such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of,” are understood to be open-ended, meaning they include but are not limited to these. Only the transitional clauses “consisting of” and “consisting essentially of” are restrictive or semi-restrictive transitional clauses, as described in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures, respectively.

[0039] Certain compounds included in the compositions of the present invention may exist in geometric or stereoisomeric forms in particular. In addition, the polymers of the present invention may also be optically active. The present invention envisions all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, which are within the scope of the present invention. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included in the present invention.

[0040] For example, if a specific enantiomer of the compound of the present invention is desired, it can be produced by asymmetric synthesis or by induction with a chiral auxiliary group. In this case, the resulting diastereomer mixture is separated, the auxiliary group is cleaved, and the pure desired enantiomer is obtained. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt is formed using a suitable optically active acid or base, and then the diastereomer thus formed is separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomer is recovered.

[0041] The structures shown herein also include compounds that differ only in the presence of one or more isotope-rich atoms. For example, replacing hydrogen with deuterium or tritium, or carbon 13 C or 14 Compounds produced by replacing carbon with carbon-rich carbon fall within the scope of the present invention.

[0042] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutic agents under physiological conditions. A common method for creating a prodrug involves a specific moiety that is hydrolyzed under physiological conditions to produce a desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal.

[0043] As used herein, the phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable substance, composition or medium, such as a liquid or solid filler, diluent, excipient, solvent or encapsulant, that is involved in the transport or delivery of the chemical substance of interest from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, is not harmful to the patient, and is substantially nonpyrogenic. Some examples of substances that can function as pharmaceutically acceptable carriers include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and (10) Soybean oil, etc.; Glycols, e.g., propylene glycol; (11) Polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) Esters, e.g., ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Water free of pyrogens; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphate buffer; and (21) Other non-toxic and suitable substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., they do not induce much of a rise in body temperature when administered to a patient.

[0044] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of compounds. These salts can be produced in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid, and then isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid, benzoate, lactic acid, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0045] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, thereby enabling the formation of pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic base addition salts of the compound. These salts can similarly be produced in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine (see, e.g., Berge et al., above).

[0046] With regard to use in treatment, the “therapeutic effective dose” (or “effective dose”) of a compound means the amount of the compound in a preparation that, when administered (to a mammal, preferably a human) as part of a desired method of administration, alleviates symptoms, restores a condition, or delays the onset of a disease state in accordance with clinically acceptable standards for the disorder or condition being treated, or for cosmetic purposes, for example, in a reasonable benefit / risk ratio applicable to any medical treatment.

[0047] The terms “preventive or therapeutic” treatment are recognized in the art and include administration of the composition to one or more hosts. If administered before the clinical manifestation of an undesirable condition (e.g., disease or other undesirable condition in the host animal), the treatment is preventive (i.e., it protects the host from the development of the undesirable condition), whereas if administered after the manifestation of the undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, restore, or stabilize an existing undesirable condition or its side effects).

[0048] The term "patient" refers to a mammal requiring a specific treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0049] Aliphatic chains include alkyl, alkenyl, and alkynyl groups of the types defined below. Linear aliphatic chains are limited to unbranched carbon chain portions. As used herein, the term “aliphatic group” refers to a linear, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0050] "Alkyl," unless otherwise specified, refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain portion having a specified number of carbon atoms, or up to 30 carbon atoms. For example, alkyls with 1 to 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl portions, as well as positional isomers of these portions. Alkyls with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, henicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, linear or branched alkyls have 30 or fewer carbon atoms (for example, C1 to C1 in the case of a linear chain). 30 In the case of branched chains, C3~C 30 ), more preferably having 20 or fewer carbon atoms in its skeleton. The alkyl group may be substituted or unsubstituted.

[0051] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, e.g., 2 to 12 carbon atoms, with two bonding sites to the rest 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 others. The alkylene group can be a cyclic or acyclic, branched or unbranched carbon chain portion and may be substituted with one or more substituents.

[0052] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbon atoms in their ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0053] Unless the number of carbons is otherwise specified, "lower alkyl", as used herein, means an alkyl group as defined above having 1 to 10 carbons, more preferably 1 to 6 carbon atoms, in its backbone structure, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl. In certain embodiments, substituents designated as alkyl herein are lower alkyl.

[0054] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having up to 26 carbon atoms and having one or more double bonds in the moiety, where the number of carbon atoms is specified or, if no limitation on the number of carbon atoms is specified. Examples of alkenyls having 6 to 26 carbon atoms include hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicoseneyl, heneicoseneyl, docosenyl, tricosenyl, and tetracosenyl in various isomeric forms, where the unsaturated bond can be located anywhere in the moiety and can have either a (Z) or (E) configuration around the double bond.

[0055] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl except having one or more triple bonds within the moiety.

[0056] The term "alkylthio" refers to an alkyl group as defined above to which a sulfur moiety is attached. In certain embodiments, the "alkylthio" moiety is -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2) m -R 1 is represented by one of, where m and R 1Alkylthio groups are defined as follows. Typical alkylthio groups include methylthio and ethylthio. The term "alkoxyl" or "alkoxy," as used herein, refers to the alkyl group defined below, to which an oxygen moiety is bonded. Typical alkoxyl groups include methoxy, ethoxy, propoxy, and tert-butoxy. An "ether" is a molecule in which two hydrocarbons are covalently bonded by an oxygen atom. Therefore, alkyl substituents that convert alkyl to ether are alkoxyl or alkoxyl-like substituents, such as -O-alkyl, -O-alkenyl, -O-alkynyl, and -O-(CH2) m -R 10 It can be represented by one of the following, m and R 10 It is described below.

[0057] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, for example, the portion that can be represented by the following formula.

[0058] [ka] In the formula, R 11 , R 12 and R 13 These are, independently, hydrogen, alkyl, alkenyl, and -(CH2) m -R 10 Represents or R 11 and R 12 These, together with the N atoms to which they are bonded, complete a heterocycle having 4 to 8 atoms in the ring structure, R 10 R represents an alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl, where m is zero or an integer in the range of 1 to 8. In certain embodiments, R 11 or R 12 Only one of them can be a carbonyl, for example, R 11 , R 12 , and nitrogen do not form imides together. In some further embodiments, R 11 and R12 (and optionally R 13 ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) m -R 10 Therefore, as used herein, the term "alkylamine" means that a substituted or unsubstituted alkyl is bonded thereto, i.e., R 11 and R 12 This means an amine group as defined above, wherein at least one of the members is an alkyl group. In certain embodiments, the amino group or alkylamine is basic, where the pK a Having a conjugate acid with a pK of >7.00, that is, these functional groups in protonated form have a pK of about 7.00 compared to water. a It means having

[0059] As used herein, the term "amide" refers to the following groups:

[0060] [ka] In the formula, each R 14 R independently represents a hydrogen or a hydrocarbyl group, or two R 14 However, these atoms, together with the N atoms to which they are bonded, complete a heterocycle containing 4 to 8 atoms within the ring structure.

[0061] As used herein, the term “aryl” includes 3- to 12-membered, substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is a carbon (i.e., a carbocyclic aryl) or one or more atoms are heteroatoms (i.e., a heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which rings is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. 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, in which the ring structure contains 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryls and heteroaryls can be monocyclic, bicyclic, or polycyclic. Each case of an aryl group may be independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or exactly 1 substituent ("substituted aryl"). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (e.g., trifluoromethyl), cyanos, etc. For example, in certain embodiments, the aryl group may be an unsubstituted C5-C12 It can be aryl, and in certain embodiments, the aryl group is substituted C5-C 10 It can be an arrow.

[0062] The terms “halo,” “halide,” or “halogen” as used herein mean halogens, including, but not limited to, fluoro, chloro, bromo, and iodine in both radioactive and non-radioactive forms. In preferred embodiments, the halo is selected from the group consisting of fluoro, chloro, and bromo.

[0063] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and more preferably a 5- to 10-membered ring, whose ring structure contains 1 to 4 heteroatoms. Heterocyclic rings can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, sinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactam, such as azetidinone and pyrrolidinone, sultam, and sultone. The heterocyclic ring may be substituted at one or more positions with substituents such as 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 moiety, -CF3, -CN, etc.

[0064] The term "carbonyl" is recognized in the art and is represented by the following formula, among other things.

[0065] [ka] In the formula, X′ represents a bond, or oxygen or sulfur, and R 15 is hydrogen, alkyl, alkenyl, -(CH2) m -R 10Or it represents a pharmaceutically acceptable salt, R 16 is hydrogen, alkyl, alkenyl or -(CH2) m -R 10 Represents m and R 10 The definition is as described above. X′ is oxygen, and R 15 or R 16 If X' is not hydrogen, the formula represents an "ester". 15 If it is as defined above, the part is referred to as a carboxyl group in this specification, and in particular R 15 When X′ is hydrogen, the formula represents a "carboxylic acid". 16 When X′ is hydrogen, the formula represents "formate". Generally, when the oxygen atom in the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. When X′ is sulfur, R 15 or R 16 If X′ is not hydrogen, the formula represents a "thioester" group. 15 If X′ is hydrogen, the formula represents a "thiocarboxylic acid" group. 16 If is hydrogen, the formula represents a "thioformate" group. On the other hand, if X′ is a bond, R 15 If X′ is not hydrogen, the above formula represents a "ketone" group. X′ is a bond, and R 15 When the group is hydrogen, the above formula represents an "aldehyde" group.

[0066] As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described herein. There are one or more acceptable substituents with respect to a given organic compound, and they may be the same or different. With respect to the present invention, heteroatoms such as nitrogen may have any acceptable substituent of the organic compound described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom. The present invention is not limited by any means by acceptable substituents of an organic compound. It will be clear that “substituted” or “substituted with” implies that such substitution is according to the acceptable valences of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.

[0067] As used herein, the term "nitro" means -NO2, the term "halogen" means -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, the term "isothiocyanato" means -NCS, and the term "cyanato" means -OCN.

[0068] The term "sulfamoyl" is recognized in the art and includes a portion that can be represented by the following formula.

[0069] [ka] In the formula, R 11 and R 12 This is defined as above.

[0070] The term "sulfate" is recognized in the art and includes a portion that can be represented by the following formula.

[0071] [ka] In the formula, R 15 This is defined as above.

[0072] The term "sulfonamide" is recognized in the art and includes a portion that can be represented by the following formula.

[0073] [ka] In the formula, R 11 and R 16 This is defined as above.

[0074] The term "sulfonate" is recognized in the art and includes a portion that can be represented by the following formula.

[0075] [ka] In the formula, R 54 These are electron pairs, hydrogen, alkyl, cycloalkyl, or aryl atoms.

[0076] As used herein, the terms "sulfoxide" or "sulfinyl" refer to the portion that can be represented by the following formula:

[0077] [ka] In the formula, R 17 This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0078] The term "urea" is recognized in the art and can be represented by the following general formula.

[0079] [ka] In the formula, each R 18 , independently, represents hydrogen or hydrocarbyl, for example, alkyl, or R 18 One of these atoms, together with other atoms and intervening atoms, completes a heterocycle having 4 to 8 atoms within the ring structure.

[0080] As used herein, the definitions of each expression, such as alkyl, m, n, etc., are independent of their definitions elsewhere in the same structure if there are multiple instances of them in any structure.

[0081] The term “substituted” refers to a portion of the core skeleton having substituents that replace hydrogen on one or more carbon atoms. It will be clear that “substituted” or “substituted with” implies that such substitution is in accordance with the acceptable valencies of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” assumes to include all acceptable substituents of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. With respect to a given organic compound, there may be one or more acceptable substituents, and they may be the same or different. For the purposes of the present invention, heteroatoms such as nitrogen may have any acceptable substituents of the organic compounds described herein that satisfy the hydrogen substituent and / or the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (e.g., carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (e.g., thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, alaralkyls, or aromatic or heteroaromatic moieties. In preferred embodiments, substituents on the substituted alkyl are C 1-6 Alkyl, C 3-6The substituents are selected from cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be apparent to those skilled in the art that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as “unsubstituted,” references to chemical parts herein are understood to include substituted parts. For example, when we say “aryl” group or part, it implicitly includes both substituted and unsubstituted parts.

[0082] With regard to the present invention, the chemical elements are identified according to the periodic table of elements, CAS version, on the inside cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0083] <Example Compounds of the Invention> In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0084] [ka] During the ceremony, A is

[0085] [ka] and; B is alkylene, -alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-, or -alkylene-O-alkylene-; C is

[0086] [ka] and; R1 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; R2 is

[0087] [ka] The filename is TIFF0007829635000029.tif20166; R3 and R5 are independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R a is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl; n is independently 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0088] In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0089] [ka] During the ceremony, A is

[0090] [ka] and; B is alkylene, -alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-, or -alkylene-O-alkylene-; C is

[0091] [ka] and; R1 is H or an alkoxy; R2 is

[0092] [ka] The filename is TIFF0007829635000034.tif20166; R3 and R5 are independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R a is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl; n is independently 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0093] In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0094] [ka] During the ceremony, A is

[0095] [ka] and; B is alkylene, -alkylene-O-, or -alkylene-O-alkylene-; C is

[0096] [ka] and; R1 is H; R2 is

[0097] [ka] It is TIFF0007829635000039.tif21166; R3 and R5 are independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R a is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl; n is independently 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0098] In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0099] [ka] During the ceremony, A is

[0100] [ka] and; B is alkylene, or -alkylene-O-; C is

[0101] [ka] and; R1 is H; R2 is

[0102] [ka] It is TIFF0007829635000044.tif21166; R5 is independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R a is H; n is 0; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0103] In certain embodiments, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt of said compound.

[0104] [ka] During the ceremony, A is

[0105] [ka] and; B is

[0106] [ka] and; q is 0, 1, 2, or 3; C is

[0107] [ka] and; R1 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; R2 is

[0108] [ka] It is TIFF0007829635000050.tif19166; R5 is independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R a is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl; n is 0; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0109] In certain embodiments, the present invention is that A

[0110] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to A being

[0111] [ka] This relates to one of the aforementioned compounds.

[0112] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is alkylene. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -alkylene-(heterocyclyl)-alkylene-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -(heterocyclyl)-alkylene-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -cycloalkylene. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -alkylene-O-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -cycloalkylene-O-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is -alkylene-O-alkylene-. In some embodiments, -alkylene-O-alkylene- is -methylene-O-propylene, -ethylene-O-ethylene, or -propylene-O-methylene, and in certain embodiments, the present invention relates to any one of the aforementioned compounds. B is

[0113] [ka] A selection is made from the group consisting of , where q is 0, 1, 2, or 3; and p is 0, 1, or 2.

[0114] In some embodiments, B is

[0115] [ka] In some embodiments, B is

[0116] [ka] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0117] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is methyl; in certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is halide. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is alkoxy. In some embodiments, the alkoxy is methoxy, ethoxy, isopropyloxy, isobutyloxy, or tert-butyloxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is OH. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is alkylene-OH. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is NO2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R1 is -N(H)R a The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to any one of the aforementioned compounds in which R1 is NH2. In some embodiments, at least one case of R1 is alkyl, halide, OMe, OH, alkylene-OH, or NH2. In some embodiments, at least one case of R1 is OMe. In some embodiments, in any case of R1, it is H.

[0118] In certain embodiments, the present invention is such that R2

[0119] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0120] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0121] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0122] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0123] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0124] [ka] The present invention relates to any one of the aforementioned compounds. In certain embodiments, the present invention relates to R2

[0125] [ka] This relates to one of the aforementioned compounds.

[0126] In certain embodiments, the present invention relates to any one of the compounds, wherein n is 0. In certain embodiments, the present invention relates to any one of the compounds, wherein n is 1. In certain embodiments, the present invention relates to any one of the compounds, wherein n is 2. In certain embodiments, the present invention relates to any one of the compounds, wherein n is 3. In certain embodiments, the present invention relates to any one of the compounds, wherein n is 4.

[0127] In certain embodiments, the present invention relates to any one of the compounds in which m is 0. In certain embodiments, the present invention relates to any one of the compounds in which m is 1. In certain embodiments, the present invention relates to any one of the compounds in which m is 2. In certain embodiments, the present invention relates to any one of the compounds in which m is 3.

[0128] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is a halide. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is alkyl. In some embodiments, alkyl is methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is alkylene-alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is an aryl compound. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is a hydroxyl compound. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is an alkoxy compound. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is H, a halide, Me, OMe, or Ph.

[0129] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -C(F2)CH3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is heterocycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -O-alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -O-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -O-alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-O-alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-O-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-O-alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is selected from -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl. In some embodiments, alkylene R4 is methylene or ethylene.

[0130] In certain embodiments, the present invention is such that R4

[0131] [ka] The present invention relates to any one of the above compounds selected from TIFF0007829635000064.tif77166 and TIFF0007829635000065.tif18166. In certain embodiments, the present invention may have R4 substituted.

[0132] [ka] The present invention relates to any one of the above compounds selected from TIFF0007829635000067.tif16166. In certain embodiments, the present invention relates to R4

[0133] [ka] The present invention relates to any one of the above compounds. In certain embodiments, the present invention relates to R4

[0134] [ka] The present invention relates to any one of the above compounds. In certain embodiments, the present invention relates to R4

[0135] [ka] The present invention relates to any one of the above compounds. In certain embodiments, the present invention relates to R4

[0136] [ka] The present invention relates to any one of the above compounds. In certain embodiments, the present invention relates to R4

[0137] [ka] This relates to one of the aforementioned compounds selected from TIFF0007829635000073.tif96166.

[0138] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is H. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is a halide. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is F. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is CN. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is CF3. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is C(H)F2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is C(F)H2. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is alkyl. In some embodiments, alkyl is methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is an alkylene alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is an aryl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is a hydroxyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is an alkoxy. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R5 is H, a halide, Me, OMe, or Ph.

[0139] In certain embodiments, the present invention is R a The present invention relates to any one of the above compounds wherein is H. In certain embodiments, the present invention relates to R aThe present invention relates to any one of the above compounds, wherein is a (C1-C6)alkyl group. In some embodiments, the (C1-C6)alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In certain embodiments, the present invention relates to R a The present invention relates to any one of the above compounds, wherein is -(C1-C6)alkylene-O-(C1-C6)alkyl. In certain embodiments, the present invention relates to R a This relates to any one of the above compounds, wherein is -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl.

[0140] In certain embodiments, the present invention relates to one of the aforementioned compounds, wherein the absolute configuration at any of the stereocenters is R. In certain embodiments, the present invention relates to one of the aforementioned compounds, wherein the absolute configuration at any of the stereocenters is S. In certain embodiments, the present invention relates to one of the aforementioned compounds, wherein the absolute configuration at any of the stereocenters is a mixture of R and S.

[0141] In certain embodiments, the present invention relates to one of the aforementioned compounds, wherein the compound is a pharmaceutically acceptable salt.

[0142] In certain embodiments, the present invention

[0143] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000075.tif61166TIFF0007829635000076.tif241166TIFF0007829635000077.tif147166.

[0144] In certain embodiments, the present invention

[0145] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000079.tif66166TIFF0007829635000080.tif234166TIFF0007829635000081.tif113166.

[0146] In certain embodiments, the present invention

[0147] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000083.tif59166 and TIFF0007829635000084.tif123166.

[0148] In certain embodiments, the present invention

[0149] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000086.tif64166.

[0150] In certain embodiments, the present invention

[0151] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000088.tif22166.

[0152] In certain embodiments, the present invention

[0153] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000090.tif138166TIFF0007829635000091.tif231166TIFF0007829635000092.tif208166TIFF0007829635000093.tif112166.

[0154] In certain embodiments, the present invention relates to a compound of the following formula.

[0155] [ka]

[0156] In certain embodiments, the present invention

[0157] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000096.tif226166TIFF0007829635000097.tif225166TIFF0007829635000098.tif187166.

[0158] In certain embodiments, the present invention

[0159] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000100.tif226166TIFF0007829635000101.tif162166TIFF0007829635000102.tif95166.

[0160] In certain embodiments, the present invention

[0161] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000104.tif60166.

[0162] In certain embodiments, the present invention

[0163] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000106.tif68166.

[0164] In certain embodiments, the present invention relates to a compound of the following formula.

[0165] [ka]

[0166] In certain embodiments, the present invention relates to a compound of the following formula.

[0167] [ka]

[0168] In certain embodiments, the present invention

[0169] [ka] This relates to compounds selected from the group consisting of the following.

[0170] In certain embodiments, the present invention relates to a compound of the following formula.

[0171] [ka]

[0172] In certain embodiments, the present invention

[0173] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000112.tif50166TIFF0007829635000113.tif186166TIFF0007829635000114.tif230166TIFF0007829635000115.tif245166TIFF0007829635000116.tif197166TIFF0007829635000117.tif208166.

[0174] In certain embodiments, the present invention

[0175] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000119.tif146166 and TIFF0007829635000120.tif209166.

[0176] In certain embodiments, the present invention

[0177] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000122.tif159166TIFF0007829635000123.tif244166TIFF0007829635000124.tif223166TIFF0007829635000125.tif224166TIFF0007829635000126.tif190166.

[0178] In certain embodiments, the present invention

[0179] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000128.tif117166.

[0180] In certain embodiments, the present invention

[0181] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000130.tif208166 and TIFF0007829635000131.tif136166.

[0182] In certain embodiments, the present invention

[0183] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000133.tif59166.

[0184] In certain embodiments, the present invention

[0185] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000135.tif59166 and TIFF0007829635000136.tif137166.

[0186] In certain embodiments, the present invention

[0187] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000138.tif51166.

[0188] In certain embodiments, the present invention

[0189] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000140.tif122166.

[0190] In certain embodiments, the present invention

[0191] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000142.tif69166.

[0192] In certain embodiments, the present invention

[0193] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000144.tif52166.

[0194] In certain embodiments, the present invention

[0195] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000146.tif40166 and TIFF0007829635000147.tif75166.

[0196] In certain embodiments, the present invention

[0197] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000149.tif51166 and TIFF0007829635000150.tif215166.

[0198] In certain embodiments, the present invention

[0199] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000152.tif150166.

[0200] In certain embodiments, the present invention

[0201] [ka] This relates to compounds selected from the group consisting of the following.

[0202] In some embodiments, the present invention

[0203] [ka] This relates to compounds selected from the group consisting of TIFF0007829635000155.tif68166.

[0204] <Example pharmaceutical composition> In certain embodiments, the present invention relates to a pharmaceutical composition comprising one of the above-described compounds and a pharmaceutically acceptable carrier.

[0205] Patients, including but not limited to humans, may be treated by administering an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof to the patient in the presence of a pharmaceutically acceptable carrier or diluent. The active substance may be administered in liquid or solid form via any suitable route, e.g., orally, parenterally, intravenously, intradermally, subcutaneously, or topically.

[0206] The concentration of the active compound in a drug composition is determined by the drug's absorption, inactivation, and elimination rates, as well as other factors known to those skilled in the art. It should be noted that the dose also varies depending on the severity of the condition to be improved. Furthermore, it should be understood that for specific subjects, the specific administration method should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. The concentration ranges described herein are merely illustrative and do not limit the scope or implementation of the claimed composition. The active ingredient may be administered in a single dose or divided into several smaller doses with varying time intervals.

[0207] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions generally include an inert diluent or an edible carrier. These can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated into an excipient and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or auxiliary materials can be included as part of the composition.

[0208] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch, or lactose; disintegrants, e.g., alginic acid, Primogel, or corn starch; lubricants, e.g., magnesium stearate or Sterotes; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose or saccharin; or flavorings, e.g., peppermint, methyl salicylate, or orange flavoring. If the unit formulation is a capsule, it may contain a liquid carrier, e.g., fatty oil, in addition to the above types of materials. In addition, the unit formulation may contain various other materials that alter the physical form of the dose unit, e.g., sugar coatings, shellac, or other enteric drugs.

[0209] The compound can be administered as an ingredient in elixirs, suspensions, syrups, wafers, chewing gum, etc. In addition to the active compound, the syrup may contain sucrose or sweeteners as a sweetener, as well as certain preservatives, dyes and colorants, and flavorings.

[0210] Compounds or pharmaceutically acceptable prodrugs or salts thereof may also be mixed with other active substances that do not interfere with the desired effect, or with materials that assist the desired effect, such as antibiotics, antifungals, anti-inflammatory agents, or other antiviral agents, e.g., nucleoside compounds (but not limited to these). Liquids or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: sterile diluents, e.g., water for injection, saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetates, citrates, or phosphates; and tonicity adjusters, e.g., sodium chloride or glucose. Parental formulations may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0211] When administered intravenously, the carrier contains physiological saline and phosphate-buffered saline (PBS).

[0212] In certain embodiments, the active compound is formulated with a carrier that protects the compound from rapid elimination from the body, such as sustained-release formulations including implants and microencapsulated delivery systems (but not limited to these). Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyacid anhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. For example, enteric coating compounds can be used to protect against cleavage by gastric acid. Methods for preparing such formulations are obvious to those skilled in the art. Suitable materials can also be commercially available.

[0213] Liposome suspensions (including, but not limited to, liposomes that have monoclonal antibodies against viral antigens and target infected cells) 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, a liposome formulation can be prepared by dissolving a suitable lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, then distilling off the solvent, leaving a dry lipid film on the surface of a container. Next, an aqueous solution of the active compound is introduced into the container. Then, the container is manually swirled to remove the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0214] <Exemplary Method of the Invention> In certain embodiments, the present invention relates to a method for treating a disease or condition selected from the group consisting of idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological malignancies, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, comprising administering a therapeutically effective amount of any one of the above compounds to a person in need of treatment.

[0215] In certain embodiments, the present invention relates to any one of the above methods, wherein the disease or condition is a solid tumor (sarcoma, carcinoma, and lymphoma). Exemplary tumors that can be treated according to the present invention include, for example, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, myelosarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, adenoma of the colon and rectum, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal cancer, gastric cancer, gastric cancer, glial cell tumors (e.g., adult, pediatric brainstem, pediatric brain astrocytoma, pediatric visual tract and hypothalamus), glioblastoma, endometrial cancer M, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body, cervical cancer of the uterus, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, brain cancer (e.g., brainstem glial cell tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant gliomas, ependymal cell tumor, medulloblastoma, supratentorial primitive neuroectodermal tumor, glial cell tumor of the visual tract and hypothalamus), lips and oral cavity and pharynx, larynx, small intestine, melanoma, chorionic colon adenoma, neoplasms, epithelial neoplasms, lymphoma (e.g., AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma and primary central nervous system lymphoma), breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratometriosis, tumor diseases including solid tumors, tumors of the neck or head, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenström macroglobulinemia, adrenal cortical carcinoma, cancers associated with AIDS, pediatric cerebellar astrocytoma, basal cell carcinoma, extrahepatic cholangiocarcinoma, malignant fibrous histiocytoma, bone cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, primary central nervous system Nervous system, cerebellar astrocytoma, childhood cancer, ependymal cell tumor, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal carcinoid tumor, germ cell tumor (e.g., extracranial, extragonadal, and ovarian), gestational trophoblastoma, hepatocellular carcinoma, hypopharyngeal cancer, glial cell tumor of the hypothalamus and visual tract, islet cell carcinoma (endocrine pancreas), laryngeal cancer, malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma, mesothelioma, metastatic cervical squamous cell carcinoma of unknown primary origin, prediabetes, multiple myeloma / plasmacytic neoplasm, mycosis fungoides,These include nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian epithelial cancer, ovarian germ cell tumor, low-grade ovarian tumor, islet cell pancreatic cancer, parathyroid cancer, pheochromocytoma, pineal gland tumor, pituitary tumor, pleuropulmonary blastoma, ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sézary syndrome, non-melanoma skin cancer, Merkel cell carcinoma, squamous cell carcinoma, testicular cancer, thymoma, gestational trophoblastoma, and Wilms' tumor.

[0216] In certain embodiments, the present invention relates to any one of the above methods, wherein the disease or condition is a hematological malignancy. Exemplary hematological malignancies that can be treated according to the present invention include, for example, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma.

[0217] In certain embodiments, the present invention relates to one of the above methods, wherein the disease or condition is selected from the group consisting of idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with myositis, interstitial lung disease associated with systemic lupus erythematosus, rheumatoid arthritis, and related interstitial lung diseases.

[0218] In certain embodiments, the present invention relates to one of the above methods, wherein the disease or condition is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, and chronic kidney disease.

[0219] In certain embodiments, the present invention relates to one of the above methods, wherein the disease or condition is selected from the group consisting of non-alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis.

[0220] In certain embodiments, the present invention relates to any one of the above methods, wherein the subject is a mammal. In certain embodiments, the present invention relates to any one of the above methods, wherein the subject is a human.

[0221] <Another Numeric Embodiment>

[0222] 1. A compound of the following formula (I) or a pharmaceutically acceptable salt of said compound.

[0223] [ka] During the ceremony, A is

[0224] [ka] and; B is alkylene, -alkylene-(heterocyclyl)-alkylene-, -(heterocyclyl)-alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-, or -alkylene-O-alkylene-; C is

[0225] [ka] and; R1 can be independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, or -N(H)R a and; R2 is

[0226] [ka] The filename is TIFF0007829635000160.tif20166; R3 and R5 are independently selected from H, -CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; Ra is H, (C1-C6)alkyl, -(C1-C6)alkylene-O-(C1-C6)alkyl, or -(C1-C6)alkylene-OC(O)O(C1-C6)alkyl; n is independently 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

[0227] 2.B is,

[0228] [ka] Selected from the group consisting of; q is 0, 1, 2, or 3; The compound of Embodiment 1, wherein p is 0, 1, or 2.

[0229] 3. The compound of Embodiment 1, wherein B is -alkylene-O-alkylene-.

[0230] 4. The compound of Embodiment 3, wherein the alkylene-O-alkylene is methylene-O-propylene, ethylene-O-ethylene, or propylene-O-methylene.

[0231] 5. Any one of the compounds from Embodiments 1 to 4, wherein at least one of R1 is alkyl, halide, OMe, OH, alkylene-OH, or NH2.

[0232] 6. The compound of Embodiment 5, wherein at least one of the R1 is OMe.

[0233] 7. Any one of the compounds from Embodiments 1 to 4, wherein R1 is H in all cases.

[0234] 8. R2

[0235] [ka] A compound which is any one of embodiments 1 to 7.

[0236] 9. The compound of Embodiment 8, wherein n in R2 is 0.

[0237] 10. The compound of Embodiment 8, wherein n in R2 is 1.

[0238] 11. R2

[0239] [ka] A compound which is any one of embodiments 1 to 7.

[0240] 12. The compound of Embodiment 11, wherein m in R2 is 0.

[0241] 13. The compound of Embodiment 11, wherein m in R2 is 1.

[0242] 14. Compounds of Embodiments 1, 8, 10, 11, or 13, wherein R5 is F.

[0243] 15. Compounds of Embodiments 1, 8, 10, 11, or 13, wherein R5 is CN.

[0244] 16. R2

[0245] [ka] A compound which is any one of embodiments 1 to 7.

[0246] 17. Any one of the compounds from Embodiments 1 to 16, wherein the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0247] 18. Any one of the compounds from Embodiments 1 to 16, wherein the alkyl group is methyl, ethyl, isopropyl, or tert-butyl.

[0248] 19. A compound from any one of Embodiments 1 to 18, wherein R3 is H, halide, Me, OMe, or Ph.

[0249] 20. A compound from any one of Embodiments 1 to 19, wherein R4 is independently selected from -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl.

[0250] 21. The compound of Embodiment 20, wherein the alkylene in R4 is methylene or ethylene.

[0251] 22.R4

[0252] [ka] A compound selected from TIFF0007829635000166.tif112166, any one of embodiments 1 to 19.

[0253] 23.R4

[0254] [ka] A compound selected from TIFF0007829635000168.tif98166, any one of embodiments 1 to 19.

[0255] 24.R a A compound from any one of embodiments 1 to 23, wherein the compound is H.

[0256] <Example> Although the present invention is generally described herein, it will be more readily understood by referring to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0257] <General diagram and procedure for the production of the compound of the present invention> Parts R1 and R2 represent appropriate substituents; L represents an appropriate linking group; and X represents an appropriate halogen, such as Br, Cl, or I, or another leaving group, such as a mesylate or tosylate.

[0258] [ka] This represents pyrrolidine, which may be appropriately substituted.

[0259] [ka] This represents tetrahydronaphthiridine, which may be appropriately substituted.

[0260] [ka] This represents naphthyridine, which may be appropriately substituted.

[0261] <General diagram for the synthesis of αvβ6 inhibitors>

[0262] [ka]

[0263] <General Procedure> 9-BBN and Suzuki reaction

[0264] [ka]

[0265] Alkene intermediates can be cross-coupled to 2-halonaphthiridine or tetrahydronaphthiridine by the following procedure: Alkene (1 equivalent) in anhydrous THF (2-10 mL / mmol) under Ar was mixed with 9-BBN (0.5 M THF solution, 1-2 equivalents). The reaction mixture was stirred at 40-80°C for 1-4 hours, then cooled to room temperature. This solution was added to a mixture of 2-halonaphthiridine or Boc-protected 2-halotetrahydronaphthiridine (1-1.5 equivalents), cesium carbonate (2-5 equivalents), and Pd(PPh3)4 or another suitable Pd / ligand combination (0.05-0.1 equivalents) in 1,4-dioxane (2-10 mL / mmol). The reaction mixture was stirred at 80-100°C for 12-24 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the alkyl-linked naphthyridine product.

[0266] Transatlantic reaction

[0267] [ka]

[0268] Naphthyrizines can also be prepared from methyl ketones by the following procedure: A mixture of methyl ketone (1 equivalent), 2-aminonicotinaldehyde (1-2 equivalents), and a secondary amine, such as pyrrolidine or L-proline (1-2 equivalents), in DMF or EtOH (1-10 mL / mmol) was stirred at 70-100°C for 2-10 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column to obtain the desired naphthyrizine product.

[0269] Naphthyridine reduction

[0270] [ka]

[0271] Naphthyrizines can be reduced to tetrahydronaphthyrizines by the following procedure. A mixture of appropriate naphthyrizine (1 equivalent) and Pd / C (5-20% Pd, 0.05-0.2 equivalents) in ethyl acetate or another suitable solvent (2-10 mL / mmol) was stirred under an H2 balloon at room temperature to 50°C for 2-20 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the desired tetrahydronaphthyrizine product.

[0272] Boc deprotection

[0273] [ka]

[0274] Boc-protected amine (1 equivalent) was treated with HCl (4-100 equivalents) / 1,4-dioxane (1-50 mL / mmol amine) for 1-4 hours at room temperature to 50°C. The reaction mixture was concentrated under reduced pressure, and the amine product was used either as the crude product or after purification by silica gel column. The amine could be used as the crude dihydrochloride salt, or it could be converted to a free base by dissolving it in a suitable solvent and washing with an aqueous NaHCO3 solution.

[0275] Amine alkylation

[0276] [ka]

[0277] A mixture of amine (1 equivalent), alkylating agent (1-1.5 equivalents), and K2CO3 or N,N-diisopropylethylamine (2-10 equivalents) in MeCN or DMF (3-10 mL / mmol amine) was stirred at room temperature to 80°C for 4-16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain the desired aminoacetic acid ester. The amine used can be a free base or a salt such as a hydrochloride or dihydrochloride. When using a salt of the amine in the reaction, an additional equivalent of base may be required.

[0278] Kenka

[0279] [ka]

[0280] In the case of R1=Me or certain esters such as ethyl, the ester can be saponified under basic conditions. One equivalent of the ester was treated with LiOH-H2O (3-5 equivalents) / MeOH (3-10 mL / mmol ester) and water (3-10 mL / mmol ester) at room temperature to 50°C for 1-16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired carboxylic acid product.

[0281] In the case of certain esters, such as R1=tert-butyl, the ester can be saponified under acidic conditions. One equivalent of the ester was treated with 4N HCl (4-100 equivalents) / 1,4-dioxane (1-25 mL / mmol ester) at room temperature to 50°C for 1-16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired carboxylic acid product.

[0282] Petasis reaction

[0283] [ka]

[0284] As an alternative to amine alkylation / saponification procedures, certain aryl analogs can be produced using the petasis reaction. A mixture of amine (1 equivalent), arylboronic acid or arylboronic acid ester (1-1.5 equivalents), and 2-oxoacetic acid (1.5-2 equivalents) in MeCN or DMF (2-10 mL / mmol amine) was stirred at 50-80°C for 2-16 hours. The reaction product was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the desired aminoacetic acid.

[0285] <Analysis method> Preparative HPLC method The crude sample was dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument with a detection wavelength of 214 nm.

[0286] 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.

[0287] 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.

[0288] Preparative HPLC C: Column: XBridge OBD C18, 19×100 mm, 5 μm; Mobile phase: A Water, B CH3CN; Gradient elution as described in the text; Flow rate: 20 mL / min.

[0289] Preparative Chiral SFC Method Using an SFC-80 (Thar, Waters) instrument and a detection wavelength of 214 nm, the racemic product was separated into individual enantiomers by chiral preparative SFC.

[0290] Preparative chiral SFC A: Column: (R,R)-Whelk-O1, 20×250mm, 5μm (Decial), Column temperature: 35℃, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80g / min, Back pressure: 100bar.

[0291] Preparative chiral SFC B: Column: AD 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / methanol (0.2% m methanol ammonia) = 60 / 40, Flow rate: 80g / min, Back pressure: 100bar.

[0292] Preparative chiral SFC C: Column: AS 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80g, Back pressure: 100bar.

[0293] Preparative chiral SFC D: Column: OD20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80 g / min, Back pressure: 100 bar.

[0294] Preparative chiral SFC E: Column: Cellulose-SC20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80g / min, Back pressure: 100bar.

[0295] Preparative chiral SFC F: Column: 20 oz x 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80 g / min, Back pressure: 100 bar.

[0296] Preparative chiral SFC G: Column: IC20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80 g / min, Back pressure: 100 bar.

[0297] Preparative chiral SFC H: Column: (S,S)-Whelk-O1, 20×250mm, 5μm (Decial), Column temperature: 35℃, Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, Flow rate: 80g / min, Back pressure: 100bar.

[0298] Analytical Chiral SFC Method Chiral products were analyzed using a chiral SFC with an SFC-80 (Thar, Waters) instrument and a detection wavelength of 214 nm.

[0299] 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), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0300] Chiral SFC B: Column: AD 4.6×100mm, 5μm (Daicel), Column temperature: 40℃, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4g / min, Back pressure: 120bar.

[0301] Chiral SFC C: Column: AS 4.6 × 100 mm, 5 μm (Daicel), Column temperature: 40°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0302] Chiral SFC D: Column: OD 4.6 × 100 mm, 5 μm (Daicel), Column temperature: 40°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0303] Chiral SFC E: Column: Cellulose-SC 4.6 × 100 mm, 5 μm (Daicel), Column temperature: 40°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0304] Chiral SFC F: Column: 4.6 x 100 mm OZ, 5 μm (Daicel), Column temperature: 40°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0305] Chiral SFC G: Column: IC 4.6 × 100 mm, 5 μm (Daicel), Column temperature: 40°C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Fixed composition elution as described in the text, Flow rate: 4 g / min, Back pressure: 120 bar.

[0306] Chiral SFC H column: (S,S)-Whelk-O1, 4.6 × 100 mm, 5 μm (Decial), column temperature: 40°C, mobile phase: CO2 / methanol (0.2% methanol ammonia), fixed composition elution as described in the text, flow rate: 4 g / min, back pressure: 120 bar.

[0307] Chiral SFC I: Column: IC 4.6 × 250 mm, 5 μm (SHIMADZU), Column temperature: 40°C, Mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), Fixed composition elution as described in the text, Flow rate: 1 mL / min.

[0308] Chiral SFC J: Column: (S,S)-Whelk-O1 4.6×250mm, 5μm (SHIMADZU), Column temperature: 40℃, Mobile phase: n-hexane (0.1%DEA):EtOH (0.1%DEA), Fixed composition elution as described in the text, Flow rate: 1mL / min.

[0309] Chiral SFC K: Column: OZ-H 4.6 × 250 mm, 5 μm (SHIMADZU), Column temperature: 40°C, Mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), Fixed composition elution as described in the text, Flow rate: 1 mL / min.

[0310] Chiral SFC L: Column: Chiral PAK IG 4.6×250mm, 5μm (SHIMADZU), Column temperature: 35℃, Mobile phase: n-hexane (0.1%DEA):EtOH (0.1%DEA), Fixed composition elution as described in the text, Flow rate: 1mL / min.

[0311] Chiral SFC M: Column: EnantioPak OJ 4.6×250mm, 5μm (Decial), Column temperature: 40℃, Mobile phase: n-hexane (0.1%DEA):EtOH (0.1%DEA), Fixed composition elution as described in the text, Flow rate: 1mL / min.

[0312] <Synthesis of intermediates> For use in the synthesis example, the following intermediates were prepared according to the following procedure.

[0313] Manufacturing of (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride Step 1: tert-butyl(R)-3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate

[0314] [ka]

[0315] A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.09 g, 5.41 mmol), 2-(4-bromobutyl)-2-methyl-1,3-dioxolane (1.2 g, 5.41 mmol), and sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at 100°C for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 10:1) to obtain the desired product (R)-tert-butyl 3-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil (380 mg). Yield 21% (ESI 330.2 (M+H) + ).

[0316] Step 2: (R)-tert-butyl 3-(5-oxohexyloxy)pyrrolidine-1-carboxylate

[0317] [ka]

[0318] (R)-tert-butyl 3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate (1.3 g, 3.95 mmol) was treated with HCl / dioxane solution (4.0 M, 10 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with acetone (10 mL) and H2O (1 mL). Potassium carbonate was added to adjust the pH to 8-9, and then Boc2O (1.24 g, 5.69 mmol) was added. The reaction mixture was stirred at room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: HCl 15:1) to obtain the desired product (R)-tert-butyl 3-(5-oxohexyloxy)pyrrolidine-1-carboxylate as a colorless oil (820 mg). Yield 73% (ESI 186(M-100)). + , 230 (M-56) + ).

[0319] Step 3: (R)-tert-butyl3-(4-(1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate

[0320] [ka]

[0321] A mixture of (R)-tert-butyl 3-(5-oxohexyloxy)pyrrolidine-1-carboxylate (820 mg, 2.88 mmol), 2-aminonicotinaldehyde (456 mg, 3.77 mmol), and pyrrolidine (265 mg, 3.77 mmol) in DMF (5 mL) was stirred at 85°C for 4 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 15:1) to obtain the desired product (R)-tert-butyl 3-(4-(1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil (750 mg). Yield 70% (ESI 372.2 (M+H)). + ).

[0322] Stage 4: (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride

[0323] [ka]

[0324] A mixture of (R)-tert-butyl 3-(4-(1,8-naphthiridine-2-yl)butoxy)pyrrolidine-1-carboxylate (750 mg, 2.02 mmol) and Pd / C (10%, 500 mg) in siRNA (10 mL) was stirred under hydrogen at 60°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was treated with a solution of HCl / dioxane (4.0 M, 4 mL) at room temperature for 2 hours, and the solvent was removed under reduced pressure to obtain the desired product, (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine 2-hydrochloride (600 mg), as a white solid. Yield 96% (ESI 276.2 (M+H)). + ).

[0325] Manufacturing of (R)-5-methoxy-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyrizine dihydrochloride Step 1: (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-1-carboxylate

[0326] [ka]

[0327] To a solution of tert-butyl(R)-3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in n-heptane (10 mL), 50% aqueous sodium hydroxide solution (5 mL, 31.2 mmol), tetrabutylammonium bromide (43.0 mg, 0.13 mmol), and 1,4-dibromobutane (1.595 mL, 13.35 mmol) were added. The mixture was stirred at 80°C for 2 hours, then cooled to room temperature, diluted with water (10 mL), and extracted with diethyl ether (three times with 10 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA = 4:1) to obtain the desired product (R)-tert-butyl3-(4-bromobutoxy)pyrrolidine-1-carboxylate as a colorless oil (686 mg). Yield 80% (ESI 314(M+H-Boc)) + ).

[0328] Stage 2: (R)-tert-butyl 3-(buta-3-enyloxy)pyrrolidine-1-carboxylate

[0329] [ka]

[0330] To a solution of tert-butyl(R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylate (512 mg, 1.58 mmol) in THF (10 mL), t-BuOK (446 mg, 3.97 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (20 mL), and extracted with diethyl ether (three times with 20 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product (R)-tert-butyl3-(buta-3-enyloxy)pyrrolidine-1-carboxylate as a colorless oil (355 mg). Yield 90% (ESI 186(M+H-Boc)). + ).

[0331] Step 3: (R)-tert-butyl3-(4-(4-chloro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate

[0332] [ka]

[0333] To a solution of tert-butyl(R)-tert-butyl 3-(buta-3-enyloxy)pyrrolidine-1-carboxylate (486 mg, 1.8 mmol) in THF (anhydrous, 2 mL), 9-BBN (0.5 M THF solution, 7.2 mL, 3.6 mmol) was added under Ar. The reaction mixture was stirred at 50°C for 2 hours and then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-1,8-naphthyridine (360 mg, 1.8 mmol), cesium carbonate (1730 mg, 5.4 mmol), and Pd(PPh3)4 (208 mg, 0.18 mmol) in 1,4-dioxane (7 mL). The reaction mixture was stirred at 90°C for 1.5 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ELISA 1:1 to 1:10) to obtain the desired product (R)-tert-butyl 3-(4-(4-chloro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate as a yellow oil (300 mg). Yield 41% (ESI 406(M+H) + ).

[0334] Stage 4: (R)-tert-butyl3-(4-(4-methoxy-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate

[0335] [ka]

[0336] A solution of (R)-tert-butyl 3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (76 mg, 0.13 mmol) in MeOH (5 mL) was added to NaOMe (45 mg, 0.26 mmol). The reaction mixture was stirred under reflux overnight, concentrated under reduced pressure, diluted with ethyl acetate (30 mL), washed with water (twice with 20 mL), dehydrated with MgSO4, filtered, and concentrated under reduced pressure to obtain the desired product (R)-tert-butyl 3-(4-(4-methoxy-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil (60 mg). Yield 80% (ESI 402 (M+H) + ).

[0337] Step 5: (R)-5-Methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride

[0338]

Chemical formula

[0339] A mixture of (R)-tert-butyl 3-(4-(4-methoxy-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (60 mg, 0.15 mmol) and Pd / C (10%, 30 mg) in EtOAc (10 mL) was stirred at 30 °C for 17 h under balloon hydrogen. The mixture was filtered and concentrated under reduced pressure. The residue was treated with 4M HCl / dioxane (3 mL, 12 mmol) at room temperature for 2 h. The solvent was removed under reduced pressure to obtain the desired product (R)-5-methoxy-7-(4-(pyrrolidin-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride as a colorless oil (45 mg). Yield 88% (ESI 306 (M+H) + ).

[0340] Preparation of (R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride Step 1: (R)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate

[0341] [ka]

[0342] A solution of PPh3 (5.11 g, 19.5 mmol) and 1H-imidazole (1.33 g, 19.5 mmol) in DCM (50 mL) was cooled to 0°C and slowly treated with I2 (4.95 g, 19.5 mmol). After stirring at 0°C for 30 minutes, a solution of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate in DCM (10 mL) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with DCM (three times with 30 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and removed under reduced pressure. The residue was purified by silica gel column (petroleum ether: Depositphotos 10:1) to obtain the desired product (R)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate as a colorless oil (3.7 g). Yield 80%. (ESI 256(M+H-56) + ).

[0343] Stage 2: (R)-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium

[0344] [ka]

[0345] A solution of (R)-tert-butyl 3-(iodomethyl)pyrrolidine-1-carboxylate (3.7 g, 12 mmol) and PPh3 (4.1 g, 15.5 mmol) in DMF (50 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 10:1) to obtain the crude product. Diethyl ether (30 mL) was added to the crude product, and the mixture was stirred at room temperature for 30 minutes and filtered. The filter cake was vacuum-dried to obtain the desired product, (R)-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium, as a white solid (5.6 g). Yield 84%. (ESI N / A).

[0346] Step 3: Ethyl 4-(2-methyl-1,3-dioxolan-2-yl)butanoate

[0347] [ka]

[0348] A solution of ethyl 5-oxohexanoate (2 g, 13.9 mmol), ethylene glycol (2.6 g, 42 mmol), and p-toluenesulfonic acid (478 mg, 2.78 mmol) in toluene (50 mL) was stirred under reflux for 6 hours, and water was removed by a Dean-Stark trap. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO₂ 10:1) to obtain the desired product, ethyl 4-(2-methyl-1,3-dioxolan-2-yl)butanoate, as a colorless oil (1.4 g, yield 50%). (ESI 203(M+H)) + ).

[0349] Stage 4: 4-(2-methyl-1,3-dioxolan-2-yl)butanal

[0350] [ka]

[0351] To a solution of ethyl 4-(2-methyl-1,3-dioxolan-2-yl)butanoate (500 mg, 2.48 mmol) in DCM (10 mL), DIBAL-H (1 M, 3.7 mL, 3.7 mmol) was slowly added under Ar at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, 20 mL of water was added, and the temperature was raised to room temperature. Extraction was performed using DCM (three times with 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA 2:1) to obtain the desired product, 4-(2-methyl-1,3-dioxolan-2-yl)butanal, as a colorless oil (220 mg). Yield 56%. (ESI 159(M+H)) + ).

[0352] Stage 5: (S)-tert-butyl3-(5-(2-methyl-1,3-dioxolan-2-yl)penta-1-enyl)pyrrolidine-1-carboxylate

[0353] [ka]

[0354] (R)-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium (2.0 g, 3.6 mmol) was dissolved in DCM (30 mL) and LiHMDS (1 M, 5.4 mL, 5.4 mmol) was added under N2 at 0°C. The mixture was stirred at 0°C for 30 minutes and 4-(2-methyl-1,3-dioxolan-2-yl)butanal (565 mg, 3.6 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and MeOH (20 mL) was added. The solvent was removed under reduced pressure and the residue was purified by silica gel column (petroleum ether: Â1 3:1) to obtain the desired product (S)-tert-butyl3-(5-(2-methyl-1,3-dioxolan-2-yl)penta-1-enyl)pyrrolidine-1-carboxylate as a yellow oil (500 mg). Yield 43%. (ESI 226(M+H-100) + ).

[0355] Stage 6: (R)-tert-butyl 3-(6-oxoheptyl)pyrrolidine-1-carboxylate

[0356] [ka]

[0357] (S)-tert-butyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)penta-1-enyl)pyrrolidine-1-carboxylate (500 mg, 1.54 mmol) was dissolved in ethyl acetate (20 mL), to which Pd / C (10%, 50 mg) was added, and the mixture was stirred overnight at 40°C under H2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was treated with TsOH (264 mg, 1.54 mmol) / acetone (5 mL). The mixture was stirred at room temperature for 6 hours, ethyl acetate (20 mL) was added, and it was washed with saturated NaHCO3 solution (20 mL) and brine. The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product (R)-tert-butyl 3-(6-oxoheptyl)pyrrolidine-1-carboxylate as a yellow oil (200 mg). Yield 46% (ESI 184(M+H-100)) + ).

[0358] Step 7: (R)-tert-butyl3-(5-(1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-carboxylate

[0359] [ka]

[0360] (R)-tert-Butyl 3-(6-oxoheptyl)pyrrolidine-1-carboxylate (300 mg, 1.06 mmol) in EtOH (10 mL) was added 2-aminonicotinaldehyde (155 mg, 1.27 mmol) and pyrrolidine (90 mg, 1.27 mmol). The reaction mixture was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column (DCM:MeOH = 20:1) to give the desired product (R)-tert-butyl 3-(5-(1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate as a yellow oil (220 mg). Yield 56%. (ESI 370 (M+H) + ).

[0361] Step 8: (R)-7-(5-(Pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride

[0362] [Chemical formula]

[0363] (R)-tert-Butyl 3-(5-(1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate (220 mg, 0.60 mmol) in EtOAc (10 mL) was added Pd / C (10%, 30 mg). The mixture was stirred at 40 °C overnight under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with HCl / dioxane solution (4.0 M, 5 mL) at room temperature for 2 h and the solvent was removed under reduced pressure to give the desired product (R)-7-(5-(pyrrolidin-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride as a yellow oil (160 mg). Yield 86%. (ESI 274 (M+H) + ).

[0364] Preparation of (R)-7-(3-(pyrrolidin-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyridine 2 hydrochloride Step 1: 2-(3-Bromopropyl)-2-methyl-1,3-dioxolane

[0365] [ka]

[0366] A solution of 5-bromopentan-2-one (2.0 g, 12.12 mmol) in toluene (40 mL) was treated with ethylene glycol (6.93 g, 111.7 mmol) and TsOH (384 mg, 0.22 mmol) under N2 in a flame-dried round-bottom flask fitted with a magnetic stirring bar and a Dean-Stark trap. The reaction mixture was heated under reflux for 1 hour, allowed to cool to room temperature, diluted with saturated NaHCO3 aqueous solution (60 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (twice with 100 mL), dehydrated with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: SiO 4:1) to obtain the desired product as a colorless oil (1.5 g). Yield 59%.

[0367] Step 2: (R)-tert-butyl3-(3-(2-methyl-1,3-dioxolan-2-yl)propoxy)pyrrolidine-1-carboxylate

[0368] [ka]

[0369] A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (894 mg, 4.78 mmol) and NaH (287 mg, 7.18 mmol) in DMF (10 mL) was stirred at 0°C for 1 hour. A solution of 2-(3-bromopropyl)-2-methyl-1,3-dioxolane (1 g, 4.78 mmol) in DMF (5 mL) was added dropwise at 0°C, and the reaction mixture was stirred overnight at 100°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 1:1) to obtain the desired product as a colorless oil (500 mg). Yield 33% (ESI 216(M+H-100)). + ).

[0370] Step 3: (R)-tert-butyl 3-(4-oxopentyloxy)pyrrolidine-1-carboxylate

[0371] [ka]

[0372] (R)-tert-butyl 3-(3-(2-methyl-1,3-dioxolan-2-yl)propoxy)pyrrolidine-1-carboxylate (500 mg, 1.59 mmol) and p-toluenesulfonic acid monohydrate (151 mg, 0.79 mmol) were mixed in acetone (10 mL) and H2O (5 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (three times with 10 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired product as a colorless oil (380 mg). Yield 88% (ESI 172(M+H-100)). + ).

[0373] Stage 4: (R)-tert-butyl3-(3-(1,8-naphthyrizin-2-yl)propoxy)pyrrolidine-1-carboxylate

[0374] [ka]

[0375] A mixture of (R)-tert-butyl 3-(4-oxopentyloxy)pyrrolidine-1-carboxylate (380 mg, 1.40 mmol), 2-aminonicotinaldehyde (171 mg, 1.40 mmol), and pyrrolidine (99 mg, 1.40 mmol) in ethanol (8 mL) was refluxed overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 40:1) to obtain the desired product as a colorless oil (310 mg). Yield 62% (ESI 358(M+H) + ).

[0376] Stage 5: (R)-7-(3-(pyrrolidine-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride

[0377] [ka]

[0378] A mixture of (R)-tert-butyl 3-(3-(1,8-naphthiridine-2-yl)propoxy)pyrrolidine-1-carboxylate (310 mg, 0.87 mmol) and Pd / C (10%, 30 mg) in ELISA (30 mL) was stirred at room temperature for 16 hours under balloon hydrogen. The mixture was filtered and concentrated under reduced pressure. The residue was treated with HCl / 1,4-dioxane (4 M, 5 mL) at 25 °C for 2 hours. The solvent was removed under reduced pressure to obtain (R)-7-(3-(pyrrolidine-3-yloxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthiridine 2-hydrochloride as a colorless oil (240 mg). Yield 83% (ESI 262(M+H) + ).

[0379] Manufacturing of (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride Stage 1: 2-(5-bromopentyl)-2-methyl-1,3-dioxolane

[0380] [ka]

[0381] In a three-necked flask fitted with a Dean-Stark trap, 14 g, 73 mmol of 7-bromoheptan-2-one was dissolved in toluene (150 mL), to which ethane-1,2-diol (15 g, 255 mmol) and p-toluenesulfonic acid (251 mg, 1.46 mmol) were added. The reaction mixture was stirred under reflux for 20 hours. The reaction mixture was cooled to room temperature and washed with saturated NaHCO3 solution, water, and brine. The organic phase was concentrated, and the residue was separated by silica gel column (7% siRNA / petroleum ether) to obtain 2-(5-bromopentyl)-2-methyl-1,3-dioxolane (16 g, 92%).

[0382] Step 2: (R)-tert-butyl3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate

[0383] [ka]

[0384] (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.5 g, 18.7 mmol) was dissolved in DMF (25 mL) and NaH (830 mg, 20.6 mmol) was added in small increments at 0°C. The reaction mixture was stirred at 0°C for 1 hour. 2-(5-bromopentyl)-2-methyl-1,3-dioxolane (4.9 g, 20.6 mmol) was added, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was placed in ice water and extracted with ethyl acetate (three times with 150 mL). The combined organic phase was washed with brine and dehydrated with Na₂SO₄. The organic phase was concentrated, and the residue was chromatographically purified with silica gel (20% siRNA / petroleum ether) to obtain the product (R)-tert-butyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate as a yellow oil (3.7g, 57%); (ESI 344.3(M+H) + ).

[0385] Stage 3: (R)-tert-butyl 3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate

[0386] [ka]

[0387] (R)-tert-butyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate (3.7 g, 10.8 mmol) was dissolved in acetone (70 mL) and water (7 mL), to which p-toluenesulfonic acid (927 mg, 5.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution and concentrated under reduced pressure. The residue was extracted with ELISA (three times at 100 mL). The combined organic phases were washed with brine, dehydrated with Na2SO4, and concentrated to obtain the product (R)-tert-butyl 3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate as a yellow oil (2.99 g, 92%); (ESI 300.1(M+H) + ).

[0388] Stage 4: (R)-tert-butyl3-(5-(1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate

[0389] [ka]

[0390] (R)-tert-butyl 3-(6-oxoheptyloxy)pyrrolidine-1-carboxylate (2.9 g, 9.7 mmol) was dissolved in EtOH (40 mL), to which 2-aminonicotinaldehyde (1.2 g, 9.7 mmol) and L-proline (558 mg, 4.8 mmol) were added. The reaction mixture was stirred under reflux for 16 hours. Next, the reaction mixture was concentrated, and the residue was separated by silica gel column (5% MeOH / SiO2) to obtain (R)-tert-butyl 3-(5-(1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate as a yellow solid (2.4 g, 64%); (purity 95%, UV=214 nm, ESI 386.0 (M+H)). + ).

[0391] Step 5: (R)-tert-butyl3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate

[0392] [ka]

[0393] (R)-tert-butyl 3-(5-(1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate (2.4 g, 6.2 mmol) was dissolved in EtOH (30 mL) and Pd / C (10%, 300 mg) was added. The reaction mixture was degassed and purged with H2 three times, and stirred under H2 at 45°C for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain (R)-tert-butyl 3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate as a yellow oil (2.5 g, 100%); (ESI 390.5(M+H) + ).

[0394] Stage 6: (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine 2-hydrochloride

[0395] [ka]

[0396] (R)-tert-butyl3-(5-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)pentyloxy)pyrrolidine-1-carboxylate (2.4 g, 6.2 mmol) was dissolved in DCM (10 mL) and HCl / 1,4-dioxane (4 mol / L, 30 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthiridine 2-hydrochloride as a yellow oil (2.9 g, 100%); (ESI 290.4(M-55) + ).

[0397] Preparation of 7-(5-(3-fluoropyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride Step 1: tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate

[0398] [ka]

[0399] To a mixture of ((4-bromobutoxy)methyl)benzene (9.45 g, 38.87 mmol) and Mg (1.89 g, 77.74 mmol) in Et2O (20 mL), I2 (202 mg, 1.09 mmol) was added. The reaction mixture was stirred at 40 °C for 1 hour. After cooling to room temperature, the mixture was added at 5 °C to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.4 g, 12.96 mmol) in Et2O (30 mL). The reaction mixture was stirred overnight at room temperature, the reaction was stopped with aqueous NH4Cl (10 mL), and the mixture was extracted with ELISA (three times with 30 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: siRNA 5:1 to 2:1) to obtain the desired product, tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate, as a yellow oil (1.7 g). Yield 38% (ESI 294(M+H-56)). + ).

[0400] Step 2: tert-butyl 3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate

[0401] [ka]

[0402] A mixture of tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate AS (1.7 g, 4.86 mmol) and BAST (10.76 g, 48.6 mmol) in DCM (30 mL) was stirred at 40°C for 24 hours. The reaction mixture was diluted with MeOH (2 mL), washed with water (20 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ELISA 20:1 to 10:1) to obtain the desired product, tert-butyl 3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate, as a bright yellow oil (1.1 g). Yield 64% (ESI 296(M+H-56)). + ).

[0403] Stage 3: (tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate)

[0404] [ka]

[0405] A mixture of tert-butyl 3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate (1.1 g, 3.13 mmol) and Pd / C (5%, 1.1 g) in toluene (100 mL) was stirred overnight at 45°C under hydrogen. The mixture was filtered and concentrated under reduced pressure to obtain the desired product, tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate, as a bright yellow oil (780 mg). Yield 95% (ESI 206(M+H-56)). + ).

[0406] Stage 4: tert-butyl 3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate

[0407] [ka]

[0408] To a solution of triphenylphosphine (1.58 g, 6.04 mmol) and imidazole (411 mg, 6.04 mmol) in DCM (40 mL), I2 (835 mg, 3.29 mmol) was added at 5°C. The reaction mixture was stirred at 5°C for 15 minutes, and a solution of (tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate) in DCM (15 mL) was added. The reaction mixture was stirred at 5°C for 1 hour, concentrated under reduced pressure at 15°C, and the residue was purified by silica gel column (petroleum ether: Â1 20:1 to 10:1) to obtain the desired product, tert-butyl 3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate, as a bright yellow oil (700 mg). Yield 63% (ESI 316(M+H-56) + ).

[0409] Stage 5: tert-butyl 3-(5-(1,8-naphthyridine-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate

[0410] [ka]

[0411] (R)-tert-butyl 3-(1,1-difluoro-4-iodobutyl)pyrrolidine-1-carboxylate (700 mg, 1.88 mmol) and 2-methyl-1,8-naphthiridine (407 mg, 2.82 mmol) were dissolved in THF (12 mL) and LiHMDS (2.82 mL, 1 M, 2.82 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 3 hours, stopped with saturated ammonium chloride solution (6 mL), diluted with water (15 mL), and extracted with ethyl acetate (twice with 30 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the desired product, tert-butyl 3-(5-(1,8-naphthiridine-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate, as a bright yellow solid (350 mg). Yield 48% (ESI 388(M+H)) + ).

[0412] Stage 6: 7-(5-(3-fluoropyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine 2-hydrochloride

[0413] [ka]

[0414] A mixture of 3-(5-(1,8-naphthiridine-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate (200 mg, 0.516 mmol) and Pd / C (5%, 200 mg) in ELISA (20 mL) was stirred overnight at 45°C under hydrogen. The reaction mixture was filtered and concentrated under reduced pressure. To the residue, 1,4-dioxane (2 mL) and HCl / dioxane (2 mL, 4 M) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to obtain the desired product, 7-(5-(3-fluoropyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthiridine 2-hydrochloride, as a bright yellow solid (140 mg). Yield 93% (ESI 292(M+H)) + ).

[0415] Preparation of 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride Stage 1: tert-butyl(R)-3-(hexa-5-en-1-yloxy)pyrrolidine-1-carboxylate

[0416] [ka]

[0417] To a suspension of tert-butyl(R)-3-hydroxypyrrolidine-1-carboxylate (12.8 g, 68.4 mmol), tetrabutylammonium bromide (1.102 g, 3.42 mmol), and 6-bromo-1-hexene (13.71 mL, 103 mmol) in heptane (256 mL), sodium hydroxide (128 mL, 68.4 mmol, 50 wt% aqueous solution) was added. The mixture was stirred at high pressure at 80°C for 2 hours, cooled to room temperature, diluted with water, and extracted twice with heptane and then with diethyl ether / heptane. The combined organic layer was washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (600 g silica, 5% to 14% ethyl acetate / heptane) yielded the desired product, tert-butyl(R)-3-(hexa-5-en-1-yloxy)pyrrolidine-1-carboxylate (14.93 g). Yield: 81%. 1 ¹H NMR (400MHz, chloroform-d) δ 5.87-5.74 (m, 1H), 5.05-4.91 (m, 2H), 4.04-3.95 (m, 1H), 3.48-3.27 (m, 6H), 2.07 (q, J=7.2Hz, 2H), 2.02-1.84 (m, 2H), 1.60-1.51 (m, 2H), 1.51-1.38 (m, 11H).

[0418] Step 2: tert-butyl(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate

[0419] [ka]

[0420] To a solution of tert-butyl(R)-3-(hexa-5-en-1-yloxy)pyrrolidine-1-carboxylate (14.93 g, 55.4 mmol) in THF (420 mL) and water (140 mL), sodium periodate (26.1 g, 122 mmol) and osmium tetroxide (1.5 mL, 0.232 mmol, 4% aqueous solution) were added. After 1 hour, an additional sodium periodate (5 g, 23.38 mmol) was added. After 30 minutes, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (approximately 600 g silica, 20% to 50% ethyl acetate / heptane). This yielded the desired product, tert-butyl(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (10.97 g). Yield: 72%. 1 ¹H NMR (400MHz, chloroform-d): δ 9.77 (s, 1H), 4.03-3.94 (m, 1H), 3.50-3.27 (m, 6H), 2.47 (t, J=7.2Hz, 2H), 2.02-1.84 (m, 2H), 1.77-1.65 (m, 2H), 1.65-1.54 (m, 2H), 1.46 (s, 9H).

[0421] Stage 3: tert-butyl(3R)-3-((5-hydroxyhepta-6-en-1-yl)oxy)pyrrolidine-1-carboxylate

[0422] [ka]

[0423] To a solution of tert-butyl(R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (10.97 g, 40.4 mmol) in THF (70 mL), vinyl magnesium bromide (66.4 mL, 46.5 mmol, 0.7 M THF solution) was added dropwise at 0°C. After 16 hours, the mixture was stopped with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated with sodium sulfate, concentrated, and the residue was purified by flash column chromatography (20% to 50% ethyl acetate / heptane) to obtain the desired product, tert-butyl(3R)-3-((5-hydroxyhepta-6-en-1-yl)oxy)pyrrolidine-1-carboxylate (7.68 g). Yield 63%. 1 ¹H NMR (400 MHz, chloroform-d) δ 5.93-5.80 (m, 1H), 5.28-5.17 (m, 1H), 5.15-5.06 (m, 1H), 4.17-4.05 (m, 1H), 3.99 (s, 1H), 3.52-3.23 (m, 6H), 2.03-1.83 (m, 2H), 1.65-1.50 (m, 5H), 1.50-1.33 (m, 11H).

[0424] Stage 4: tert-butyl(R)-3-((7-(2-chloropyridine-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate

[0425] [ka]

[0426] Tert-butyl(3R)-3-((5-hydroxyhepta-6-en-1-yl)oxy)pyrrolidine-1-carboxylate (10.48 g, 35.0 mmol), 2-chloro-3-iodopyridine (4.19 g, 17.50 mmol), tetrabutylammonium chloride (0.486 g, 1.750 mmol), and sodium bicarbonate (3.68 g, 43.8 mmol) were dissolved / suspended in DMF (35 mL) under argon, and argon was blown over the mixture for 15 minutes. Palladium(II) acetate (0.393 g, 1.750 mmol) was added, the mixture was heated to 50°C for 24 hours, cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dehydrated with sodium sulfate, concentrated, and the residue purified by column chromatography (silica, 20% to 55% toluene / heptane) to obtain the desired product tert-butyl(R)-3-((7-(2-chloropyridine-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate (3.05 g). Yield 42%. 1 H NMR (400MHz, chloroform-d) δ8.25(dd, J=4.7, 1.9Hz, 1H), 7.62(dd, J=7.5, 1.9Hz, 1H), 7.17(dd, J=7.5, 4.7Hz, 1H), 4.04-3.93(m, 1H), 3.5 1-3.25(m, 6H), 2.99(t, J=7.3Hz, 2H), 2.79(t, J=7.3Hz, 2H), 2.43(t, J=7.2Hz, 2H), 2.01-1.83(m, 2H), 1.72-1.48(m, 4H), 1.30(s, 9H).

[0427] Stage 5: tert-butyl(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate

[0428] [ka]

[0429] (R)-(+)-2-methyl-2-propanesulfinamide (1.799 g, 14.84 mmol) and tert-butyl(R)-3-((7-(2-chloropyridine-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate (3.05 g, 7.42 mmol) were dissolved in THF (30 mL) and titanium(IV) ethoxide (7.24 mL, 22.27 mmol) was added. The resulting mixture was heated to 50°C and allowed to stand for 20 hours. It was then added to a semi-saturated sodium bicarbonate aqueous solution, stirred for 10 minutes, transferred to two centrifuge vials, and centrifuged at 7800 rpm for 5 minutes. The liquids were gently poured into a separatory funnel. Next, the vials were filled with ethyl acetate, shaken vigorously, and centrifuged again at 7800 rpm for 5 minutes. The liquids were combined in the separatory funnel. The layers were separated, and the aqueous phase was extracted again with ethyl acetate. The combined organic layers were washed with brine, dehydrated with sodium sulfate, concentrated, and the residue was purified by flash column chromatography (300 g silica, 35% to 65% ethyl acetate / heptane) to obtain the desired product, tert-butyl(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (3.15 g). Yield 78% (ESI 514 / 516(M+H)). + ). 1 H NMR (400MHz, chloroform-d) δ8.27(dd, J=4.7, 1.9Hz, 1H), 7.64(dd, J=62.5, 7.4Hz, 1H), 7.19(dd, J=7.5, 4.8Hz, 1H), 3.99(s, 1H), 3.54-3 .24(m, 6H), 3.16-2.87(m, 2H), 2.87-2.60(m, 2H), 2.60-2.35(m, 1H), 1.94(s, 2H), 1.77-1.53(m, 5H), 1.45(s, 9H), 1.35-1.11(m, 9H).

[0430] Stage 6: tert-butyl(3R)-3-((5-(((R)-tert-butylsulfinyl)amino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate

[0431] [ka]

[0432] To a solution of tert-butyl(R)-3-((5-(((R)-tert-butylsulfinyl)imino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (3.15 g, 6.13 mmol) in methanol (20 mL), sodium borohydride (0.278 g, 7.35 mmol) was added. After 2 hours, the mixture was stopped with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dehydrated with sodium sulfate, concentrated, and the residue was purified by flash column chromatography (50% to 100% ethyl acetate / heptane) to obtain the desired product tert-butyl(3R)-3-((5-(((R)-tert-butylsulfinyl)amino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (3.05 g). Yield: 85%. 1 H NMR (400MHz, chloroform-d) δ8.28-8.22(m, 1H), 7.72-7.51(m, 1H), 7.22-7.15(m, 1H), 4.03-3.95(m, 1H), 3.49-3.22(m, 7H), 3.1 6-3.06(m, 1H), 2.96-2.64(m, 2H), 2.00-1.83(m, 4H), 1.80-1.70(m, 1H), 1.65-1.51(m, 3H), 1.51-1.37(m, 11H), 1.25(s, 9H).

[0433] Step 7: tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate

[0434] [ka]

[0435] To a solution of tert-butyl(3R)-3-((5-(((R)-tert-butylsulfinyl)amino)-7-(2-chloropyridine-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (3.05 g, 5.20 mmol) in 1,4-dioxane (25 mL), Xantphos (0.602 g, 1.040 mmol) and cesium carbonate (3.39 g, 10.40 mmol) were added. Argon was blown over the mixture for 15 minutes. Palladium(II) acetate (0.117 g, 0.520 mmol) was added, and argon was blown over the reaction mixture for 1 minute. The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, stopped with water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dehydrated with sodium sulfate, concentrated, and the residue purified by flash column chromatography (40% to 100% toluene / heptane) to obtain the desired product, tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate (928 mg). Yield 36% (ESI 480(M+H) + The compound was separated by chiral SFC to obtain stereoisomers A and B. Equipment: Waters Prep 100 SFC UV-directed system; Waters 2998 Photodiode Array (PDA) detector; Waters 2767 Sample Manager; Masslynx (trademark) software; FractionLynx (trademark) Application Manager, Acq. Method: Cell-2_f70_10_50_8mn_SW_120bar, Load: 50mg, Column: Phenomenex Lux Cellulose-2 (250×21.2mm, 5μm), Flow rate: 70mL / min, Column temperature: 35℃; ABPR: 120bar; Eluent A: CO2, Eluent B: 20mM ammonia / methanol, Linear gradient: t=0min 10%B, t=5min 50%B, t=7.5min 50%B, t=8min 10%B. Injection: Sandwich 100μL methanol, Detection PDA: 210~320nm, Recovery: Based on PDA TIC.

[0436] tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate stereoisomer A: 0.58g, LC / MS ESI 480(M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δ 8.06-7.98 (m, 1H), 7.37-7.29 (m, 1H), 6.73-6.63 (m, 1H), 4.20-4.09 (m, 1H), 4.03-3.93 (m, 1H), 3.50-3.25 (m, 6H), 2.94-2.79 (m, 1H), 2.77-2.65 (m, 1H), 2.20-2.08 (m, 1H), 2.00-1.49 (m, 7H), 1.46 (s, 9H), 1.43-1.27 (m, 2H), 1.21 (s, 9H).

[0437] tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate stereoisomer B: 0.45g, LC / MS ESI 480(M+H) + . 1 ¹H NMR (400MHz, chloroform-d) δ 8.20-8.09 (m, 1H), 7.39-7.31 (m, 1H), 6.90-6.80 (m, 1H), 4.25-4.12 (m, 1H), 4.04-3.92 (m, 1H), 3.51-3.24 (m, 6H), 2.87-2.62 (m, 2H), 2.11-1.83 (m, 3H), 1.76-1.49 (m, 6H), 1.46 (s, 9H), 1.40-1.27 (m, 10H).

[0438] Stage 8: 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyrizine stereoisomer A2 hydrochloride

[0439] [ka]

[0440] To a solution of tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate stereoisomer A (0.58 g, 1.209 mmol) in methanol (5 mL), hydrochloric acid (5 mL, 20.00 mmol, solution in 4N dioxane) was added. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and removed with methanol. Upon addition of diethyl ether, slow crystallization of the product began. After standing overnight, the crystals were scraped off and the obtained material was ground with diethyl ether. After several hours, the solid was filtered, washed with fresh diethyl ether, and vacuum-dried to obtain the desired product, 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine stereoisomer A·2 hydrochloride (438 mg), as a beige solid. Yield 100%. LC / MS ESI 276(M-2HCl+H) + . 1 H NMR (400MHz, methanol-d4) δ7.75-7.66(m, 2H), 6.80(t, J=6.8Hz, 1H), 4.30-4.23(m, 1H), 3.67-3.56(m, 1H), 3.56-3.44(m, 2H), 3.44-3.3 3(m, 3H), 3.25(dd, J=12.5, 4.2Hz, 1H), 2.96-2.78(m, 2H), 2.26-2.16(m, 1H), 2.13-1.99(m, 2H), 1.77-1.46(m, 7H), 1.23-1.12(m, 1H). Specific optical rotation: 33.9° c=0.5, MeOH, 22.7°C, 589nm.

[0441] Stage 9: 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyrizine stereoisomer B2 hydrochloride

[0442] [ka]

[0443] To a solution of tert-butyl(3R)-3-(4-(1-((R)-tert-butylsulfinyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-carboxylate stereoisomer B (0.45 g, 0.938 mmol) in methanol (5 mL), hydrochloric acid (5 mL, 20.00 mmol, solution in 4N dioxane) was added. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and removed with methanol. Upon addition of diethyl ether, slow crystallization of the product began. After standing overnight, the crystals were scraped off and the obtained material was ground with diethyl ether. After several hours, the solid was filtered, washed with fresh diethyl ether, and vacuum-dried to obtain the desired product, 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine stereoisomer B·2 hydrochloride (289 mg), as a beige solid. Yield 85%. LC / MS ESI 276(M-2HCl+H) + . 1 H NMR (400MHz, methanol-d4) δ7.74-7.66(m, 2H), 6.80(t, J=6.8Hz, 1H), 4.30-4.23(m, 1H), 3.66-3.57(m, 1H), 3.57-3.45(m, 2H), 3.45-3.33(m, 3H), 3.29-3.21(m, 1H), 2.96-2.78(m, 2H), 2.26-2.16(m, 1H), 2.13-1.97(m, 2H), 1.76-1.44(m, 7H). Specific optical rotation: -48.3° c=0.5, MeOH, 22.7°C, 589nm.

[0444] Compounds 1 to 21 were prepared using the following method. [Examples]

[0445] [Example 1]: Preparation of 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 1-E1 and 1-E2)

[0446] Step 1: Ethyl 2-(2-cyclopropylphenyl)acetate

[0447] [ka]

[0448] A mixture of ethyl 2-(2-bromophenyl)acetate (5.0 g, 20.57 mmol), cyclopropylboronic acid (3.54 g, 41.14 mmol), Pd(OAc)2 (922 mg, 4.12 mmol), tricyclohexylphosphine (1.73 g, 6.17 mmol), and tripotassium phosphate (15.3 g, 72.01 mmol) in toluene (60 mL) and water (7.5 mL) was stirred overnight at 120 °C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO20:1) to obtain the desired product, ethyl 2-(2-cyclopropylphenyl)acetate, as a colorless oil (4.0 g). Yield 95%. 1 H NMR (400MHz, CDCl3) δ7.21-7.18(m, 4H), 4.18-4.16(q, 2H), 3.83(s, 2H), 1.52-1.48(m, 1H), 1.29-1.18(t, 3H), 0.94-0.64(m, 4H).

[0449] Step 2: Ethyl 2-bromo-2-(2-cyclopropylphenyl)acetate

[0450] [ka]

[0451] To a solution of ethyl 2-(2-cyclopropylphenyl) acetate (1 g, 4.9 mmol) in THF (16 mL), a solution of 2.0 M lithium diisopropylamide in THF / hexane (6.2 mL, 12.4 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. Next, a solution of chlorotrimethylsilane (1.3 g, 12.25 mmol) in THF (5 mL) was added, and the reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (1.5 g, 12.25 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product, ethyl 2-bromo-2-(2-cyclopropylphenyl) acetate, as a yellow oil (350 mg). Yield 25%.

[0452] Step 3: Ethyl 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)acetate

[0453] [ka]

[0454] Ethyl 2-bromo-2-(2-cyclopropylphenyl)acetate (350 mg, 1.24 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (341 mg, 1.24 mmol), and K2CO3 (513 mg, 3.72 mmol) were mixed in acetonitrile (8 mL) and stirred at 60°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, ethyl 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)butoxy)pyrrolidine-1-yl)acetate, as a yellow oily substance (150 mg). Yield 25% (ESI 478(M+H)) + ).

[0455] Step 4: 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 1-E1 and 1-E2)

[0456] [ka]

[0457] Ethyl 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (150 mg, 0.31 mmol) was treated with LiOH-H2O (52 mg, 1.24 mmol) in MeOH (4 mL) and H2O (1 mL) at 60°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 1 as a white solid (110 mg, yield 77%). The racemic product was separated by preparative chiral SFC A to obtain the diastereomer products compound 1-E1 (25 mg) and compound 1-E2 (26 mg) as white solids.

[0458] Compound 1-E1 LC / MS ESI 450.6(M+H) + . 1 H NMR (400MHz, MeOD) δ7.60(d, J=7.6Hz, 1H), 7.28(m, 2H), 7.15(d, J=7.3Hz, 2H), 6 .37(d, J=7.3Hz, 1H), 5.31(s, 1H), 4.21(s, 1H), 3.72-3.32(m, 6H), 3.24-3.02(m , 2H), 2.71(t, J=6.3Hz, 2H), 2.54(t, J=7.5Hz, 2H), 2.31-1.95(m, 3H), 1.94-1.7 9(m, 2H), 1.77-1.66(m, 2H), 1.58(m, 2H), 1.05-0.87(m, 3H), 0.67-0.38(m, 1H). Chiral SFC A (45%MeOH): ee98%, Rt=1.97 min.

[0459] Compound 1-E2 LC / MS ESI 450.6(M+H) + . 1 H NMR (400MHz, MeOD) δ7.60(d, J=7.6Hz, 1H), 7.28(m, 2H), 7.15(d, J=7.3Hz, 2H), 6 .37(d, J=7.3Hz, 1H), 5.31(s, 1H), 4.21(s, 1H), 3.72-3.32(m, 6H), 3.24-3.02(m , 2H), 2.71(t, J=6.3Hz, 2H), 2.54(t, J=7.5Hz, 2H), 2.31-1.95(m, 3H), 1.94-1.7 9(m, 2H), 1.77-1.66(m, 2H), 1.58(m, 2H), 1.05-0.87(m, 3H), 0.67-0.38(m, 1H). Chiral SFC A (45%MeOH): ee98%, Rt=2.59 min.

[0460] [Example 2]: Preparation of 2-(2-cyclopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 2-E1 and 2-E2)

[0461] Stage 1: 1-Bromo-2-cyclopropoxybenzene

[0462] [ka]

[0463] A mixture of 2-bromophenol (2.0 g, 11.6 mmol), bromocyclopropane (4.6 g, 38.1 mmol), and K2CO3 (5.2 g, 38.1 mmol) in 10 mL of dehydrated DMF was sealed in a tube and heated by microwave at 140°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether (three times in 100 mL increments). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0% to 10% siRNA / hexane) to obtain the desired product as a colorless oil (400 mg). Yield: 17% 1H NMR (400MHz, CDCl3) δ7.52(d, J=7.2Hz, 1H), 7.30-7.27(m, 2H), 6.88-6.84(m, 1H), 3.83-3.80(m, 1H), 0.90-0.82(m, 4H).

[0464] Stage 2: 2-Cyclopropoxyphenylboronic acid

[0465] [ka]

[0466] 1-Bromo-2-cyclopropoxybenzene (800 mg, 3.75 mmol) was dissolved in THF (20 mL) and n-BuLi (2.5 M, 4.5 mmol) was added dropwise. The reaction mixture was stirred under Ar at -78°C for 1 hour. Trimethylborate (779 mg, 7.5 mmol) was dissolved in THF (5 mL) and the reaction mixture was stirred at -78°C for another 1 hour, then slowly raised to room temperature and stirred overnight. HCl aqueous solution (1 N, 20 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes and extracted by DCM (3 times with 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: HCl = 1:1) to obtain the desired product as a white solid (400 mg). Yield: 60% (ESI: 178 [MH]) - ).

[0467] Step 3: 2-(2-cyclopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 2-E1 and 2-E2)

[0468] [ka]

[0469] A mixture of 2-cyclopropoxyphenylboronic acid (400 mg, 2.25 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (476 mg, 1.73 mmol), and 2-oxoacetic acid (304 mg, 3.45 mmol) in DCM (5 mL) was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 2 as a white solid (205 mg, yield 26%). The racemic product was separated by preparative chiral SFC A to obtain the diastereomer products compound 2-E1 (110 mg) and compound 2-E2 (79 mg) as white solids.

[0470] Compound 2-E1 LC / MS ESI 466(M+H) + . 1 H NMR (400MHz, MeOD) δ7.48(d, J=7.6Hz, 1H), 7.41-7.40(m, 2H), 7.13(d, J=7 .6Hz, 1H), 7.04-7.00(m, 1H), 6.38(d, J=7.6Hz, 1H), 4.92(s, 1H), 4.18-4.1 6(m, 1H), 3.90-3.85(m, 1H), 3.56-3.36(m, 5H), 3.27-3.01(m, 3H), 2.70(t, J=6.0Hz, 2H), 2.56(t, J=7.2Hz, 2H), 2.09-1.55(m, 8H), 0.85-0.70(m, 4H). Chiral SFC A (40% MeOH): ee 85.4%, Rt = 2.39 mins.

[0471] Compound 2-E2 LC / MS ESI 466(M+H) + . 1H NMR (400MHz, MeOD) δ7.52(d, J=7.6Hz, 1H), 7.41-7.40(m, 2H), 7.13(d, J=7 .2Hz, 1H), 7.03-6.99(m, 1H), 6.37(d, J=7.2Hz, 1H), 4.86(s, 1H), 4.15-4.1 2(m, 1H), 3.92-3.75(m, 1H), 3.56-3.36(m, 5H), 3.27-3.14(m, 3H), 2.70(t, J=6.0Hz, 2H), 2.53(t, J=7.6Hz, 2H), 2.20-1.55(m, 8H), 0.85-0.70(m, 4H). Chiral SFC A (40% MeOH): ee 95.4%, Rt = 3.27 mins.

[0472] [Example 3]: Preparation of 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 3-E1 and 3-E2)

[0473] Step 1: 3-Bromo-2-cyclopropylpyridine

[0474] [ka]

[0475] Pd(PPh3)4 (740 mg, 0.64 mmol) was added to a solution of 2,3-dibromopyridine (3 g, 12.8 mmol) and cyclopropylzinc(II) bromide (76 mL, solution in 0.5 M THF) in THF (30 mL). The mixture was stirred under N2 at 70°C for 4 hours, diluted with water (50 mL), and extracted with siRNA (three times in 50 mL increments). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:siRNA 10:1) to obtain the desired product, 3-bromo-2-cyclopropylpyridine, as a yellow oil (1.2 g). Yield 48% (ESI 198(M+H)). + ).

[0476] Step 2: Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-hydroxyacetate

[0477] [ka]

[0478] To a solution of EtMgBr (1M, 3.65mL, 3.65 mmol) in THF (20mL), n-BuLi (2.9mL, 7.3 mmol) was added under N2 conditions at 0°C. The solution was stirred at 0°C for 30 minutes, and 3-bromo-2-cyclopropylpyridine (1.2g, 6.1 mmol) in THF (5mL) was added at -10°C. The mixture was stirred at the same temperature for 30 minutes, and ethyl 2-oxoacetate (solution in 50% toluene, 5g, 24.4 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours, the reaction was stopped with saturated K2CO3 solution (20mL), and the mixture was extracted with siRNA (3 times with 50mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether: siRNA 2:1) using silica gel to obtain the desired product, ethyl 2-(2-cyclopropylpyridine-3-yl)-2-hydroxyacetate, as a yellow oil (700 mg). Yield 52% (ESI 222(M+H) + ).

[0479] Step 3: Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-(methylsulfonyloxy)acetate

[0480] [ka]

[0481] Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-hydroxyacetate (300 mg, 1.36 mmol) and triethylamine (411 mg, 4.1 mmol) were dissolved in DCM (5 mL) and MsCl (232 mg, 2 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and purified by silica gel column (petroleum ether: siRNA 4:1) to obtain the desired product, ethyl 2-(2-cyclopropylpyridine-3-yl)-2-(methylsulfonyloxy)acetate, as a yellow oil (190 mg). Yield 47% (ESI 300(M+H) + ).

[0482] Step 4: Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetate

[0483] [ka]

[0484] A mixture of (R)-7-(5-(pyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine hydrochloride (300 mg, 0.87 mmol), ethyl 2-(2-cyclopropylpyridine-3-yl)-2-(methylsulfonyloxy)acetate (286 mg, 0.96 mmol), and diisopropylethylamine (337 mg, 2.6 mmol) in acetonitrile (10 mL) was stirred overnight at 50°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH=0% to 20%) to obtain the desired product as a yellow oil (245 mg). Yield 54% (ESI 477(M+H) + ).

[0485] Step 2: 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 3-E1 and 3-E2)

[0486] [ka]

[0487] Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl) acetate (245 mg, 0.51 mmol) was treated with LiOH-H2O (210 mg, 5.0 mmol) in MeOH (4 mL) and H2O (1 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 60% MeCN) to obtain compound 3 as a white solid (110 mg, yield 48%). The racemic product was separated by preparative chiral SFC H to obtain the diastereomer products compound 3-E1 (42 mg) and compound 3-E2 (45 mg) as white solids.

[0488] Compound 3-E1 LC / MS ESI 449(M+H) + . 1 H NMR (400MHz, MeOD) δ8.39(t, J=6.1Hz, 1H), 7.98(d, J=7.9Hz, 1H), 7.19-7.10(m, 2H), 6.35(d , J=7.3Hz, 1H), 5.06(s, 1H), 3.40-3.31(m, 3H), 3.15-3.08(m, 2H), 2.84-2.81(m, 1H), 2.70- 2.67(m, 2H), 2.59-2.56(m, 1H), 2.55-2.47(m, 2H), 2.36-2.26(m, 1H), 2.21-2.13(m, 1H), 1. 90-1.84(m, 2H), 1.66-1.57(m, 3H), 1.44-1.26(m, 7H), 1.08-1.05(m, 2H), 0.93-0.90(m, 1H). Chiral SFC H(45%MeOH): ee92%, Rt=2.11 min.

[0489] Compound 3-E2 LC / MS ESI 449(M+H) + . 1H NMR (400MHz, MeOD) δ8.36(t, J=6.1Hz, 1H), 8.01(d, J=7.9Hz,1H), 7.20-7.11(m, 2H), 6.35(d, J=8Hz, 1H), 4.91(s, 1H), 3.51-3.36(m, 3H), 3.20-2. 91(m, 2H), 2.71-2.29(m, 7H), 2.14-2.09(m, 1H), 1.90-1.84(m, 2H), 1.64 -1.57(m, 3H), 1.433-1.23(m, 7H), 1.06-1.01(m, 2H), 0.92-0.88(m, 1H). Chiral SFC H (45% MeOH): ee 100%, Rt = 3.77 mins.

[0490] [Example 4]: Preparation of 2-(2-cyclopropyl-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 4-E1 and 4-E2)

[0491] Step 1: 2-Cyclopropyl-5-Fluoroaniline

[0492] [ka]

[0493] A mixture of 2-bromo-5-fluoroaniline (3.0 g, 15.8 mmol), cyclopropylboronic acid (2.7 g, 31.4 mmol), PCy3 (440 mg, 1.57 mmol), Pd(OAc)2 (352 mg, 1.57 mmol), and K3PO4 (20 g, 94.3 mmol) in toluene (50 mL) and H2O (10 mL) was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL), and extracted with pharmaceutically acceptable phosphate (three times in 100 mL). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: HCl 2:1) to obtain the desired product as a colorless oil (1.8 g). Yield 75% (ESI: 152 [M+H]) + ).

[0494] Stage 2: 1-Cyclopropyl-4-fluoro-2-iodobenzene

[0495] [ka]

[0496] 2-Cyclopropyl-5-fluoroaniline (1.8 g, 11.9 mmol) was added to a solution of p-toluenesulfonic acid monohydrate (6.8 g, 35.8 mmol) in acetonitrile (60 mL). The reaction mixture was stirred at room temperature for 10 minutes and cooled to 10°C. A solution of sodium nitrite (2.0 g, 29.0 mmol) and potassium iodide (4.0 g, 24.1 mmol) in water (20 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 4 hours, made basic with sodium bicarbonate aqueous solution to pH 9-10, and diluted with siRNA (100 mL) and 10% sodium metabisulfite aqueous solution (20 mL). The phases were separated, and the aqueous layer was extracted with siRNA (twice with 100 mL). The organic layers were combined, washed with brine, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: SiO 10:1) to obtain the desired product as a colorless oil (1.3 g). Yield 42% (ESI: N / A).

[0497] Stage 3: 2-Cyclopropyl-5-Fluorophenylboronic Acid

[0498] [ka]

[0499] To a solution of 1-cyclopropyl-4-fluoro-2-iodobenzene (1.3 g, 4.96 mmol) in THF (50 mL), n-BuLi (2.5 M, 2.2 mL, 5.5 mmol) was added dropwise. The reaction mixture was stirred under Ar at -78°C for 1 hour. A solution of trimethylborate (1.0 g, 9.62 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at -78°C for another 1 hour. The temperature was slowly raised to room temperature, and the mixture was stirred overnight. 1N aqueous HCl (20 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Extraction was performed by DCM (3 times with 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA = 1:1) to obtain the desired product as a white solid (500 mg). Yield: 56% (ESI: 179 [MH]) - ).

[0500] Step 4: 2-(2-cyclopropyl-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 4-E1 and 4-E2)

[0501] [ka]

[0502] A mixture of 2-cyclopropyl-5-fluorophenylboronic acid (200 mg, 1.11 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (306 mg, 1.11 mmol), and 2-oxoacetic acid (123 mg, 1.66 mmol) in MeCN (5 mL) was stirred at 60°C for 15 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 4 as a white solid (120 mg, yield 23%). The racemic product was separated by preparative chiral SFC A to obtain the diastereomer products compound 4-E1 (34 mg) and compound 4-E2 (41 mg) as white solids.

[0503] Compound 4-E1 LC / MS ESI 468(M+H) + . 1 H NMR (400MHz, MeOD) δ7.41(d, J=10.0Hz, 1H), 7.20-7.01(m, 3H), 6.38(d, J=7.2Hz, 1H), 5.28(s, 1H), 4.21(s, 1H), 3.55-3.05(m, 8H), 2.71(t, J=6.4Hz, 2H), 2.55(t, J=7.6Hz, 2H), 2.19-2.05(m, 3H), 1.92-1.55(m, 6H), 0.95-0.80(m, 3H), 0.55-0.50(m, 1H). Chiral SFC A (35%MeOH): ee100%, Rt=2.69 min.

[0504] Compound 4-E2 LC / MS ESI 468(M+H) + . 1 H NMR (400MHz, MeOD) δ7.41(d, J=10.0Hz, 1H), 7.20-7.01(m, 3H), 6.38(d, J=7.2Hz, 1H), 5.19(s, 1H), 4.18(s, 1H), 3.54-3.19( m, 8H), 2.71(t, J=6.0Hz, 2H), 2.59-2.53(m, 2H), 2.22-2.14(m, 3H), 1.92-1.55(m, 6H), 0.98-0.85(m, 3H), 0.55-0.50(m, 1H). Chiral SFC A (35%MeOH): ee97%, Rt=3.26 min.

[0505] [Example 5]: Preparation of 2-(2-cyclopropylphenyl)-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)pyrrolidine-1-yl)acetic acid (compounds 5-E1 and 5-E2)

[0506] Step 1: 2-(2-cyclopropylphenyl)-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)propoxy)pyrrolidine-1-yl)acetic acid (compounds 5-E1 and 5-E2)

[0507] [ka]

[0508] A mixture of 2-cyclopropylphenylboronic acid (102 mg, 0.63 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (140 mg, 0.42 mmol), and 2-oxoacetic acid (47 mg, 0.63 mmol) in DCM (5 mL) was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 5 as a white solid (95 mg, yield 52%). The racemic product was separated by preparative chiral SFC H to obtain the diastereomer products compound 5-E1 (15 mg) and compound 5-E2 (9 mg) as white solids.

[0509] Compound 5-E1 LC / MS ESI 436.4(M+H) + . 1 H NMR (400MHz, MeOD) δ7.64(d, J=7.6Hz, 1H), 7.33-7.12(m, 4H), 6.36(d, J=7.2Hz, 1H), 5.26(s, 1H), 4.18(s, 1H), 3.55-3.22(m, 8H), 2.69(t, J=6.4Hz, 2H), 2.60(t, J=7.2Hz, 2H), 2.30-2.13(m, 3H), 1.92-1.84(m, 4H), 1.08-0.90(m, 3H), 0.65-0.55(m, 1H). Chiral SFC H(35%MeOH): ee98%, Rt=2.74 min.

[0510] Compound 5-E2 LC / MS ESI 436.4(M+H) + . 1H NMR (400MHz, MeOD) δ7.61(d, J=7.6Hz, 1H), 7.32-7.12(m, 4H), 6.36(d, J=7.2Hz, 1H), 5.33(s, 1H), 4.21(s, 1H), 3.55-3.09(m, 8H), 2.70(t, J=6.4Hz, 2H), 2.60(t, J=7.2Hz, 2H), 2.25-2.00(m, 3H), 1.93-1.84(m, 4H), 1.08-0.90(m, 3H), 0.65-0.55(m, 1H). Chiral SFC H(35%MeOH): ee99%, Rt=3.55 min.

[0511] [Example 6]: Preparation of 2-(2,6-dicyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 6-E1 and 6-E2)

[0512] Stage 1: 2,6-Dicyclopropylpyridine-3-amine

[0513] [ka]

[0514] A mixture of ethyl 2,6-dibromopyridine-3-amine (6.0 g, 23.8 mmol), cyclopropylboronic acid (6.14 g, 71.4 mmol), Pd(OAc)2 (267 mg, 2.38 mmol), tricyclohexylphosphine (668 mg, 6.17 mmol), and tripotassium phosphate (17.7 g, 83.3 mmol) in toluene (80 mL) and water (10 mL) was stirred overnight at 120 °C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 4:1) to obtain the desired product, 2,6-dicyclopropylpyridine-3-amine, as a colorless oil (3.0 g). Yield 95% (ESI 175.0 (M+H)). + ).

[0515] Stage 2: 2,6-Dicyclopropylpyridine-3-amine

[0516] [ka]

[0517] A mixture of ethyl 2,6-dicyclopropylpyridine-3-amine (3.0 g, 17.2 mmol), tert-butyl nitrite (2.66 g, 25.8 mmol), and cuprous bromide (17.7 g, 25.8 mmol) in acetonitrile (20 mL) was stirred at 65°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 6:1) to obtain the desired product, 3-bromo-2,6-dicyclopropylpyridine, as a yellow oil (820 mg). Yield 20% (ESI 239.0 (M+H)). + ).

[0518] Stage 3: tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl)acetate

[0519] [ka]

[0520] A mixture of 3-bromo-2,6-dicyclopropylpyridine (800 mg, 3.36 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution in 0.5 M THF (26.9 mL, 13.44 mmol), Pd2(dba)3 (156 mg, 0.17 mmol), and Qphos (121 mg, 0.17 mmol) in THF (12 mL) was stirred at 65°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 4:1) to obtain the desired product, tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl)acetate, as a yellow oil (550 mg). Yield 60% (ESI 274.0 (M+H)). + ).

[0521] Stage 4: tert-butyl 2-bromo-2-(2,6-dicyclopropylpyridine-3-yl)acetate

[0522] [ka]

[0523] To a solution of tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl) acetate (300 mg, 1.1 mmol) in THF (10 mL), a 2.0 M lithium diisopropylamide solution in THF / hexane (1.4 mL, 2.8 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, and a solution of chlorotrimethylsilane (297 mg, 2.75 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (325 mg, 2.75 mmol) in THF (5 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), concentrated under reduced pressure, and purified by silica gel column (petroleum ether: siRNA 4:1) to obtain the desired product, tert-butyl 2-bromo-2-(2,6-dicyclopropylpyridine-3-yl) acetate, as a yellow oil (80 mg). Yield 21% (ESI 353(M+H) + ).

[0524] Step 5: tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0525] [ka]

[0526] A mixture of tert-butyl 2-bromo-2-(2,6-dicyclopropylpyridine-3-yl)acetate (80 mg, 0.23 mmol), ((R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (64 mg, 0.23 mmol), and K2CO3 (96 mg, 0.69 mmol) in acetonitrile (8 mL) was stirred at 60°C for 16 hours. The solvent was removed under reduced pressure, and the residue was collected by a silica gel column (DCM:MeOH). Purified by 20:1, the desired product tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate was obtained as a yellow oil (90 mg). Yield 72% (ESI 547(M+H) + ).

[0527] Step 6: 2-(2,6-dicyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 6-E1 and 6-E2)

[0528] [ka]

[0529] tert-butyl 2-(2,6-dicyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (90 mg, 0.16 mmol) was treated with HCl / 1,4-dioxane (4 M, 4 mL) at 25 °C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain the diastereomer products compound 6-E1 (11 mg) and compound 6-E2 (38 mg) as white solids.

[0530] Compound 6-E1 LC / MS ESI 491.6(M+H) + .1 H NMR (400MHz, MeOD) δ8.52(s, 1H), 7.77(d, J=7.9Hz, 1H), 7.67-7.44(m, 1H), 7.03(d, J=7.9Hz, 1H), 6.53(d, J=7.3Hz, 1H), 5.18(s, 1H), 4.22(s, 1H), 3.76-3.40(m, 6H), 3 .31-3.28(m, 2H), 2.79-2.66(m, 4H), 2.39(d, J=5.6Hz, 1H), 2.19(s, 2H), 1.98-1.93 (m, 3H), 1.76-1.74(m, 2H), 1.64-1.62(m, 2H), 1.25-1.14(m, 1H), 1.06-0.72(m, 8H).

[0531] Compound 6-E2 LC / MS ESI 491.6(M+H) + . 1 H NMR (400MHz, MeOD) δ8.52(s, 1H), 7.77(d, J=7.9Hz, 1H), 7.67-7.44(m, 1H), 7.03(d, J=7.9Hz, 1H), 6.53(d, J=7.3Hz, 1H), 5.27(s, 1H), 4.23(s, 1H), 3.76-3.40(m, 6H), 3 .31-3.28(m, 2H), 2.79-2.66(m, 4H), 2.39(d, J=5.6Hz, 1H), 2.19(s, 2H), 1.98-1.93 (m, 3H), 1.76-1.74(m, 2H), 1.64-1.62(m, 2H), 1.25-1.14(m, 1H), 1.06-0.72(m, 8H).

[0532] [Example 7]: Preparation of 2-(2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 7-E1 and 7-E2)

[0533] Stage 1: 1-Bromo-2-(isopropoxymethyl)benzene

[0534] [ka]

[0535] To a solution of isopropanol (0.72 g, 12 mmol) in DMF (15 mL), NaH (480 mg, 12 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, and 1-bromo-2-(bromomethyl)benzene (3.0 g, 12 mmol) from DMF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, the reaction was stopped with H₂O (10 mL), and the mixture was extracted with ethyl acetate (twice with 20 mL). The combined organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product, 1-bromo-2-(isopropoxymethyl)benzene (1.6 g). Yield 58% (ESI 229(M+H)). + ).

[0536] Stage 2: 2-(isopropoxymethyl)phenylboronic acid

[0537] [ka]

[0538] To a solution of 1-bromo-2-(isopropoxymethyl)benzene (300 mg, 1.32 mmol) in THF (5 mL), nBuLi (2.5 M, 0.6 mL, 1.45 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour, and trimethylborate (500 mg, 2.64 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, the reaction was stopped with aqueous HCl (1 N, 10 mL), and the mixture was extracted with HCl (3 times with 10 mL). The combined organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: HCl = 2:1) to obtain the desired product, 2-(isopropoxymethyl)phenylboronic acid, as a white solid (120 mg). Yield: 47% (ESI 193 (MH)) - .

[0539] Step 3: 2-(2-(isopropoxymethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 7-E1 and 7-E2)

[0540] [ka]

[0541] A mixture of (3R)-tert-butyl 3-(4-(5-methyl-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-carboxylate (131 mg, 0.48 mmol), 2-(isopropoxymethyl)phenylboronic acid (120 mg, 0.62 mmol), and 50% 2-oxoacetic acid (92 mg, 0.62 mmol) in MeCN (5 mL) was stirred at 70°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC B (30% to 65% MeCN) to obtain the diastereomer products compound 7-E1 (40 mg) and compound 7-E2 (34 mg) as HCOOH salts.

[0542] Compound 7-E1 LC / MS ESI 482(M+H) + . 1 H NMR (400MHz, MeOD) δ8.33(s, 2H), 7.68-7.66(m, 1H), 7.52-7.50(m, 1H), 7.46-7.42(m, 3H), 6.56(d, J=7.2Hz, 1H), 5.09(s, 1H), 4.90-4.88(m , 1H), 4.52-4.50(m, 1H), 4.23-4.21(m, 1H), 3.82-3.80(m, 1H), 3.66-3 .44(m, 7H), 3.21-3.19(m, 1H), 2.81-1.60(m, 12H), 1.25-1.23(m, 6H).

[0543] Compound 7-E2 LC / MS ESI 482(M+H) + . 1H NMR (400MHz, MeOD) δ8.33(s, 2H), 7.65-7.63(m, 1H), 7.52-7.50(m, 1H), 7.44-7.42(m, 3H), 6.56(d, J=7.2Hz, 1H), 4.97(s, 1H), 4.8 6-4.50(m, 2H), 4.26-4.24(m, 1H), 3.85-3.82(m, 1H), 3.61-3.40(m, 5H), 3.26-3.22(m, 3H), 2.81-1.60(m, 12H), 1.28-1.23(m, 6H).

[0544] [Example 8]: Preparation of 2-(2-(tert-butoxymethyl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (Compound 8)

[0545] Stage 1: 1-Bromo-2-(tert-butoxymethyl)-4-fluorobenzene

[0546] [ka]

[0547] NaH (60%, 600 mg, 15 mmol) was added at 0°C to a solution of 2-methylpropan-2-ol (7.4 g, 100 mmol) in THF (30 mL). The mixture was stirred at 0°C for 0.5 hours, and 2-bromo-1-(bromomethyl)-4-fluorobenzene (2.68 g, 10 mmol) was added. The mixture was stirred overnight at 80°C, cooled to room temperature, stopped with water (50 mL), and extracted with siRNA (50 mL). The organic layer was dehydrated with Na2SO4. 、 The solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dimethyl 15:1) to obtain the desired product as a yellow oily substance (300 mg). Yield 11% (ESI 261(M+H)). + ).

[0548] Stage 2: 2-(tert-butoxymethyl)-4-fluorophenylboronic acid

[0549] [ka]

[0550] n-BuLi (0.4 mL, 1 mmol in 2.5 M hexane solution) was added dropwise at -78°C to a solution of 1-bromo-2-(tert-butoxymethyl)-4-fluorobenzene (150 mg, 0.57 mmol) and triisopropyl borate (188 mg, 1 mmol) in THF (5 mL). The mixture was stirred at -78°C for 1 hour, and then stirred at 25°C for another 1 hour. The reaction was stopped by adjusting the pH of the mixture to 5 with aqueous HCl (2N) and extracted with SiO2 (10 mL). The organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:SiO2 2:1) to obtain the desired product as a colorless oil (70 mg). Yield 54% (ESI 225 (MH)). - ).

[0551] Step 3: 2-(2-(tert-butoxymethyl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 8)

[0552] [ka]

[0553] A mixture of 2-(tert-butoxymethyl)-4-fluorophenylboronic acid (75 mg, 0.33 mmol), 2-oxoacetic acid (88 mg, 50% aqueous solution, 0.6 mmol), and (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (91 mg, 0.33 mmol) in CH3CN (5 mL) was stirred overnight at 60°C. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (33% to 65% MeCN) to obtain compound 8 as a white solid (22 mg, yield 13%).

[0554] Compound 8 LC / MS ESI 514(M+H) + . 1 H NMR (400MHz, MeOD) δ7.50-7.42(m, 2H), 7.17-7.08(m, 2H), 6.37(d, J=7.2Hz, 1H), 4.81-4.74(m, 2H), 4.55-4.43(m , 1H), 4.17(s, 1H), 3.55-3.32(m, 6H), 3.20-2.95(m, 2H), 2.72-2.52(m, 4H), 2.25-1.55(m, 8H), 1.34-1.28(m, 9H).

[0555] [Example 9]: Preparation of 2-(2-cyclopropylpyridine-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 9-E1 and 9-E2)

[0556] Step 1: Ethyl 2-chloro-2-(2-cyclopropylpyridine-3-yl) acetate

[0557] [ka]

[0558] A solution of ethyl 2-(2-cyclopropylpyridine-3-yl)-2-hydroxyacetate (500 mg, 2.26 mmol) in SOCl2 (5 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 4:1) to obtain the desired product, ethyl 2-chloro-2-(2-cyclopropylpyridine-3-yl)acetate, as a yellow oil (210 mg). Yield 39% (ESI 240(M+H)). + ).

[0559] Step 2: Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetate

[0560] [ka]

[0561] A mixture of 7-(5-(3-fluoropyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (230 mg, 0.632 mmol), ethyl 2-chloro-2-(2-cyclopropylpyridine-3-yl) acetate (378 mg, 1.580 mmol), and K2CO3 (262 mg, 1.896 mmol) in acetonitrile (8 mL) was stirred at 60°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, ethyl 2-(2-cyclopropylpyridine-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)pentyl)pyrrolidine-1-yl) acetate, as a yellow oily substance (120 mg). Yield 38% (ESI 495(M+H)) + ).

[0562] Step 3: 2-(2-cyclopropylpyridine-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 9-E1 and 9-E2)

[0563] [ka]

[0564] Ethylethyl 2-(2-cyclopropylpyridine-3-yl)-2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl) acetate (120 mg, 0.24 mmol) was treated with LiOH-H2O (40 mg, 0.97 mmol) in MeOH (4 mL) and H2O (1 mL) at 60°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 9 as a white solid (60 mg, yield 53%). The racemic product was separated by preparative chiral SFC F to obtain the diastereomer products compound 9-E1 (10 mg) and compound 9-E2 (10 mg) as white solids, which were mixtures of two stereoisomers, respectively.

[0565] Compound 9-E1 (mixture of two stereoisomers) LC / MS ESI 467.4(M+H) + . 1 H NMR (400MHz, MeOD) δ8.32(s, 1H), 8.03(d, J=7.3Hz, 1H) 7.28(m, 2H), 6.41(d, J=7.3Hz, 1H), 4.81(s, 1H), 3.40-2.95(m, 6H), 2.80-2.50(m, 5H), 2.25-1.20(m, 12H), 1.10-0.85(m, 4H). Chiral SFC F(45%MeOH): ee76%, Rt=2.72 min.

[0566] Compound 9-E1 (mixture of two stereoisomers) LC / MS ESI 467.4(M+H) + . 1 H NMR (400MHz, MeOD) δ8.39(s, 1H), 8.01(d, J=7.3Hz, 1H) 7.33(m, 2H), 6.47(d, J=7.3Hz, 1H), 4.96(s, 1H), 3.45-2.95(m, 6H), 2.80-2.50(m, 5H), 2.25-1.20(m, 12H), 1.10-0.85(m, 4H). Chiral SFC F(45%MeOH): ee53%, Rt=3.36 min.

[0567] [Example 10]: Preparation of 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (Compound 10)

[0568] Step 1: Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0569] [ka]

[0570] A mixture of (R)-5-methoxy-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine hydrochloride (215 mg, 0.63 mmol), ethyl 2-chloro-2-(2-cyclopropylpyridine-3-yl) acetate (150 mg, 0.63 mmol), and diisopropylethylamine (245 mg, 1.89 mmol) in acetonitrile (8 mL) was stirred under reflux for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, ethyl 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate, as a yellow oil (80 mg). Yield 25% (ESI 509(M+H) + ).

[0571] Step 2: 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 10)

[0572] [ka]

[0573] Ethyl 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (105 mg, 0.21 mmol) was treated with LiOH-H2O (87 mg, 2.1 mmol) in MeOH (4 mL) and H2O (1 mL) at room temperature for 17 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 10 as a white solid (25 mg, yield 25%).

[0574] Compound 10 LC / MS ESI 481(M+H) + . 1 H NMR (400MHz, MeOD) δ8.26-8.25(m, 1H), 8.08-8.06(m, 1H), 7.15-7.11(m, 1H), 6.26-6.24(m, 1H), 4.57-4.52(m, 1 H), 4.08-4.07(m, 1H), 3.85(s, 1H), 3.46-3.41(m, 2H), 3.25-2.50(m, 7H), 2.10-1.50(m, 8H), 1.10-0.80(m, 4H).

[0575] [Example 11]: Preparation of 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 11-E1 and 11-E2)

[0576] Stage 1: 3-bromo-2-cyclobutylpyridine

[0577] [ka]

[0578] A mixture of magnesium shavings (612 mg, 25.5 mmol) and cyclobutyl bromide (3.4 g, 25.5 mmol) in anhydrous THF (50 mL) was heated at 60°C for 3 hours until the magnesium was completely dissolved. The solution was cooled to -78°C and treated with ZnCl2 (3.48 g, 25.5 mmol) in THF (50 mL). The resulting white suspension was gradually heated to room temperature and stirred for 1 hour. Next, a solution of 2,3-dibromopyridine (4 g, 17 mmol) and Pd(PPh3)4 (983 mg, 0.85 mmol) in THF (30 mL) was added to the reaction mixture. The mixture was stirred under N2 at 60°C for 1 hour, diluted with water (100 mL), and extracted with SiO2 (three times in 50 mL increments). The combined organic layers were dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:siRNA = 10:1) to obtain the desired product, 3-bromo-2-cyclopropylpyridine, as a yellow oil (2.3 g). Yield 94% (ESI 212(M+H)). + ).

[0579] Step 2: Ethyl 2-(2-cyclobutylpyridine-3-yl)-2-hydroxyacetate

[0580] [ka]

[0581] To a solution of EtMgBr (1M, 6.54 mL, 6.54 mmol) in THF (20 mL), n-BuLi (2.5M, 5.2 mL, 13.08 mmol) was added under N2 conditions at 0°C. The solution was stirred at 0°C for 30 minutes, and then 3-bromo-2-cyclobutylpyridine (2.3 g, 10.9 mmol) in THF (5 mL) was added at -10°C. The mixture was stirred at that temperature for 30 minutes. Next, ethyl 2-oxoacetate (solution in 50% toluene, 8.9 g, 43.6 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. The mixture was then added to 20 mL of saturated K2CO3 solution and extracted with siRNA (three times in 50 mL batches). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: siRNA = 2:1) to obtain the desired product, ethyl 2-(2-cyclopropylpyridine-3-yl)-2-hydroxyacetate, as a yellow oil (1.1 g). Yield 43% (ESI 236(M+H)). + ).

[0582] Step 3: Ethyl 2-chloro-2-(2-cyclobutylpyridine-3-yl)acetate

[0583] [ka]

[0584] A solution of ethyl 2-(2-cyclobutylpyridine-3-yl)-2-hydroxyacetate (480 mg, 2 mmol) in SOCl2 (5 mL) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, the pH was adjusted to 8 with aqueous NaHCO3 solution, and extracted with ethyl phosphate (three times with 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl = 10:1) to obtain the desired product, ethyl 2-chloro-2-(2-cyclobutylpyridine-3-yl)acetate, as a yellow oil (310 mg). Yield 47% (ESI 254(M+H)). + ).

[0585] Step 4: Ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0586] [ka]

[0587] A mixture of ethyl 2-chloro-2-(2-cyclobutylpyridine-3-yl)acetate (310 mg, 1.2 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (370 mg, 1.35 mmol), and diisopropylethylamine (464 mg, 3.6 mmol) in acetonitrile (10 mL) was stirred overnight at 50°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH = 0% to 10%) to obtain the desired product, ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate, as a colorless oil (165 mg, 0.36 mmol). Yield 28% (ESI 493(M+H) + ).

[0588] Step 5: 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 11-E1 and 11-E2)

[0589] [ka]

[0590] Ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (165 mg, 0.36 mmol) was treated with LiOH-H2O (70 mg, 1.8 mmol) in MeOH (4 mL) and H2O (1 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 60% MeCN) to obtain compound 11 as a white solid (110 mg, yield 70%). The racemic product was separated by preparative chiral SFC A to obtain the diastereomer products compound 11-E1 (35 mg) and compound 11-E2 (35 mg) as white solids.

[0591] Compound 11-E1 LC / MS ESI 465(M+H) + . 1 H NMR (500MHz, MeOD) δ8.54(d, J=4.5Hz,1H), 8.02(d, J=7.5Hz,1H), 7.29-7.23(m, 2H), 6.43(d, J=7.0Hz,1H), 4.71(s, 1H), 4.26-4.15(m, 2H), 3.54- 3.38(m, 4H), 3.22-3.07(m, 4H), 2.75-2.55(m, 5H), 2.44-2.33(m, 3H), 2. 13-2.05(m, 3H), 1.92-1.87(m, 3H), 1.79-1.74(m, 2H), 1.67-1.63(m, 2H). Chiral SFC E (45% MeOH): ee 100%, Rt = 2.99 mins.

[0592] Compound 11-E2 LC / MS ESI 465(M+H) + . 1H NMR (500MHz, MeOD) δ8.55(d, J=4.5Hz,1H), 7.99(d, J=7.5Hz,1H), 7.30-7.22(m, 2H), 6.44(d, J=6.0Hz,1H), 4.80(s, 1H), 4.20-4.16(m, 2 H), 3.51-3.39(m, 5H), 3.24-3.22(m, 1H), 3.01-2.91(m, 2H), 2.75-2.59(m, 5H), 2.42-2.30(m, 3H), 2.08-2.02(m, 3H), 1.92-1.64(m, 7H). Chiral SFC E (45% MeOH): ee 100%, Rt = 5.21 mins.

[0593] [Example 12]: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compound 12)

[0594] Step 1: Methyl 2-(2-iodophenyl)acetate

[0595] [ka]

[0596] 2-(2-iodophenyl)acetic acid (3.67 g, 14 mmol) was dissolved in MeOH (35 mL) and 2 mL of concentrated H2SO4 was added. The reaction mixture was stirred at 85°C for 2 hours, concentrated under reduced pressure, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. Extraction was performed with siRNA (twice with 30 mL). The combined organic phases were washed with brine, dehydrated with Na2SO4, and concentrated to obtain the desired product, methyl 2-(2-iodophenyl)acetate (3.7 g), as an orange-red oil. Yield 96% (ESI 277(M+H)). + ).

[0597] Step 2: Methyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)phenyl)acetate

[0598] [ka]

[0599] A mixture of methyl 2-(2-iodophenyl)acetate (828 mg, 3.0 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (945 mg, 4.5 mmol), PdCl2(PPh3)2 (89 mg, 0.12 mmol), and Na2CO3 (636 mg, 6 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was stirred overnight at 90°C under N2. The mixture was diluted with H2O (10 mL) and extracted with siRNA (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate, as a pale orange-red oily substance (488 mg). Yield 70% (ESI 255.1(M+Na)). + ).

[0600] Step 3: Methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate

[0601] [ka]

[0602] A mixture of tert-butyl 2-(3-(2-methoxypropan-2-yl)isochroman-5-yl) acetate (488 mg, 2.1 mmol) and Pd(OH)2 / C (20%, 120 mg) in MeOH (20 mL) was stirred under balloon hydrogen at 35°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the desired product, methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl) acetate (460 mg), as a colorless oil. Yield 95% (ESI 235.2(M+H)). + ).

[0603] Stage 4: tert-butyl 2-bromo-2-(3-(2-methoxypropan-2-yl)isochroman-5-yl)acetate

[0604] [ka]

[0605] To a solution of 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (234 mg, 1.0 mmol) in THF (10 mL), a 2.0 M lithium diisopropylamide solution in THF / hexane (1.0 mL, 2.0 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of chlorotrimethylsilane (218 mg, 2.0 mmol) in THF (0.5 mL) was added, and the reaction mixture was stirred for a further 10 minutes at -78°C. Next, a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was added, and the reaction mixture was stirred at -78°C for 10 minutes. The mixture was then added to water (10 mL) and extracted with  (20 mL). The organic phase was washed with saturated NaHCO3 solution and water, and concentrated under reduced pressure to obtain the crude product as a yellow oily substance (320 mg). Yield 48% (ESI 315.1(M+H)) + ).

[0606] Step 5: Methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate

[0607] [ka]

[0608] A mixture of tert-butyl 2-bromo-2-(3-(2-methoxypropan-2-yl)isochroman-5-yl) acetate (320 mg, 47% purity, 0.48 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (132 mg, 0.48 mmol), and diisopropylethylamine (186 mg, 1.44 mmol) in acetonitrile (12 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (25 mL). The organic phase was washed with brine, dehydrated with Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3, H2O / MeCN) to obtain methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl) acetate as a white solid (135 mg). Yield 55% (ESI 508.1(M+H) + ).

[0609] Step 6: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compound 12)

[0610] [ka]

[0611] A solution of methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl) acetate (115 mg) in THF (5 mL) was treated overnight at room temperature with LiOH (solution in 1 M H2O, 2.7 mL). The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 64% MeCN / H2O) to obtain compound 12 as a white solid (82 mg).

[0612] Compound 12 LC / MS ESI 494.2(M+H) + . 1 H NMR (500MHz, MeOD) δ7.64(m, 1H), 7.41(m, 2H), 7.28(m, 1H), 7.16(m, 1H), 6.39(m, 1H), 4.94(m, 1H), 4.22(m, 1H), 4.01(m, 2H), 3.55-3.64(m, 4H), 3.40(m, 3H), 3.33-3.37(m, 3H), 2.72(t, J=6.5Hz, 2H), 2.57(t, J=6.5Hz, 2H), 2.01-2.24(m, 2H), 1.88-1.98(m, 4H), 1.61-1.77(m, 6H).

[0613] [Example 13]: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compounds 13-E1 and 13-E2)

[0614] Step 1: Methyl 2-(2-chloropyridine-3-yl)acetate

[0615] [ka]

[0616] To a solution of 2-(2-chloropyridine-3-yl)acetic acid (1.71 g, 10 mmol) in MeOH (35 mL), concentrated H2SO4 (2 mL) was added. The reaction mixture was stirred at 85°C for 2 hours, concentrated under reduced pressure, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. Extraction was performed with siRNA (twice with 30 mL). The combined organic phases were washed with brine, dehydrated with Na2SO4, and concentrated to obtain the desired product, methyl 2-(2-chloropyridine-3-yl)acetate, as an orange-red oil (1.51 g, yield 81%). (ESI 186(M+H)) + ).

[0617] Step 2: Methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-yl)acetate

[0618] [ka]

[0619] A mixture of methyl 2-(2-chloropyridine-3-yl)acetate (372 mg, 2.0 mmol), 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 2.0 mmol), X-Phos Pd G4 (68 mg, 0.08 mmol), and K2CO3 (552 mg, 4 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was heated by microwave at 115°C for 2 hours. The mixture was diluted with H2O (10 mL) and extracted with  (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: siRNA 10:1) to obtain the desired product, methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-yl)acetate, as a pale orange-red oily substance (308 mg). Yield 66% (ESI 234.1(M+H)). + ).

[0620] Step 3: Methyl 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate

[0621] [ka]

[0622] A mixture of methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-yl) acetate (302 mg, 1.3 mmol) and Pd(OH)2 / C (20%, 100 mg) in MeOH (16 mL) was stirred under a balloon H2 at 35°C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the desired product, methyl 2-(2-(tetrahydro-2H-pyran-2-yl)pyridine-3-yl) acetate, as an orange-red oil (301 mg). Yield 94% (ESI 236.2(M+H)). + ).

[0623] Step 4: Methyl 2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)pyridine-3-yl)acetate

[0624] [ka]

[0625] To a solution of 2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate methyl 2-(2-(tetrahydro-2H-pyran-2-yl)pyridine-3-yl)acetate (301 mg, 1.28 mmol) in THF (8 mL), lithium diisopropylamide solution in THF / hexane (1.28 mL, 2.56 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 20 minutes. Next, chlorotrimethylsilane (278 mg, 2.56 mmol) in THF (0.5 mL) was added, and the reaction mixture was stirred for a further 10 minutes at -78°C. Next, NBS (456 mg, 2.56 mmol) in THF (4 mL) was added, and the reaction mixture was stirred at -78°C for 10 minutes, then added to water (10 mL) and extracted with  (20 mL). The organic phase was washed with saturated NaHCO3 solution and water, and concentrated under reduced pressure to obtain the crude product as a yellow oily substance (390 mg, purity 40%). Yield 39%. (ESI 315.1(M+H)) + ).

[0626] Step 5: Methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)pyrizin-3-yl)acetate

[0627] [ka]

[0628] A mixture of methyl 2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)pyridine-3-yl) acetate (390 mg, 40% purity), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (137 mg, 0.50 mmol), and diisopropylethylamine (194 mg, 1.50 mmol) in acetonitrile (10 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (8 mL) and extracted with ethyl acetate (25 mL). The organic phase was washed with brine, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC A (40% to 75% MeCN) to obtain the desired product, methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)pyridine-3-yl)acetate (105 mg), as a white solid. Yield 41% (ESI 509.2(M+H)). + ).

[0629] Step 6: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl)acetic acid (compounds 13-E1 and 13-E2)

[0630] [ka]

[0631] A solution of ethyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)phenyl) acetate (71 mg, 0.14 mmol) in THF (5 mL) was treated overnight at room temperature with LiOH (solution in 1 M H2O, 2.1 mL). The mixture was adjusted to pH 5-6 with aqueous HCl (1 N), concentrated under reduced pressure, and the residue was purified by preparative HPLC A (30% to 64% MeCN) to obtain the diastereomer products compound 13-E1 (23 mg) and compound 13-E2 ​​(12 mg) as white solids, which were mixtures of two stereoisomers, respectively.

[0632] Compound 13-E1 (mixture of two stereoisomers) LC / MS ESI 495.3(M+H) + . 1 H NMR (500MHz, MeOD) δ8.46(m, 1H), 8.21(m, 1H), 7.33(m, H), 7.16(m, 1H), 6.38(m, 1H), 5.12(m, 1H), 4.41(m, 1H), 4.05(m, 2H), 3.75(m, 1H), 3.75-3.37(m, 4H), 3.30-2.80(m, 2H), 2.73-2.69(m, 4H), 2.64-2.54(m, 2H), 1.96(m, 1H), 1.91-1.87(m, 6H), 1.78-1.58(m, 7H).

[0633] Compound 13-E2 ​​(mixture of two stereoisomers) LC / MS ESI 495.3(M+H) + . 1 H NMR (500MHz, MeOD) δ8.46(m, 1H), 8.14(m, 1H), 7.34(m, 1H), 7.16(m, 1H), 6.38(m, 1H), 5.04(m, 1H), 4.11(m, 2H), 3.68(m , 1H), 3.69-3.37(m, 5H), 3.11-2.98(m, 2H), 2.87-2.70(m, 4H), 2.56-2.54(m, 2H), 2.06-1.80(m, 7H), 1.78-1.59(m, 7H).

[0634] [Example 14]: Preparation of 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 14-E1 and 14-E2)

[0635] Step 1: Sodium (2-cyclopropylpyridine-3-yl)(hydroxy)methanesulfonate

[0636] [ka]

[0637] 2-Bromo-3-pyridinecarboxaldehyde (1 g, 5.38 mmol), cyclopropylboronic acid (1.385 g, 16.13 mmol), and sodium carbonate (2.279 g, 21.50 mmol) were dissolved in 1,2-dimethoxyethane (20 mL) and water (5 mL). Argon was passed over the mixture, and bis(triphenylphosphine)palladium(II) dichloride (0.377 g, 0.538 mmol) was added. The reaction was sealed and heated at 100 °C for 16 hours, diluted with water, and extracted with diethyl ether. The organic layer was washed twice with water, and a solution of sodium bisulfite (1.119 g, 10.75 mmol) in water and a small amount of methanol were added. The diethyl ether was removed under reduced pressure, and the resulting water / methanol mixture was used directly in the next step.

[0638] Step 2: 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)acetonitrile

[0639] [ka]

[0640] A water / methanol mixture containing sodium (2-cyclopropylpyridine-3-yl)(hydroxy)methanesulfonate (1.352 g, 5.38 mmol) was added to (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (0.963 g, 3.50 mmol), followed by the addition of potassium cyanide (1.752 g, 26.9 mmol). After 16 hours, a small amount of methanol was added. After 64 hours, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layer was dehydrated with sodium sulfate and concentrated under reduced pressure to obtain the desired product, 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)butoxy)pyrrolidine-1-yl)acetonitrile (1.511 g). Yield 65% (ESI 430(MH)) - ).

[0641] Step 3: 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetamide

[0642] [ka]

[0643] To a solution of 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetonitrile (1.511 g, 3.5 mmol) in dichloromethane (10 mL), sulfuric acid (25 mL, 469 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, then stopped on ice, neutralized with aqueous ammonia, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dehydrated with sodium sulfate, concentrated, and the residue purified by reverse-phase chromatography (10 mM ammonium bicarbonate aqueous solution, 20% to 60% acetonitrile) to obtain the desired product 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)acetamide (399 mg). Yield 25% (ESI 450(M+H) + ).

[0644] Step 4: 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 14-E1 and 14-E2)

[0645] [ka]

[0646] A solution of 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetamide (399 mg, 0.887 mmol) in hydrochloric acid (10 mL, 40 mmol, 4N aqueous solution) was stirred at 70°C for 88 hours. The mixture was concentrated, the residue was dissolved in water, and freeze-dried. The residue was dissolved in water (10 mL) and purified by reverse-phase chromatography to obtain 2-(2-cyclopropylpyridine-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid compound 14 (311 mg) as a diastereomer mixture. Yield 78% (ESI 451(M+H)) + The mixture was separated by chiral SFC to obtain the diastereomer products compound 14-E1 (107 mg) and compound 14-E2 (100 mg). Method: Water Acquity UPC2 (Binary Solvent Manager, Isocratic Solvent Manager, Sample Manager, Column Manager 30S, Convergence Manager, PDA Detector, Acquity QDa Detector); Column: Chiralpak IC for SFC (100 × 4.6 mm, 5 μm). Temperature: 35 °C. Back pressure: 170 bar. Flow rate: 2.5 mL / min. Eluent A: CO2. Eluent B: Methanol + 20 mM ammonia. Gradient: t0 = 5% B, t2.5 min = 50% B, t30 min = 50% B, Post-time: 0.5 min. Detection PDA: 210~320 nm. Detection MS: ESI, Mass range: 700~1250 (positive) 1Hz, Cone: 15V.

[0647] Compound 14-E1: 107mg, LC / MS ESI 451(M+H) + . 1H NMR (400MHz, methanol-d4) δ8.37 (dd, J=4.7, 1.7Hz, 1H), 7.97 (dd, J=8.0, 1.8Hz, 1H) , 7.24-7.08(m, 2H), 6.40(d, J=7.3Hz, 1H), 5.04(s, 1H), 4.22-4.13(m, 1H), 3.55-3 .33(m, 5H), 3.23-3.10(m, 2H), 2.79-2.66(m, 2H), 2.66-2.46(m, 3H), 2.22-2.05(m , 2H), 1.94-1.82(m, 2H), 1.80-1.45(m, 5H), 1.27-1.15(m, 1H), 1.07-0.88(m, 3H).

[0648] Compound 14-E2: 100mg, LC / MS ESI 451(M+H) + . 1 H NMR (400MHz, methanol-d4) δ8.38 (dd, J=4.8, 1.7Hz, 1H), 7.94 (dd, J=7.8, 1.7Hz, 1H), 7.24-7. 13(m, 2H), 6.40(d, J=7.3Hz, 1H), 5.13(s, 1H), 4.25-4.14(m, 1H), 3.58-3.32(m, 6H), 3.27-3 .14(m, 1H), 3.07-2.95(m, 1H), 2.78-2.66(m, 2H), 2.64-2.49(m, 2H), 2.49-2.38(m, 1H), 2.1 8-2.02(m, 2H), 1.95-1.82(m, 2H), 1.81-1.45(m, 5H), 1.30-1.15(m, 1H), 1.06-0.86(m, 3H).

[0649] [Example 15]: Preparation of 2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-yl)acetic acid (compounds 15-E1 and 15-E2)

[0650] Step 1: 2-(2-cyclopropylphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyloxy)pyrrolidine-1-yl)acetic acid (compounds 15-E1 and 15-E2)

[0651] [ka]

[0652] (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine dihydrochloride (200 mg, 0.55 mmol) was dissolved in DMF (2 mL), to which 2-cyclopropylphenylboronic acid (116 mg, 0.72 mmol) and 2-oxoacetic acid (56 mg, 0.6 mmol) were added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was purified by preparative HPLC (40% to 65% MeCN) to obtain 90 mg of the racemic compound 15. The racemic product was separated by preparative chiral SFC A to obtain the diastereomer products compound 15-E1 (23 mg) and compound 15-E2 (22 mg) as white solids.

[0653] Compound 15-E1 LC / MS ESI 464.2(M+H) + . 1 H NMR (500MHz, MeOD) δ7.61(d, J=7.1Hz, 1H), 7.31(m, 2H), 7.16(dd, J=21.5, 7.4H z, 2H), 6.37(d, J=7.3Hz, 1H), 5.35(s, 1H), 4.23(s, 1H), 3.65(m, 1H), 3.49(t, J= 6.4Hz, 2H), 3.42-3.36(m, 2H), 3.30-2.99(m, 3H), 2.70(t, J=6.3Hz, 2H), 2.53(t , J=7.5Hz, 2H), 2.21(m, 3H), 1.88(m, 2H), 1.12-0.94(m, 3H), 0.70-0.51(m, 1H). Chiral SFC A (40%MeOH): ee98%, Rt=2.46 min.

[0654] Compound 15-E2 LC / MS ESI 464.2(M+H) + . 1H NMR (500MHz, MeOD) δ7.54(d, J=7.5Hz, 1H), 7.17(m, 2H), 7.07-6.97(m, 2H), 6. 26(d, J=7.3Hz, 1H), 5.08(s, 1H), 4.06(s, 1H), 3.43-3.24(m, 5H), 3.14-2.98(m , 2H), 2.59(t, J=6.2Hz, 2H), 2.48-2.36(m, 2H), 2.15(m, 3H), 1.81-1.70(m, 2H) ), 1.63-1.45(m, 4H), 1.39-1.26(m, 2H), 0.96-0.77(m, 3H), 0.55-0.42(m, 1H). Chiral SFC A (40%MeOH): ee98%, Rt=3.5 min.

[0655] [Example 16]: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetic acid (compounds 16-E1 and 16-E2)

[0656] Step 1: Methyl 2-(2-(furan-2-yl)phenyl)acetate

[0657] [ka]

[0658] To a solution of methyl 2-(2-iodophenyl)acetate (552 mg, 2 mmol) in anhydrous DMF (5 mL), furan-2-ylboronic acid (224 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (91.5 mg, 0.1 mmol), X-Phos (47.6 mg, 0.1 mmol), and potassium phosphate (424 mg, 2 mmol) were added. The mixture was stirred under N2 at 60°C for 1 hour. The reaction solution was allowed to cool and diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (twice with 20 mL). The combined organic layers were washed with brine and dehydrated with anhydrous sodium 2 SO4. After filtration and concentration, the residue was chromatographically purified using 5% to 20% SiO2 / petroleum ether as the eluent (Combiflash) to obtain 340 mg (78.3%) of methyl 2-(2-(furan-2-yl)phenyl) acetate; (ESI 217(M+H) + ).

[0659] Step 2: Methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate

[0660] [ka]

[0661] To a solution of methyl 2-(2-(furan-2-yl)phenyl)acetate (340 mg, 1.57 mmol) in anhydrous MeOH (10 mL), Pd / C (30 mg) was added. The mixture was stirred at 40°C for 3 hours under an H2 atmosphere (balloon). After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographically purified using 5% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (290 mg, 84%) as an oil. (ESI 221(M+H)) + ).

[0662] Step 3: Methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate

[0663] [ka]

[0664] A solution of methyl 2-(2-(tetrahydrofuran-2-yl)phenyl) acetate (220 mg, 1 mmol) in THF (10 mL) was cooled to -78°C under N2 and treated with LDA (1.25 mL, 2.5 mmol, in 2 M THF solution). The reaction mixture was stirred for 0.5 hours and treated with TMSCl (324 mg, 3 mmol) and, after 0.25 hours, with NBS (534 mg, 3 mmol) in 10 mL of anhydrous THF solution. The mixture was stirred at -78°C for 0.5 hours and the reaction was stopped by adding water (10 mL). The mixture was extracted with ethyl acetate (twice with 20 mL). The combined organic layers were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate (210 mg, 70.5%); (ESI 299(M+H) + ).

[0665] Step 4: Methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate

[0666] [ka]

[0667] To a solution of methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate (100 mg, 0.33 mmol) in acetonitrile (5 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (92 mg, 0.33 mmol) and diisopropylethylamine (129 mg, 1 mmol) were added. The reaction mixture was stirred for 2 hours, diluted with water (10 mL), and extracted with ethyl acetate (three times with 20 mL). The combined organic layers were washed with brine and dehydrated with anhydrous sodium 2SO4. After filtration and concentration, the residue was chromatographically purified using 20% ​​to 80% ethyl alcohol / petroleum ether as the eluent (Combiflash) to obtain methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (90 mg, 54.4%). (ESI 494(M+H) + ).

[0668] Stage 5: 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetic acid (compounds 16-E1 and 16-E2)

[0669] [ka]

[0670] To a solution of methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (90 mg, 0.18 mmol) in (5 mL) methanol, LiOH (9 mg, 0.4 mmol) and water (2 mL) were added. The reaction mixture was stirred for 5 hours, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase half-step HPLC to obtain diastereomer products, compound 16-E1 (40 mg, yield 45.7%) and compound 16-E2 (19 mg, yield 22.7%), which were mixtures of two stereoisomers, respectively.

[0671] Compound 16-E1 (mixture of two stereoisomers): LC / MS ESI 480.2(M+H) + . 1 H NMR (500MHz, MeOD) δ7.69(dd, J=11.4, 7.8Hz, 1H), 7.55(d, J=7.8Hz, 1H), 7.41(t, J=7.5Hz, 1H), 7.38-7.29(m, 1H), 7.15(d, J=7. 3Hz, 1H), 6.39(dd, J=7.3, 2.7Hz, 1H), 5.30(dt, J=33.4, 7.0Hz, 1H), 4.97(s, 1H), 4.17(d, J=21.0Hz, 1H), 4.08(dd, J=14.1, 6.9H) z, 1H), 3.90(ddt, J=14.0, 9.6, 6.9Hz, 1H), 3.57(s, 1H), 3.51-3.35(m, 4H), 3.29-2.98(m, 3H), 2.71(t, J=6.3Hz, 2H), 2.56(t, J= 7.6Hz, 2H), 2.52-2.42(m, 1H), 2.18-1.94(m, 5H), 1.88(dd, J=11.5, 6.1Hz, 2H), 1.77-1.69(m, 2H), 1.62(dd, J=13.6, 6.7Hz, 2H).

[0672] Compound 16-E2 (mixture of two stereoisomers) LC / MS ESI 480.2(M+H) + . 1H NMR (500MHz, MeOD) δ7.65(d, J=5.5Hz, 1H), 7.46(d, J=7.6Hz, 1H), 7.41-7.30(m, 2H), 7.16(d, J=7.3Hz) , 1H), 6.39(dd, J=7.3, 1.6Hz, 1H), 5.23-5.10(m, 1H), 4.96(s, 1H), 4.19-4.06(m, 2H), 3.93-3.84(m, 1 H), 3.57(s, 1H), 3.50-3.36(m, 5H), 3.16-2.96(m, 2H), 2.75-2.65(m, 2H), 2.56(t, J=7.4Hz, 2H), 2.45 -2.35(m, 1H), 2.16-1.99(m, 5H), 1.88(dd, J=11.4, 5.8Hz, 2H), 1.76-1.68(m, 2H), 1.65-1.59(m, 2H).

[0673] [Example 17]: Preparation of 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetic acid (compound 17)

[0674] Step 1: Methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl)acetate

[0675] [ka]

[0676] To a solution of methyl 2-(2-iodophenyl)acetate (1.3 g, 4.8 mmol) in anhydrous DME (20 mL) and EtOH (5 mL), 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0) (277 mg, 0.24 mmol), and sodium carbonate (1.0 g, 9.6 mmol) were added, and the mixture was heated under N2 at 100°C for 12 hours. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (50 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times with 50 mL). The organic phases were combined, washed with brine, and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl) acetate (0.4 g, 36%) as an oily substance. (ESI 233.1(m+1)) + ).

[0677] Step 2: Methyl 2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0678] [ka]

[0679] A mixture of methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)phenyl) acetate (300 mg, 1.3 mmol) and Pd(OH)2 / C (100 mg) in MeOH (25 mL) was hydrogenated at 35°C for 3 hours (balloon). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (180 mg, 60%) as an oily substance. (ESI 235.1(m+1)) + ).

[0680] Step 3: Methyl 2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0681] [ka]

[0682] A solution of methyl 2-(2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (150 mg, 0.64 mmol) in THF (10 mL) was stirred, and LDA (1.25 mL, 2.5 mmol, in 2 M THF solution) was added to it under N2 at -78°C. The reaction mixture was stirred for 0.5 hours, TMSCl (324 mg, 3.0 mmol) was added, the reaction mixture was stirred for 0.25 hours, and NBS (445 mg, 2.5 mmol) was added as a solution in THF (10 mL). The reaction mixture was stirred at -78°C for 0.5 hours, and the reaction was stopped by adding water (10 mL). The mixture was extracted with ethyl acetate (3 times with 30 mL), the combined organic phase was washed with brine, and dehydrated with anhydrous Na2SO4. After filtration and concentration, the product was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (65 mg, 33%). (ESI 313.2(m+1) + ) was obtained.

[0683] Step 4: Methyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0684] [ka]

[0685] A mixture of methyl 2-bromo-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (65 mg, 0.21 mmol), (57 mg, 0.21 mmol), and diisopropylethylamine (65 mg, 0.5 mmol) in acetonitrile (8 mL) was stirred at 25°C for 16 hours. The solvent was removed under reduced pressure, and the residue was chromatographically purified using silica gel (DCM:MeOH 20:1) to obtain ethylmethyl 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (30 mg, 28%) as an oily substance. (ESI 508.1(m+1)) + ).

[0686] Stage 5: 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)-2-(2-(tetrahydro-2H-pyran-2-yl)phenyl)acetic acid (compound 17)

[0687] [ka]

[0688] Methyl 2-(2-cyclopropylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (30 mg, 0.28 mmol) was treated with LiOH (52 mg, 1.24 mmol) in MeOH (4 mL) and H2O (1 mL) for 3 hours at 25°C. The solvent was removed under reduced pressure, and the residue was separated using preparative reverse-phase HPLC (preparative HPLC A, 30% to 65% MeCN) to obtain compound 17 as a solid (10 mg, 34%).

[0689] Compound 17: LC / MS ESI 494.2(M+H) + . 1 1H NMR (400 MHz, MeOD) δ 1H NMR (500MHz, MeOD) δ7.68(t, J=8.3Hz, 1H), 7.57(d, J=7.8Hz, 1H), 7.40(dt, J=13.8, 7.5Hz, 2H), 7.15(d, J=7 .3Hz, 1H), 6.38(dd, J=7.3, 3.3Hz, 1H), 4.89-4.76(m, 2H), 4.18(d, J=17.9Hz, 1H), 4.09-3.94(m, 1H), 3.72( dd, J=22.4, 10.7Hz, 1H), 3.54-3.43(m, 2H), 3.38(dd, J=10.1, 4.5Hz, 3H), 2.77-2.65(m, 2H), 2.55(t, J=6.7 Hz, 2H), 2.17-1.97(m, 4H), 1.93-1.85(m, 2H), 1.81-1.58(m, 8H), 1.51-1.45(m, 1H), 1.33(d, J=22.7Hz, 3H).

[0690] [Example 18]: Preparation of 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 18-E1 and 18-E2)

[0691] Step 1: Methyl 2-(2-bromo-5-fluorophenyl)acetate

[0692] [ka]

[0693] 2-(2-bromo-5-fluorophenyl)acetic acid (10 g, 43 mmol) was dissolved in MeOH (60 mL) and 0.5 mL of H2SO4 was added. The mixture was refluxed for 4 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The resulting pale yellow oily substance (10 g, 94.3%) was used without further purification. (ESI 246.1(M+H)) + ).

[0694] Step 2: Methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate

[0695] [ka]

[0696] To a solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (6.3 g, 25.6 mmol) in DMF (60 mL), 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester (5 g, 23.8 mmol), tris(dibenzylideneacetone)dipalladium (0) (468 mg, 0.52 mmol), X-Phos (238 mg, 0.52 mmol), and potassium phosphate (2.1 g, 25.6 mmol) were added. The mixture was stirred under N2 at 60°C for 12 hours. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate (120 mL) and water (120 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (three times with 60 mL). The combined organic phases were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (5.2g, 87.4%). (ESI 251.1(M+H) + ).

[0697] Step 3: Methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0698] [ka]

[0699] To a solution of methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (500 mg, 2 mmol) in anhydrous MeOH (25 mL), diisopropylethylamine (0.5 mL) and Pd / C (100 mg) were added. The mixture was stirred under H2 (with a balloon) at 40°C for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (260 mg, 52%) as an oil. (ESI 253.1(M+H)) + ).

[0700] Stage 4: Methyl 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0701] [ka]

[0702] LDA (1.25 mL, 2.5 mmol, in 2M THF solution) was added to methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (260 mg, 1.03 mmol) in THF (10 mL) under N2 conditions at -78°C. The reaction mixture was stirred for 0.5 hours, and TMSCl (324 mg, 3 mmol) was added. After another 0.25 hours, NBS (534 mg, 3 mmol) in THF (10 mL) solution was added, and the reaction mixture was stirred at -78°C for 0.5 hours. The mixture was heated to room temperature and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 times with 30 mL), the combined organic phase was washed with brine, and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 0% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (280 mg, 84.8%). (ESI 333.1(M+H)+ ).

[0703] Step 5: Methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0704] [ka]

[0705] To a solution of methyl 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (70 mg, 0.21 mmol) in DMF (5 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (57 mg, 0.21 mmol) and diisopropylethylamine (81 mg, 0.63 mmol) were added, and the reaction mixture was stirred for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (twice with 20 mL). The combined organic phases were washed with brine and dehydrated with anhydrous sodium 2SO4. After filtration and concentration, the residue was chromatographically purified using 20% ​​to 80% ethyl acetate / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate (70 mg, 62.8%). (ESI 526.2(M+H) + ).

[0706] Step 6: 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 18-E1 and 18-E2)

[0707] [ka]

[0708] To a solution of methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (70 mg, 0.13 mmol) in MeOH (5 mL), LiOH (10 mg, 0.4 mmol) and water (2 mL) were added. The reaction mixture was stirred for 2 hours, filtered, and concentrated under reduced pressure. Half of the residue was taken and chromatographically purified by reverse-phase HPLC to obtain the diastereomer products compound 18-E1 (25 mg, 36.7%) and compound 18-E2 (13 mg, yield 18.3%), which were mixtures of two stereoisomers, respectively.

[0709] Compound 18-E1 (mixture of two stereoisomers): LC / MS ESI 512.2(M+H) + . 1 H NMR (500MHz, MeOD) δ7.58(dd, J=8.8, 5.9Hz, 1H), 7.52-7.42(m, 1H), 7.21-7.11(m, 2H), 6.40(d, J=7.3Hz, 1 H), 4.80(dd, J=21.1, 11.7Hz, 2H), 4.22-4.12(m, 1H), 4.04(dd, J=10.4, 5.6Hz, 1H), 3.76-3.66(m, 1H), 3.61 (d, J=8.1Hz, 1H), 3.49(dtd, J=12.6, 6.3, 3.3Hz, 2H), 3.42-3.34(m, 3H), 3.22-2.99(m, 2H), 2.72(t, J=6.2H) z, 2H), 2.60-2.51(m, 2H), 2.16-1.96(m, 4H), 1.92-1.82(m, 2H), 1.70(dddd, J=28.3, 22.6, 9.4, 4.8Hz, 9H).

[0710] Compound 18-E2 (mixture of two stereoisomers): LC / MS ESI 512.2(M+H) + . 1H NMR (500MHz, MeOD) δ7.44 (dt, J=8.5, 6.0Hz, 2H), 7.18 (t, J=7.7Hz, 1H), 7.10 (qd, J=8.4, 2.6Hz, 1H), 6. 39(dd, J=7.3, 4.0Hz, 1H), 5.21(s, 1H), 4.74(dd, J=29.6, 11.1Hz, 1H), 4.10(dd, J=26.7, 15.4Hz, 2H), 3. 66(dd, J=20.8, 9.7Hz, 1H), 3.54-3.37(m, 6H), 3.15-2.96(m, 2H), 2.72(t, J=6.2Hz, 2H), 2.58(dt, J=14 .9, 6.9Hz, 2H), 2.10(dd, J=34.9, 11.9Hz, 2H), 1.99-1.80(m, 5H), 1.77-1.66(m, 4H), 1.63-1.55(m, 3H).

[0711] [Example 19]: Preparation of 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 19-E1, 19-E2, 19-E3 and 19-E4)

[0712] Step 1: Methyl 2-(2-bromo-5-fluorophenyl)acetate

[0713] [ka]

[0714] 2-(2-bromo-5-fluorophenyl)acetic acid (10 g, 43 mmol) was dissolved in MeOH (60 mL) and 0.5 mL of H2SO4 was added. The mixture was refluxed for 4 hours, allowed to cool to room temperature, and the solvent was removed under reduced pressure. The resulting oily substance (10 g, 94.3%) was used without further purification. (ESI 246.1(M+H)) + ).

[0715] Step 2: Methyl 2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)acetate

[0716] [ka]

[0717] To a solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (492 mg, 2 mmol) in DMF (5 mL), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (392 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.1 mmol), X-Phos (47.6 mg, 0.1 mmol), and potassium phosphate (424 mg, 2 mmol) were added. The resulting mixture was stirred under N2 at 60°C for 2 hours, allowed to cool to room temperature, and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times with 20 mL). The combined organic phases were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 20% ​​to 80% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)acetate (350 mg, 73%). (ESI 237.2(M+H) + ).

[0718] Step 3: Methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate

[0719] [ka]

[0720] To a solution of methyl 2-(2-(2,5-dihydrofuran-3-yl)-5-fluorophenyl)acetate (350 mg, 1.48 mmol) in methanol (10 mL), Pd / C (50 mg) was added. The mixture was stirred under H2 (in a balloon) at 40°C for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographically purified using 5% to 20% siRNA / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate (260 mg, 73%) as an oily substance. LCMS: 239(M+H) + .

[0721] Stage 4: Methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)acetate

[0722] [ka]

[0723] A solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl) acetate (260 mg, 1.09 mmol) in THF (10 mL) was cooled to -78°C under N2, treated with LDA (1.25 mL, 2.5 mmol, in 2 M THF solution), and the mixture was stirred for 0.5 hours. TMSCl (324 mg, 3 mmol) was added, and the reaction mixture was stirred for 0.25 hours. NBS (534 mg, 3 mmol) in THF (10 mL) was added. The reaction mixture was stirred for 0.5 hours, diluted with water, and extracted with ethyl acetate (three times with 30 mL). The combined organic phases were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using 5% to 20% butyl / petroleum ether as the eluent (Combiflash) to obtain methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl) acetate (250 mg, 71.8%) as an oily substance. (ESI 317.2)(M+H) + ).

[0724] Step 5: Methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0725] [ka]

[0726] To a solution of methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl) acetate (100 mg, 0.31 mmol) in anhydrous DMF (5 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (87 mg, 0.31 mmol) and diisopropylethylamine (120 mg, 0.93 mmol) were added. The reaction mixture was stirred for 2 hours, diluted with water (10 mL), and extracted with ethyl acetate (three times with 20 mL). The combined organic phase was washed with brine and dehydrated with anhydrous sodium 2SO4. After filtration and concentration, the residue was chromatographically purified using 20% ​​to 80% ethyl alcohol / petroleum ether as the eluent (Combiflash) to obtain methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (110 mg, 68%) as a solid. (ESI 512(M+H) + ).

[0727] Step 6: 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 19-E1, 19-E2, 19-E3 and 19-E4)

[0728] [ka]

[0729] To a solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-3-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (110 mg, 0.21 mmol) in methanol (5 mL), LiOH (20 mg, 0.8 mmol) and water (4 mL) were added. The reaction mixture was stirred for 2 hours, filtered, and concentrated under reduced pressure. The resulting residue was chromatographically purified using reverse-phase HPLC to obtain the diastereomer compounds compound 19-E1 (10 mg, yield 9.3%), compound 19-E2 (10 mg, yield 9.3%), compound 19-E3 (10 mg, yield 9.3%), and compound 19-E4 (10 mg, yield 9.3%).

[0730] Compound 19-E1: LC / MS ESI 498.2(M+H) + . 1 H NMR (500MHz, MeOD) δ7.48 (dd, J=8.8, 5.7Hz, 1H), 7.42 (dd, J=10.1, 2.7Hz, 1H), 7.23 (d, J=7.3Hz, 1H), 7.14 (td, J=8.4, 2.8Hz, 1H), 6.41 (dd, J=20.8, 7.3Hz, 1H), 4.95(s, 1H), 4.58-4.46(m, 1H), 4.18(d, J=18.9Hz, 1H), 4.05-3.98(m, 2H), 3.86(dd, J=15.5, 7.5Hz, 2H), 3.79 (dd, J=8.3, 6.3Hz, 1H), 3.50(t, J=6.2Hz, 2H), 3.42(dd, J=14.2, 8.7Hz, 3H), 3.28(s, 1H), 3.12-2.98(m, 2H), 2.73(t, J=6.2Hz, 2H), 2.6 0(ddd, J=15.0, 9.5, 5.5Hz, 2H), 2.51-2.38(m, 1H), 2.08(ddd, J=14.9, 8.4, 4.6Hz, 3H), 1.90(dd, J=11.8, 5.7Hz, 2H), 1.80-1.60(m, 4H).

[0731] Compound 19-E2: LC / MS ESI 498.2(M+H) + . 11H NMR (500 MHz, MeOD) δ 7.51 - 7.46 (m, 1H), 7.42 (dd, J = 10.1, 2.7 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 6.43 (d, J = 7.3 Hz, 1H), 4.94 (s, 1H), 4.17 (dd, J = 19.1, 11.5 Hz, 2H), 4.11 - 4.03 (m, 1H), 3.95 - 3.80 (m, 3H), 3.76 - 3.68 (m, 1H), 3.52 - 3.46 (m, 3H), 3.43 - 3.37 (m, 2H), 3.26 (d, J = 12.5 Hz, 1H), 3.13 - 2.99 (m, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.42 - 2.29 (m, 1H), 2.07 (dtd, J = 42.5, 12.5, 7.8 Hz, 4H), 1.94 - 1.86 (m, 2H), 1.78 - 1.69 (m, 2H), 1.68 - 1.58 (m, 3H).

[0732] Compound 19-E3: LC / MS ESI 498.2 (M+H) + . 1 1H NMR (500 MHz, MeOD) δ 7.52 - 7.39 (m, 2H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 6.42 (t, J = 10.9 Hz, 1H), 4.87 - 4.81 (m, 1H), 4.17 (s, 1H), 4.04 (ddt, J = 33.6, 28.5, 7.3 Hz, 3H), 3.88 (dd, J = 15.7, 7.6 Hz, 1H), 3.79 (dd, J = 8.2, 6.2 Hz, 1H), 3.56 - 3.51 (m, 1H), 3.46 - 3.34 (m, 4H), 3.16 (ddd, J = 16.9, 15.7, 6.6 Hz, 3H), 2.73 (t, J = 6.2 Hz, 2H), 2.62 (dd, J = 16.3, 7.8 Hz, 2H), 2.48 (d, J = 7.6 Hz, 1H), 2.18 - 2.12 (m, 2H), 2.09 - 2.01 (m, 1H), 1.92 - 1.86 (m, 2H), 1.75 (dd, J = 12.1, 7.4 Hz, 2H), 1.68 - 1.60 (m, 2H).

[0733] Compound 19-E4: LC / MS ESI 498.2 (M+H)+ . 1 H NMR (500MHz, MeOD) δ7.46 (ddd, J=13.0, 9.5, 4.3Hz, 2H), 7.24 (d, J=7.3Hz, 1H), 7.13 (td, J=8.4, 2.8Hz, 1H), 6.43 (d, J=7.3Hz, 1H), 4.86 (s, 1H), 4.23-4.14(m, 2H), 4.09(td, J=8.3, 4.6Hz, 1H), 3.98(dd, J=14.8, 7.4Hz, 1H), 3.86(dd, J=15.9, 7.7Hz, 1H), 3.71(dd, J=8.6, 6.5 Hz, 1H), 3.54(dt, J=9.1, 6.1Hz, 1H), 3.46-3.35(m, 4H), 3.25-3.08(m, 3H), 2.73(t, J=6.2Hz, 2H), 2.69-2.54(m, 2H), 2.39(d, J=7.8Hz, 1H), 2.16(d, J=3.6Hz, 2H), 2.02(dq, J=12.4, 7.8Hz, 1H), 1.95-1.83(m, 2H), 1.75(dd, J=12.3, 7.4Hz, 2H), 1.62(dd, J=13.6, 7.0Hz, 2H).

[0734] [Example 20]: Preparation of 2-(2-cyclopropoxy-5-fluorophenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 20-E1 and 20-E2)

[0735] Stage 1: 2-bromo-1-cyclopropoxy-4-fluorobenzene

[0736] [ka]

[0737] A mixture of 2-bromo-4-fluorophenol (250 mg, 1.31 mmol), bromocyclopropane (792 mg, 6.54 mmol), NaI (2 mg, 0.013 mmol), and K2CO3 (543 mg, 3.93 mmol) in DMF (4 mL) was stirred and heated under microwave irradiation (Biotage) to 150°C for 2 hours. The reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times with 10 mL). The combined organic layer was washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using HCl / petroleum ether (1:10) as the eluent (Combiflash) to obtain 2-bromo-1-cyclopropoxy-4-fluorobenzene (50 mg, 16.5%). 1 H NMR (500MHz, CDCl3) δ7.28-7.22(m, 1H), 7.18(dd, J=9.1, 4.9Hz, 1H), 7.03-6.94(m, 1H), 3.76(tt, J=5.9, 3.1Hz, 1H), 0.87-0.69(m, 4H).

[0738] Stage 2: 2-Cyclopropoxy-5-Fluorophenylboronic Acid

[0739] [ka]

[0740] To a solution of 2-bromo-1-cyclopropoxy-4-fluorobenzene (250 mg, 1.08 mmol) in THF (15 mL), nBuLi (0.87 mL, 2.16 mmol, 2.5 M THF solution) was added under Ar at -78 °C. The mixture was stirred for 0.5 hours, and triisopropyl borate (224 mg, 1.19 mmol) was slowly added by syringe. The mixture was continuously stirred at -78 °C for 2 hours, and the reaction was stopped by adding saturated NH4Cl aqueous solution (5 mL). The mixture was heated to room temperature and partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3 times with 15 mL), washed with brine, and dehydrated with anhydrous Na2SO4. The organic phase was concentrated to dryness to obtain 2-bromo-1-cyclopropoxy-4-fluorobenzene (70 mg, yield 33.0%).

[0741] Step 3: 2-(2-cyclopropoxy-5-fluorophenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 20-E1 and 20-E2)

[0742] [ka]

[0743] A mixture of (R)-7-(5-(pyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (60 mg, 0.22 mmol), 2-cyclopropoxy-5-fluorophenylboronic acid (47 mg, 0.24 mmol), and 2-oxoacetic acid (18 mg, 0.24 mmol) in MeCN (4 mL) was stirred for 2 hours. The residue was chromatographically purified using reverse-phase HPLC (30% to 65% MeCN) to obtain compound 20 (45 mg, 42.6%). The racemic product was separated into diastereomer products, compound 20-E1 (9.3 mg) and compound 20-E2 (11.1 mg), by chiral SFC.

[0744] Compound 20-E1 LC / MS ESI 482.2 (M+H) + . 1 H NMR (500 MHz, MeOD) δ 7.42 (dd, J = 9.1, 4.5 Hz, 1H), 7.31 (dd, J = 8.9, 2.8 Hz, 1H), 7.16 (ddd, J = 20.7, 12.9, 5.2 Hz, 2H), 6.35 (d, J = 7.3 Hz, 1H), 4.86 (s, 1H), 4.11 - 3.80 (m, 1H), 3.48 - 3.35 (m, 3H), 3.17 (dd, J = 23.9, 15.4 Hz, 2H), 2.87 (s, 1H), 2.71 (t, J = 6.3 Hz, 2H), 2.50 (t, J = 7.6 Hz, 2H), 2.38 - 2.25 (m, 1H), 2.24 - 2.08 (m, 1H), 1.89 (dt, J = 12.2, 6.1 Hz, 2H), 1.62 (dd, J = 13.5, 7.4 Hz, 3H), 1.41 (s, 2H), 1.32 (dd, J = 22.3, 9.5 Hz, 5H), 0.98 - 0.71 (m, 4H).

[0745] Compound 20-E2 LC / MS ESI 482.2 (M+H) + . 1 H NMR (500 MHz, MeOD) δ 7.43 (dd, J = 9.1, 4.5 Hz, 1H), 7.33 (dd, J = 8.9, 2.9 Hz, 1H), 7.22 - 7.15 (m, 1H), 7.14 (d, J = 7.3 Hz, 1H), 6.36 (t, J = 5.8 Hz, 1H), 4.88 - 4.82 (m, 1H), 4.00 - 3.87 (m, 1H), 3.60 (s, 1H), 3.44 - 3.34 (m, 3H), 3.16 - 3.04 (m, 1H), 2.72 (dd, J = 15.9, 9.5 Hz, 3H), 2.56 - 2.46 (m, 2H), 2.42 - 2.31 (m, 1H), 2.22 - 2.07 (m, 1H), 1.94 - 1.83 (m, 2H), 1.67 - 1.60 (m, 3H), 1.43 (s, 2H), 1.35 (d, J = 4.6 Hz, 5H), 0.95 - 0.70 (m, 4H).

[0746] [Example 21]: Preparation of 2-(2-cyclobutylpyridine-3-yl)-2-((3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 21-B-E1, 21-B-E2 and 21-A)

[0747] Step 1: Ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B

[0748] [ka]

[0749] A mixture of 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyrizine stereoisomer B (120 mg, 0.44 mmol), ethyl 2-chloro-2-(2-cyclobutylpyridine-3-yl) acetate (110 mg, 0.44 mmol), and diisopropylethylamine (513 mg, 3.72 mmol) in acetonitrile (8 mL) was stirred at 50°C for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B, as a yellow oily substance (95 mg). Yield 44% (ESI 493(M+H) + ).

[0750] Stage 2: 2-(2-cyclobutylpyridine-3-yl)-2-((3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (compounds 21-B-E1 and 21-B-E2)

[0751] [ka]

[0752] Ethyl 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (95 mg, 0.19 mmol) was treated with LiOH-H2O (52 mg, 1.24 mmol) in MeOH (4 mL) and H2O (1 mL) for 4 hours at 40°C. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain compound 21-B as a white solid (68 mg, yield 77%). The racemic product was separated by preparative chiral SFC F to obtain the diastereomer products compound 21-B-E1 (4 mg) and compound 21-B-E2 (6 mg) as white solids.

[0753] Compound 21-B-E1 LC / MS ESI 465(M+H) + . 1 H NMR (500MHz, MeOD) δ8.68(m, 1H), 8.08(d, J=9.5Hz, 1H), 7.71(m, 1H), 7.31(m, 2H), 6.52(m, 1H), 4.82(s, 1H) ), 4.23(m, 2H), 3.55-3.35(m, 4H), 3.20(m, 3H), 2.76(m, 2H), 2.63-1.86(m, 9H), 1.75-1.50(m, 7H), Chiral SFC F:ee100%, Rt=7.78 minutes.

[0754] Compound 21-B-E2 LC / MS ESI 465(M+H) + . 1H NMR (500MHz, MeOD) δ8.58(m, 1H), 8.08(d, J=9.5Hz, 1H), 7.75(m, 1H), 7.31(m, 2H), 6.52(m, 1H), 4.82(s, 1H) ), 4.23(m, 2H), 3.55-3.35(m, 4H), 3.20(m, 3H), 2.76(m, 2H), 2.63-1.86(m, 9H), 1.75-1.50(m, 7H), Chiral SFC F:ee100%, Rt=12.02 minutes.

[0755] Stage 3: 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer A (compound 21-A)

[0756] [ka]

[0757] Using the same procedure as for stereoisomer B, stereoisomer A (compound 21-A) of 2-(2-cyclobutylpyridine-3-yl)-2-((R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthiridine-2-yl)butoxy)pyrrolidine-1-yl) acetate was synthesized from stereoisomer A of 2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine.

[0758] Compound 21-A LC / MS ESI 465.3(M+H) + . 1 H NMR (500MHz, MeOD) δ8.56-8.54(m, 1H), 8.08-8.01(m, 1H), 7.72-7.70(m, 1H), 7.32-7.29(m, 2H), 6.56-6.52(m, 1H), 4.82-4. 73(m, 1H), 4.30-4.18(m, 2H), 3.78-3.35(m, 4H), 3.28-2.95(m, 3H), 2.81-2.28(m, 6H), 2.24-1.88(m, 5H), 1.74-1.48(m, 7H).

[0759] [Example 22]: Preparation of 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomer compounds 92-A-E1, 92-A-E2, 92-B-E1 and 92-B-E2)

[0760] Step 1: Methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0761] [ka]

[0762] To a solution of methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (2.4 g, 9.6 mmol) in anhydrous MeOH (100 mL), Pd(OH)2 (100 mg) and TEA (2 mL) were added. The mixture was stirred at 40°C for 8 hours under an H2 (balloon) atmosphere.

[0763] The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographically purified using silica (Combiflash) with 5% to 20% siRNA / petroleum ether as the eluent to obtain racemic methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (2.2 g, 92%). By chiral separation using SFC (AY-H (250 × 4.6 mm 5 μm) mobile phase = hexane (0.1% DEA):EtOH (0.1% DEA) = 95:5), stereoisomer A (methyl(R)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate, 960 mg, 43.5%) and stereoisomer B (methyl(S)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate, 904 mg, 40.7%) were obtained; (ESI 253.2(M+H)) + ).

[0764] Stage 2: Methyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) acetate (stereoisomer B)

[0765] [ka]

[0766] LDA (25 mL, 50 mmol, in 2 M THF solution) was added to (S)-methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (stereoisomer B, 4.2 g, 16.7 mmol) in THF (100 mL) under an N2 atmosphere at -78°C. The reaction mixture was stirred for 0.5 hours, and TMSCl (5.4 g, 50 mmol) was added. After another 15 minutes, NBS (8.9 g, 50 mmol) in THF (50 mL) solution was added, and the reaction mixture was stirred at -78°C for 0.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (twice with 50 mL). The combined organic phases were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using silica (Combiflash) with 0% to 20% siRNA / petroleum ether as the eluent to obtain methyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) acetate (stereoisomer B, 4.1g, 74.5%); (ESI 331.3(M+H) + .

[0767] Stage 3: Methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate (stereoisomer B)

[0768] [ka]

[0769] To a solution of methyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) acetate (stereoisomer B, 4.1 g, 12.4 mmol) in acetonitrile (30 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthiridine (3.4 g, 12.4 mmol) and DIPEA (4.8 g, 37.2 mmol) were added. The reaction mixture was stirred at 1 c, diluted with water (50 mL), and extracted with ethyl acetate (three times with 50 mL). The combined organic phase was washed with brine and dehydrated with anhydrous sodium 2 SO4. After filtration and concentration, the residue was chromatographically purified with silica (Combiflash) using 20% ​​to 80% siRNA / petroleum ether as the eluent to obtain methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate as a mixture of diastereomers (stereoisomer B, 4.9g, 75%); (ESI 526.2(M+H) + ); 1 H NMR (500MHz, MeOD) δ7.51 (ddd, J=20.9, 8.7, 5.9Hz, 1H), 7.34 (dt, J=10.3, 3.4Hz, 1H), 7.11(d, J=7.3Hz, 1H), 7.09-7.03(m, 1H), 6.36(d, J=7.3Hz, 1H), 4.86(m, 2H), 4.47(m, 1H), 4.08-3.97(m, 2H), 3.69-3.61(m, 4H), 3.39(m, 3H), 2.87(m, 1H), 2.75-2.63(m, 3H) ), 2.56-2.35(m, 4H), 2.00(m, 1H), 1.97-1.75(m, 5H), 1.72-1.63(m, 4H), 1.57(m, 4H).

[0770] Stage 4: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 92-B-E1 and 92-B-E2)

[0771] [ka]

[0772] To a solution of methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate (stereoisomer B, 4.9 g, 9.3 mmol) in methanol (50 mL), LiOH (480 mg, 20 mmol) and water (20 mL) were added. The reaction mixture was stirred at 25°C for 16 hours, filtered, concentrated under reduced pressure, and half was taken and purified by reverse-phase HPLC to obtain the individual diastereomers (S)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid compounds Compound 92-B-E1 (1.88 g), (yield 39.4%) and (R)-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid compound 92-B-E2 (1.33 g), (yield 27.9%) were obtained.

[0773] Compound 92-B-E1: LC / MS ESI 512.3(M+H) + . 1H NMR (400MHz, MeOD) δ7.58 (dd, J=8.8, 5.9Hz, 1H), 7.46 (dd, J=10.0, 2.7Hz, 1H), 7.22-7.11 (m, 2H), 6.40 (d , J=7.3Hz, 1H), 4.90 (s, 1H), 4.77 (d, J=10.3Hz, 1H), 4.20 (m, 1H), 4.04 (dd, J=7.5, 5.6Hz, 1H), 3.68 (t, J=1 1.6Hz, 1H), 3.62 (d, J=9.2Hz, 1H), 3.49 (t, J=5.6Hz, 2H), 3.42-3.35 (m, 3H), 3.23 (d, J=12.6Hz, 1H), 3.04 (m, 1H), 2.72 (t, J=6.2Hz, 2H), 2.57 (t, J=7.6Hz, 2H), 2.2-1.95 (m, 4H), 1.9-1.8 (m, 2H), 1.8-1.55 (m, 8H).

[0774] Compound 92-B-E2: LC / MS ESI 512.3 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.47-7.39 (m, 2H), 7.19 (d, J=7.3Hz, 1H), 7.11 (td, J=8.4, 2.6Hz, 1H), 6.40 (d, J=7.3Hz, 1H), 4.75 (d, J=11.1Hz, 2H), 4.15 (d, J=9.4Hz, 1H), 4.08 (s, 1H), 3.67 (t, J=10.7Hz , 1H), 3.53-3.42(m, 3H), 3.38(d, J=5.3Hz, 2H), 3.10(m, 2H), 2.72(t, J=6.2Hz, 2H), 2.58(m, 2H) , 2.15 (s, 1H), 2.09 (s, 1H), 1.95 (d, J=7.8Hz, 2H), 1.92-1.82 (m, 3H), 1.73 (m, 4H), 1.61 (m, 4H).

[0775] Stage 5: 2-(5-フルオロ-2-((R)-テトラヒドロ-2H-ピラン-2-イル)フェニル)-2-((R)-3-(4-(5,6,7 ,8-テトラヒドロ-1,8-ナフチリジン-2-イル)ブトキシ)ピロリジン-1-イル) anhydrous acid (compounds 92-A-E1 and び92-A-E2)

[0776]

change

[0777] (R)-2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid compound 92-A-E1 and (S)-2-(5-fluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid compound 92-A-E2 were synthesized from methyl(R)-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl) acetate (stereoisomer A) using the same procedure as for stereoisomer B.

[0778] Compound 92-A-E1: LC / MS ESI 512.1(M+H) + , 1 H NMR (500MHz, MeOD) δ7.58-7.50(m, 2H), 7.16(d, J=7.4Hz, 1H), 7.11-7.04(m, 1H), 6.38 (d, J=7.3Hz, 1H), 4.87(d, J=10.9Hz, 1H), 4.62(s, 1H), 4.11(d, J=2.5Hz, 1H), 4.04(m, 1 H), 3.72(m, 1H), 3.47-3.35(m, 5H), 3.16-3.03(m, 2H), 2.70(d, J=6.1Hz, 2H), 2.58-2. 50(m, 2H), 2.16-1.95(m, 4H), 1.90-1.85(m, 2H), 1.73-1.65(m, 4H), 1.64-1.56(m, 4H).

[0779] Compound 92-A-E2: LC / MS ESI 512.1(M+H) + , 1H NMR (500MHz, MeOD) δ7.50-7.39(m, 2H), 7.16(d, J=7.3Hz, 1H), 7.09(td, J=8.4, 2.7Hz, 1H), 6 .38(d, J=7.3Hz, 1H), 5.08(s, 1H), 4.76(d, J=11.0Hz, 1H), 4.14(d, J=3.5Hz, 1H), 4.07(d, J= 12.2Hz, 1H), 3.44(m, 3H), 3.38(d, J=5.5Hz, 3H), 2.99-2.92(m, 1H), 2.71(t, J=6.2Hz, 2H), 2 .55(t, J=7.5Hz, 2H), 2.10-2.03(m, 2H), 1.95-1.81(m, 5H), 1.73-1.67(m, 4H), 1.60(m, 4H).

[0780] [Example 23]: Preparation of 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 93-A-E1, 93-A-E2, 93-B-E1 and 93-B-E2)

[0781] Step 1: Methyl 2-(2-bromo-5-fluorophenyl)acetate

[0782] [ka]

[0783] To a solution of 2-(2-bromo-5-fluorophenyl)acetic acid (10 g, 43 mmol) in MeOH (60 mL), 0.5 mL of H2SO4 was added, and the mixture was heated under reflux for 4 hours. The solvent was removed under reduced pressure to obtain methyl 2-(2-bromo-5-fluorophenyl)acetate as an oily substance (10 g, yield: 94.3%), which was used without further purification. (ESI 246.1(M+H)) + ).

[0784] Step 2: Methyl 2-(5-fluoro-2-(furan-2-yl)phenyl)acetate

[0785] [ka]

[0786] To a solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (5 g, 20.2 mmol) in DMF (100 mL), furan-2-ylboronic acid (2.72 g, 24 mmol), tris(dibenzylideneacetone)dipalladium(0) (915 mg, 1 mmol), X-Phos (476 mg, 1 mmol), and potassium phosphate (8.5 g, 40 mmol) were added. The mixture was stirred under N2 at 60°C for 8 hours. The reaction solution was diluted with 200 mL of ethyl acetate and 200 mL of water, and the organic layers were separated. The aqueous layer was extracted three times with ethyl acetate (three times with 200 mL each), and the combined organic layers were washed with brine and dehydrated with anhydrous sodium 2SO4. After filtration and concentration, the residue was chromatographically purified using silica (Combiflash) with 0% to 20% siRNA / petroleum ether as the eluent to obtain methyl 2-(5-fluoro-2-(furan-2-yl)phenyl) acetate (3.9 g, yield 82.7%); ESI 237.2(M+H) + .

[0787] Step 3: Methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)acetate

[0788] [ka]

[0789] To a solution of methyl 2-(5-fluoro-2-(furan-2-yl)phenyl) acetate (2.34 g, 10 mmol) in SiO (30 mL), Pd / C (1 g) and DIEA (2.58 g, 20 mmol) were added. The mixture was stirred at 35°C for 5 hours under an H2 atmosphere (balloon). After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographically purified using silica (Combiflash) with 5% to 20% SiO / petroleum ether as the eluent to obtain methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate (1.56 g, 66.7%) as an oil.

[0790] The racemic compound was separated by SFC (SFC(AY-H (250 × 4.6 mm 5 μm) mobile phase: hexane (0.1% DEA): EtOH (0.1% DEA) = 95:5) to obtain stereoisomer A (950 mg) and stereoisomer B (920 mg) as oily substances; ESI 239.1(M+H) + .

[0791] Stage 4: Methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer A

[0792] [ka]

[0793] To a solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer A (250 mg, 1.05 mmol) in anhydrous THF (10 mL), LDA (1.25 mL, 2.5 mmol, in 2 M THF solution) was added under N2 conditions at -78°C. The reaction mixture was stirred for 0.5 hours, and TMSCl (324 mg, 3 mmol) was added. After stirring for 15 minutes, NBS (534 mg, 3 mmol) in THF (10 mL) was added, and the mixture was stirred at -78°C for 0.5 hours. The mixture was diluted with water and extracted with ethyl acetate (3 times with 30 mL). The combined organic layers were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using silica (Combiflash) with 5% to 20% siRNA / petroleum ether as the eluent to obtain methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer A (240 mg, 71%) as an oily substance; ESI 317.2(M+H) + .

[0794] Stage 5: Methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer A

[0795] [ka]

[0796] To a solution of methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer A (240 mg, 0.76 mmol) in ACN (10 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (213 mg, 0.76 mmol) and DIPEA (295 mg, 2.28 mmol) were added. The reaction mixture was stirred for 4 hours, diluted with water (30 mL), and extracted with ethyl acetate (three times in 50 mL increments). The combined organic layers were washed with brine, dehydrated with anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographically purified using silica (Combiflash) with 20% to 80% butyl / petroleum ether as the eluent to obtain methyl 2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer A (300 mg, 77%) as a solid; ESI 512(M+H) + .

[0797] Step 6: 2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (compounds 93-A-E1 and 93-A-E2)

[0798] [ka]

[0799] To a solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer A (330 mg, 0.59 mmol) in methanol (10 mL), LiOH (40 mg, 1.6 mmol) and water (10 mL) were added. The reaction mixture was stirred at 25°C for 16 hours. 1N HCl was added to the mixture to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, and half of the residue was removed and purified by HPLC to obtain compound 93-A-E1 (56 mg, 18%) as a solid and compound 93-A-E2 (45 mg, 15%) as a solid.

[0800] Compound 93-A-E1 ESI 498.2(M+H) + , 1 H NMR (500MHz, MeOD) δ7.58(dd, J=8.8, 5.9Hz, 1H), 7.45(dd, J=10.0, 2.7Hz, 1H), 7.18(d, J=7.4Hz, 1H), 7.15(dd, J=8.4, 5.8Hz , 1H), 6.41(d, J=7.3Hz, 1H), 5.22(t, J=7.0Hz, 1H), 4.96(s, 1H), 4.19(s, 1H), 4.07(dd, J=14.4, 7.3Hz, 1H), 3.88(dt, J=14.1, 7.0Hz, 1H), 3.60-3.43(m, 3H), 3.43-3.37(m, 2H), 3.26(dd, J=33.4, 10.4Hz, 2H), 3.04(t, J=7.6Hz, 1H), 2.72(t, J=6.2Hz, 2H) ), 2.58(t, J=7.6Hz, 2H), 2.44(dt, J=12.0, 5.9Hz, 1H), 2.16-1.93(m, 5H), 1.92-1.86(m, 2H), 1.75(m, 2H), 1.68-1.56(m, 2H).

[0801] Compound 93-A-E2 ESI 498.2(M+H) + , 1H NMR (500MHz, MeOD) δ7.49 (dd, J=8.7, 5.9Hz, 1H), 7.46 (d, J=10.3Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 7.11 (t, J =6.9Hz, 1H), 6.42(d, J=7.3Hz, 1H), 5.18(s, 1H), 4.87-4.81(m, 1H), 4.16(s, 1H), 4.16-4.09(m, 1H), 3.88( t, J=7.1Hz, 1H), 3.50 (t, J=6.1Hz, 3H), 3.42-3.36 (m, 2H), 3.10 (d, J=7.6Hz, 2H), 2.73 (t, J=6.2Hz, 2H), 2 .67-2.54(m, 2H), 2.41(d, J=10.7Hz, 1H), 2.16-1.96(m, 5H), 1.93-1.85(m, 2H), 1.75(m, 2H), 1.64(m, 2H).

[0802] Stage 7: メチル2-ブロモ-2-(5-フルオロ-2-(テトラヒドロフラン-2-イル)フェニル)アセテートstereoisomorph B

[0803]

change

[0804] To a solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer B (250 mg, 1.05 mmol) in anhydrous THF (10 mL), LDA (1.25 mL, 2.5 mmol, in 2 M THF solution) was added under N2 conditions at -78°C. The reaction mixture was stirred for 0.5 hours, and TMSCl (324 mg, 3 mmol) was added. After stirring for 15 minutes, NBS (534 mg, 3 mmol) in THF (10 mL) was added, and the mixture was stirred at -78°C for 0.5 hours. The mixture was diluted with water and extracted with ethyl acetate (3 times with 30 mL). The combined organic layers were washed with brine and dehydrated with anhydrous Na2SO4. After filtration and concentration, the residue was chromatographically purified using silica (Combiflash) with 5% to 20% siRNA / petroleum ether as the eluent to obtain methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer B (235 mg, 70.8%) as an oily substance; ESI 317.2)(M+H) + .

[0805] Step 8: Methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B

[0806] [ka]

[0807] To a solution of methyl 2-bromo-2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl) acetate stereoisomer B (100 mg, 0.31 mmol) in ACN (5 mL), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (87 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol) were added. The reaction mixture was stirred for 4 hours, diluted with water (10 mL), and extracted with ethyl acetate (three times with 20 mL). The combined organic layers were washed with brine, dehydrated with anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was chromatographically purified using silica (Combiflash) with 20% to 80% SiO2 / petroleum ether as the eluent to obtain methyl 2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (120 mg, 78%) as a solid; ESI 512.2(M+H) + .

[0808] Stage 9: 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (compounds 93-B-E1 and 93-B-E2)

[0809] [ka]

[0810] To a solution of methyl 2-(5-fluoro-2-(tetrahydrofuran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate stereoisomer B (300 mg, 0.59 mmol) in methanol (10 mL), LiOH (40 mg, 1.6 mmol) and water (10 mL) were added. The reaction mixture was stirred at 25°C for 16 hours. 1N HCl was added to the mixture to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, and half of the residue was removed and purified by HPLC to obtain compound 93-B-E1 (27 mg, 9%) as a solid and compound 93-B-E2 (30 mg, 10%) as a solid.

[0811] Compound 93-B-E1 ESI 498.2(M+H) + , 1 H NMR (500MHz, MeOD) δ7.58(dd, J=8.8, 6.0Hz, 1H), 7.48(d, J=10.1Hz, 1H), 7.17(dd, J=20.5, 7.7Hz, 2H), 6.41( d, J=7.3Hz, 1H), 5.29(t, J=7.1Hz, 1H), 4.9(s, 1H), 4.17(s, 1H), 4.08(dd, J=14.6, 7.2Hz, 1H), 3.89(dd, J=13 .8, 7.8Hz, 1H), 3.60-3.38(m, 5H), 3.16(d, J=7.5Hz, 1H), 2.72(t, J=6.2Hz, 2H), 2.59(dd, J=14.4, 7.2Hz, 2H) , 2.48(dd, J=11.9, 5.2Hz, 1H), 2.18(s, 2H), 2.12-1.99(m, 2H), 2.01-1.85(m, 4H), 1.74(m, 2H), 1.64(m, 2H).

[0812] Compound 93-B-E2 ESI 498.2(M+H) + , 1H NMR (500MHz, MeOD) δ7.49(dd, J=8.7, 5.8Hz, 1H), 7.44(d, J=10.1Hz, 1H), 7.19(d, J=7.3Hz, 1H), 7.12(t , J=7.0Hz, 1H), 6.41(d, J=7.3Hz, 1H), 5.12(s, 1H), 4.97(s, 1H), 4.18(s, 1H), 4.14-4.08(m, 1H), 3.86(t , J=6.9Hz, 1H), 3.48(t, J=6.2Hz, 3H), 3.42-3.38(m, 3H), 3.19(s, 1H), 3.04(s, 1H), 2.73(t, J=6.3Hz, 2 H), 2.58(t, J=6.2Hz, 2H), 2.37(s, 1H), 2.17-1.99(m, 5H), 1.94-1.84(m, 2H), 1.74(m, 2H), 1.64(m, 2H).

[0813] [Example 24]: Preparation of 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-yl)acetic acid (compounds 94-E1 and 94-E2)

[0814] Stage 1: (R)-tert-butyl 3-(allyloxymethyl)pyrrolidine-1-carboxylate

[0815] [ka]

[0816] A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.8 mmol) and NaH (1.09 g, 27.3 mmol) in DMF (20 mL) was stirred at 0°C for 1 hour. A solution of 3-bromopropa-1-ene (4.5 g, 37.2 mmol) in DMF (10 mL) was added dropwise to the mixture at 0°C, and the reaction mixture was stirred overnight at 50°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 1:1) to obtain the desired product as a colorless oil (5.1 g). Yield 85% (ESI 186(M+H-56)). + ).

[0817] Step 2: (R)-tert-butyl 3-((3-(1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate

[0818] [ka]

[0819] (R)-tert-butyl 3-(allyloxymethyl)pyrrolidine-1-carboxylate (600 mg, 2.49 mmol) was added to a solution of (R)-tert-butyl 3-(allyloxymethyl)pyrrolidine-1-carboxylate (anhydrous, 5 mL) in THF (anhydrous), under Ar, with 9-BBN (0.5 M THF solution, 9.95 mL, 4.97 mmol). The reaction mixture was stirred at 50°C for 2 hours and then cooled to room temperature. This solution was added to a mixture of 2-bromo-1,8-naphthyridine (520 mg, 2.49 mmol), cesium carbonate (2.44 g, 7.47 mmol), and Pd(PPh3)4 (144 mg, 0.125 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 90°C for 1.5 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 30:1) to obtain the desired product (R)-tert-butyl 3-((3-(1,8-naphthyrizin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate as a yellow oil (200 mg). Yield 22% (ESI 372(M+H) + ).

[0820] Step 3: (R)-tert-butyl3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate

[0821] [ka]

[0822] A mixture of (R)-tert-butyl 3-((3-(1,8-naphthyrizin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.54 mmol) and Pd / C (40 mg, 20 wt%) in ethyl acetate (10 mL) was stirred under an H2 balloon at 40°C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product (R)-tert-butyl 3-((3-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate as a yellow oil (200 mg). Yield 99% (ESI 376(M+H) + ).

[0823] Stage 4: (R)-7-(3-(pyrrolidine-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0824] [ka]

[0825] (R)-tert-butyl 3-((3-(5,6,7,8-tetrahydro-1,8-naphthiridine-2-yl)propoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.53 mmol) was treated with HCl / 1,4-dioxane (4 M, 10 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the desired product (R)-7-(3-(pyrrolidine-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthiridine as the HCl salt (150 mg). Yield 81% (ESI 276(M+H)) + ).

[0826] Step 5: Methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-yl)acetate

[0827] [ka]

[0828] A mixture of (R)-7-(3-(pyrrolidine-3-ylmethoxy)propyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (150 mg, 0.43 mmol), methyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) acetate (142 mg, 0.43 mmol), and DIPEA (166 mg, 1.29 mmol) in acetonitrile (10 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 10:1) to obtain the desired product, methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-yl)acetate, as a yellow oil (140 mg). Yield 62%. (ESI 526(M+H) + ).

[0829] Step 6: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-yl)acetic acid (compounds 94-E1 and 94-E2)

[0830] [ka]

[0831] Methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propoxy)methyl)pyrrolidine-1-yl)acetate (140 mg, 0.27 mmol) was treated with LiOH-H2O (126 mg, 3.0 mmol) in MeOH (4 mL) and H2O (1 mL) at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 60% MeCN) to obtain the diastereomer products compound 94-E1 (17 mg) and compound 94-E2 (49 mg) as white solids.

[0832] Compound 94-E1 LC / MS ESI 512(M+H) + . 1 H NMR (500MHz, MeOD) δ7.65-7.54(m, 2H), 7.36-7.21(m, 2H), 6.62(d, J=7.5Hz, 1H), 5.06(s, 1H), 4.77-4.75 (m, 1H), 4.11-4.08(m, 1H), 3.81-3.33(m, 8H), 3.25-3.14(m, 2H), 2.95-2.66(m, 5H), 2.37-1.58(m, 13H).

[0833] Compound 94-E2 LC / MS ESI 512(M+H) + . 1 H NMR (500MHz, MeOD) δ7.48-7.39(m, 2H), 7.15-7.08(m, 2H), 6.35(d, J=7.0Hz, 1H), 5.25(s, 1H), 4.73-4.71 (m, 1H), 4.14-4.12(m, 1H), 3.81-3.33(m, 8H), 3.25-3.14(m, 2H), 2.73-2.56(m, 5H), 2.18-1.52(m, 13H).

[0834] [Example 25]: Preparation of 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)ethoxy)ethyl)pyrrolidine-1-yl)acetic acid (compounds 95-E1 and 95-E2)

[0835] Step 1: (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropa-1-enyloxy)ethyl)pyrrolidine-1-carboxylate

[0836] [ka]

[0837] (S)-tert-butyl 3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (3.3 g, 15.5 mmol) and 4-methylmorpholine (1.85 g, 18.5 mmol) were dissolved in DCM (40 mL) at room temperature, to which methylpropiolate (1.55 g, 18.5 mmol) was added. The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ELISA 4:1) to obtain (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropa-1-enyloxy)ethyl)pyrrolidine-1-carboxylate as a colorless oil (4.0 g). Yield 87% (ESI 200 (M+H-Boc)) + ).

[0838] Step 2: (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-1-carboxylate

[0839] [ka]

[0840] A mixture of (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropa-1-enyloxy)ethyl)pyrrolidine-1-carboxylate (4.0 g, 16.0 mmol) and Pd / C (10%, 200 mg) in ELISA (25 mL) was stirred overnight at room temperature under H2. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-1-carboxylate as a yellow oil (4.0 g). Yield 96% (ESI 202(M+H-Boc)). + ).

[0841] Step 3: (S)-tert-butyl 3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate

[0842] [ka]

[0843] (S)-tert-butyl 3-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-1-carboxylate (1.5 g, 5.0 mmol) and dimethylmethylphosphonate (0.682 g, 5.5 mmol) were dissolved in anhydrous THF (10 mL) and LDA (2 M THF solution, 5.25 mL, 10.5 mmol) dropwise at 0°C under Ar. After stirring at 0°C for 10 minutes, the reaction was stopped with MeOH (5 mL). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ELISA 2:1) to obtain the desired product (S)-tert-butyl 3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate as a yellow oil (1.1 g). Yield 57% (ESI 394(M+H) + ).

[0844] Stage 4: (S)-tert-butyl3-(2-(2-(1,8-naphthyridine-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate

[0845] [ka]

[0846] A mixture of 2-aminonicotinaldehyde (128 mg, 1.1 mmol), (S)-tert-butyl 3-(2-(4-(dimethoxyphosphoryl)-3-oxobutoxy)ethyl)pyrrolidine-1-carboxylate (400 mg, 1.1 mmol), and NaOH (81 mg, 2.2 mmol) in MeOH (6 mL) and H2O (2 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (40% to 70% MeCN) to obtain the desired product (S)-tert-butyl 3-(2-(2-(1,8-naphthyridine-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate as a colorless oil (60 mg). Yield 16% (ESI 372(M+H) + ).

[0847] Stage 5: (S)-7-(2-(2-(pyrrolidine-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyrizine hydrochloride

[0848] [ka]

[0849] (S)-tert-butyl 3-(2-(2-(1,8-naphthiridine-2-yl)ethoxy)ethyl)pyrrolidine-1-carboxylate (400 mg, 1.08 mmol) and Pd / C (80 mg, 10%) were mixed in ELISA (20 mL) and stirred overnight at room temperature under H2. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was treated with HCl / dioxane solution (4.0 M, 4 mL) at room temperature for 2 hours, and the solvent was removed under reduced pressure to obtain the desired product (S)-7-(2-(2-(pyrrolidine-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthiridine hydrochloride as a white solid (325 mg). Yield 96% (ESI 276.2 (M+H)). + ).

[0850] Step 6: Methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)ethoxy)ethyl)pyrrolidine-1-yl)acetate

[0851] [ka]

[0852] A mixture of (S)-7-(2-(2-(pyrroridine-3-yl)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthirizine hydrochloride (226 mg, 0.65 mmol), methyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) acetate (240 mg, 0.65 mmol), and DIEA (252 mg, 1.95 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)ethoxyethyl)pyrrolidine-1-yl)acetate, as a yellow oil (310 mg). Yield 84% (ESI 526(M+H) + ).

[0853] Step 7: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)ethoxy)ethyl)pyrrolidine-1-yl)acetic acid (compounds 95-E1 and 95-E2)

[0854] [ka]

[0855] Methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((S)-3-(2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)ethoxyethyl)pyrrolidine-1-yl)acetate (310 mg, 0.55 mmol) was treated overnight at 40°C with MeOH (5 mL) and LiOH-H2O (250 mg, 5.95 mmol) in H2O (1 mL). The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 60% MeCN) to obtain the diastereomer products compound 95-E1 (67 mg) and compound 95-E2 (37 mg) as white solids.

[0856] Compound 95-E1 LC / MS ESI 512.3(M+H) + . 1 H NMR (400MHz, MeOD) δ7.62-7.55(m, 1H), 7.54-7.50(m, 1H), 7.20-7.10(m, 2H), 6.35(d, J=7.3Hz, 1H), 4.88-4.78(m, 2H), 4.08-4.04(m, 1H), 3.82-3.75(m, 1H) ), 3.70-3.61(m, 3H), 3.49-3.40(m, 3H), 3.38-3.31(m, 2H), 3.06-2.99(m, 1H) , 2.68-2.77(m, 5H), 2.50-2.39(m, 1H), 2.20-1.90(m, 3H), 1.95-1.60(m, 9H).

[0857] Compound 95-E2 LC / MS ESI 512.3(M+H) + . 1H NMR (400MHz, MeOD) δ7.43-7.36(m, 2H), 7.18-7.09(m, 2H), 6.38-6.33(d, J=7. 3Hz, 1H), 5.42(s, 1H), 4.80-4.50(m, 1H), 4.18-4.04(m, 1H), 3.65-3.62(m, 3H) ), 3.50-3.41(m, 2H), 3.38-3.31(m, 3H), 3.20-3.00(m, 3H), 2.75-2.65(m, 4H) , 2.40-2.30(m, 1H), 2.20-2.05(m, 2H), 1.98-1.93(m, 1H), 1.90-1.58(m, 9H).

[0858] [Example 26]: Preparation of 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 96-E1 and 96-E2)

[0859] Stage 1: 1-(2-bromo-4-fluorophenyl)-4-methylpenta-4-en-1-ol

[0860] [ka]

[0861] Magnesium (0.489 g, 20.1 mmol) was placed in a three-necked round-bottom flask equipped with a magnetic stirring bar, condenser, nitrogen inlet tube, and septum. The magnesium was dried under a nitrogen stream using a heat gun while stirring, and the mixture was stirred overnight under a nitrogen stream. Next, anhydrous tetrahydrofuran (12 mL) was added, and the mixture was refluxed using a heat gun. A small amount of 1,2-dibromoethane (0.116 mL, 1.34 mmol) was added, and the mixture was refluxed again. A solution of 4-bromo-2-methylbuta-1-ene (1.6 mL, 13.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise at a rate that maintained the exothermic reaction. After the addition was complete, the grayish-brown reaction mixture was stirred for a further 20 minutes and slowly cooled to room temperature. The Grignard reagent was withdrawn into a syringe and added dropwise to a solution of 2-bromo-4-fluorobenzaldehyde (2.72 g, 13.4 mmol) in anhydrous tetrahydrofuran (15 mL) under an argon atmosphere at 0°C. After addition, the mixture was allowed to rise to room temperature, stirred for 30 minutes, stopped with saturated ammonium chloride, and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (silica, 1% to 15% diisopropyl ether / heptane) yielded the desired product, 1-(2-bromo-4-fluorophenyl)-4-methylpenta-4-en-1-ol (1.43 g). Yield 39%. 1 ¹H NMR (400MHz, chloroform-d) δ 7.58-7.51 (m, 1H), 7.30-7.23 (m, 1H), 7.11-7.02 (m, 1H), 5.09-5.01 (m, 1H), 4.76 (s, 2H), 2.29-2.10 (m, 2H), 2.03 (d, J=3.6Hz, 1H), 1.96-1.83 (m, 1H), 1.83-1.68 (m, 4H).

[0862] Stage 2: 5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran

[0863] [ka]

[0864] To a solution of 1-(2-bromo-4-fluorophenyl)-4-methylpenta-4-en-1-ol (1.43 g, 5.24 mmol) in toluene (30 mL), p-toluenesulfonic acid monohydrate (0.996 g, 5.24 mmol) was added. The mixture was stirred at 80°C for 1 hour, cooled to room temperature, and the reaction was stopped with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane. The combined organic layer was dehydrated with sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (silica, 0% to 8% diisopropyl ether / heptane) yielded the desired product, 5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran (1.28 g). Yield 89%. 1 ¹H NMR (400MHz, chloroform-d) δ 7.60-7.52 (m, 1H), 7.29-7.21 (m, 1H), 7.07-6.98 (m, 1H), 5.19 (t, J=7.2Hz, 1H), 2.64-2.53 (m, 1H), 1.93-1.77 (m, 2H), 1.74-1.61 (m, 1H), 1.42 (s, 3H), 1.36 (s, 3H).

[0865] Step 3: tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate

[0866] [ka]

[0867] Zinc powder (1.202 g, 18.4 mmol) was placed in a drying flask and heated with a heat gun under an argon stream. After cooling to room temperature, anhydrous tetrahydrofuran (26 mL) was added, followed by 1,2-dibromoethane (0.04 mL, 0.46 mmol). The mixture was heated under reflux and cooled to room temperature three times. Next, trimethylsilyl chloride (0.059 mL, 0.46 mmol) was added, causing the mixture to reflux naturally and the zinc to change its form. After stirring for 20 minutes, tert-butylbromoacetate (1.34 mL, 9.19 mmol) was added dropwise, resulting in exothermic reaction. The mixture was maintained at a high temperature (45°C) for 30 minutes and then allowed to cool to room temperature. In a separate flask, 5-(2-bromo-4-fluorophenyl)-2,2-dimethyltetrahydrofuran (1.26 g, 4.59 mmol), tri-tert-butylphosphine tetrafluoroborate (0.147 g, 0.505 mmol), and bis-(dibenzylideneacetone)palladium (0.264 g, 0.459 mmol) were placed. Argon was flowed into the reaction vessel, anhydrous tetrahydrofuran (26 mL) was added, and argon was blown in for 5 minutes. Zincate solution was added by syringe, and the reaction mixture was heated under reflux for 1 hour. The mixture was cooled and left overnight at room temperature, the reaction was stopped with saturated ammonium chloride aqueous solution, and extracted three times with heptane / ethyl acetate (1 / 1, volume ratio). The combined organic layer was dehydrated with sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (silica, 1% to 6% acetone / heptane) yielded the desired product, tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl) acetate (1.31 g). Yield: 92%. 1 ¹H NMR (400MHz, chloroform-d) δ 7.51 (dd, J=8.6, 6.0Hz, 1H), 7.00-6.88 (m, 2H), 5.10 (dd, J=8.5, 6.2Hz, 1H), 3.57 (q, J=15.5Hz, 2H), 2.38-2.28 (m, 1H), 1.92-1.71 (m, 3H), 1.43 (s, 9H), 1.40 (s, 3H), 1.34 (s, 3H).

[0868] Stage 4: tert-butyl 2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)acetate

[0869] [ka]

[0870] To a solution of tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl) acetate (200 mg, 0.65 mmol) in THF (4 mL), a 1.0 M lithium diisopropylamide solution in THF / hexane (1.3 mL, 1.3 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, chlorotrimethylsilane (141 mg, 1.3 mmol) was added, and the reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (231 mg, 1.3 mmol) in THF (2 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl) acetate, as a colorless oil (180 mg). Yield: 72%. (ESI 387(M+H)) + ).

[0871] Step 5: tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0872] [ka]

[0873] A mixture of tert-butyl 2-bromo-2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl) acetate (650 mg, 1.68 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (584 mg, 1.68 mmol), and DIPEA (650 mg, 5.04 mmol) in acetonitrile (20 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 10:1) to obtain the desired product, tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate, as a yellow oil (550 mg). Yield 56%. (ESI 582(M+H) + ).

[0874] Step 6: 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 96-E1 and 96-E2)

[0875] [ka]

[0876] tert-butyl 2-(2-(5,5-dimethyltetrahydrofuran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (550 mg, 0.95 mmol) was treated with HCl / 1,4-dioxane (4 M, 10 mL) at 25 °C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (33% to 65% MeCN) to obtain 96 as a white solid (220 mg, yield 44%). The racemic product was separated by preparative chiral SFC E to obtain diastereomer products 96-E1 (44 mg) and 96-E2 (49 mg) as white solids, which were mixtures of two stereoisomers, respectively.

[0877] Compound 96-E1 (mixture of two stereoisomers) LC / MS ESI 526(M+H) + . 1 H NMR (500MHz, MeOD) δ7.65-7.61(m, 1H), 7.48(dd, J=10Hz, 2.5Hz, 1H), 7.18-7.15(m, 2H), 6.39(d, J=7.5Hz, 1H), 5.42(m, 1H), 4.85(s, 1H), 4.20(s, 1H), 3.49-3.36(m, 5H), 3.22-3.18(m, 2H), 2.73-2.52(m, 5H), 2.21-1.87(m, 7H), 1.75-1.61(m, 4H), 1.45-1.36(m, 7H). Chiral SFC E(45%MeOH): ee100%, Rt=3.49 min.

[0878] Compound 96-E2 (mixture of two stereoisomers) LC / MS ESI 526(M+H) + . 1H NMR (500MHz, MeOD) δ7.65-7.61(m, 1H), 7.45(dd, J=10Hz, 2.5Hz, 1H), 7.18-7.16(m, 2H), 6.39(d, J=7.5Hz, 1H), 5.35(m, 1H), 4.97(s, 1H), 4.20(s, 1H), 3.54-3.36(m, 5H), 3.22-3.05(m, 2H), 2.73-2.50(m, 5H), 2.22-1.88(m, 7H), 1.76-1.62(m, 4H), 1.41-1.36(m, 7H). Chiral SFC E(45%MeOH): ee98%, Rt=4.52 min.

[0879] [Example 27]: Preparation of 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)

[0880] Stage 1: 4,4-dimethyltetrahydro-2H-pyran-2-one

[0881] [ka]

[0882] A suspension of lithium aluminum hydride (220 mg, 5.79 mmol) in THF (anhydrous, 15 mL) was added dropwise to a solution of 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (1.42 g, 10.0 mmol) in THF (10 mL) at -55°C. The reaction mixture was gradually heated to 0°C, stirred for 20 minutes, cooled to -15°C, and stopped by adding aqueous HCl (6N, 4 mL) dropwise. The mixture was extracted with ether (three times with 15 mL), and the combined organic layer was dehydrated with Na₂SO₄. The solvent was removed under reduced pressure to obtain the desired product, 4,4-dimethyltetrahydro-2H-pyran-2-one, as an oil (0.91 g, yield 71%). 1H NMR (400MHz, CDCl3) δ4.40(t, J=6.0Hz, 2H), 2.35(s, 2H), 1.75(t, J=6.0Hz, 2H), 1.10(s, 6H).

[0883] Stage 2: 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol

[0884] [ka]

[0885] To a solution of 1-bromo-2-iodobenzene (727 mg, 2.58 mmol) in THF (15 mL), isopropyl magnesium chloride solution (2 M THF solution, 1.3 mL, 2.6 mmol) was added dropwise at -25°C. The reaction mixture was stirred at -25°C for 1 hour, and then 4,4-dimethyltetrahydro-2H-pyran-2-one (300 mg, 2.34 mmol) in THF (3 mL) was added dropwise at -25°C. The reaction mixture was raised to room temperature within 1 hour, stopped with MeOH (5 mL), and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: Â1 4:1) to obtain the desired product 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol as a yellow oil (130 mg). Yield 18% (ESI 285 / 287[M+H]) + ).

[0886] Stage 3: 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran

[0887] [ka]

[0888] Et3SiH (267 mg, 2.3 mmol) was added dropwise to a solution of 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran-2-ol (130 mg, 0.46 mmol) and TFA (0.23 mL) in DCM (6 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, stopped with saturated NaHCO3 solution (20 mL), and extracted with DCM (3 times with 10 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran as a yellow oil (90 mg). Yield 78% (ESI 269 / 271[M+H]) + ).

[0889] Stage 4: tert-butyl 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate

[0890] [ka]

[0891] A mixture of 2-(2-bromophenyl)-4,4-dimethyltetrahydro-2H-pyran (180 mg, 0.68 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (0.5 M THF solution, 6.8 mL, 3.4 mmol), Pd2(dba)3 (35 mg, 0.034 mmol), and Q-phos (25 mg, 0.034 mmol) in THF (2 mL) was stirred at 80°C for 2 hours. Next, the reaction mixture was added to saturated NaHCO3 solution (50 mL) and extracted with ethyl acetate (three times with 20 mL). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate, as a red oil (150 mg). Yield 73% (ESI 327[M+Na] + ).

[0892] Stage 5: tert-butyl 2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate

[0893] [ka]

[0894] A solution of tert-butyl 2-(3-isopropyl-3,4-dihydro-1H-pyrano[3,4-c]pyridine-5-yl) acetate (600 mg, 2.0 mmol) in THF (10 mL) was added dropwise with lithium diisopropylamide solution (2.0 M, 2.5 mL, 5.0 mmol) at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, and a solution of chlorotrimethylsilane (540 mg, 5.0 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (890 mg, 5.0 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate, as a colorless oil (650 mg). Yield 86% (ESI 327[M-Bu+H]). + ).

[0895] Step 6: tert-butyl 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0896] [ka]

[0897] A mixture of tert-butyl 2-bromo-2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate (375 mg, 1.0 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (306 mg, 1.0 mmol), DIPEA (774 mg, 6.0 mmol), and NaI (50 mg) in acetonitrile (10 mL) was stirred at 40°C for 12 hours. The mixture was diluted with water (8 mL) and ethyl acetate (25 mL). The organic phase was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, tert-butyl 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate, as a colorless oil (410 mg). Yield 72% (ESI 578[M+H]). + ).

[0898] Step 7: 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)

[0899] [ka]

[0900] tert-butyl 2-(2-(4,4-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (570 mg, 1.0 mmol) was treated with HCl / 1,4-dioxane (4 M, 10 mL) at 25 °C for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (40% to 70% MeCN) to obtain 97-A (102 mg) and 97-B (130 mg). 97-A was separated by preparative chiral SFC H to obtain products 97-A-E1 (36 mg) and 97-A-E2 (31 mg) as white solids. 97-B was separated by preparative chiral SFC H to obtain products 97-B-E1 (30 mg) and 97-B-E2 (44 mg) as white solids.

[0901] Compound 97-A-E1 LC / MS ESI 522(M+H) + . 1 H NMR (400MHz, MeOD) δ7.68-7.66(m, 1H), 7.54-7.52(m, 1H), 7.41-7.34(m, 2H), 7.15-7.13(m, 1 H), 6.36(d, J=7.6Hz, 1H), 5.02-4.95(m, 2H), 4.21-4.19(m, 1H), 3.88-3.86(m, 2H), 3.62-3.60 (m, 1H), 3.50-3.41(m, 5H), 3.20-3.18(m, 1H), 3.05-3.02(m, 1H), 2.70-2.68(m, 2H), 2.55-2. 52(m, 2H), 2.10-2.07(m, 2H), 1.90-1.50(m, 9H), 1.31-1.29(m, 1H), 1.20(s, 3H), 1.05(s, 3H). Chiral SFC H(40%MeOH): ee100%, Rt=2.81 min.

[0902] Compound 97-A-E2 LC / MS ESI 522(M+H) + . 1H NMR (400MHz, MeOD) δ7.69-7.67(m, 1H), 7.54-7.52(m, 1H), 7.41-7.31(m, 2H), 7.15-7.13(m, 1H), 6.36(d, J=7.6Hz, 1H), 5.02-5.00(m, 1H), 4.84(s, 1H), 4.16-4.14(m, 1H), 3.90-3.88(m , 2H), 3.62-3.60 (m, 1H), 3.50-3.41 (m, 5H), 3.20-3.18 (m, 2H), 2.70-2.68 (m, 2H), 2.54-2.52 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H). SFC-H (40% MeOH): ee 100%, Rt = 3.78 min.

[0903] Compound 97-B-E1 LC / MS ESI 522 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.68-7.66 (m, 1H), 7.54-7.52 (m, 1H), 7.41-7.34 (m, 2H), 7.15-7.13 (m, 1 H), 6.36 (d, J=7.6Hz, 1H), 5.02-4.90 (m, 2H), 4.16-4.14 (m, 1H), 3.90-3.88 (m, 2H), 3.62-3.60 (m, 1H), 3.50-3.41 (m, 5H), 3.20-3.18 (m, 1H), 3.05-3.02 (m, 1H), 2.70-2.68 (m, 2H), 2.54-2.52 (m, 2H), 2.10-2.07 (m, 2H), 1.90-1.50 (m, 9H), 1.31-1.29 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H). SFC-H (40% MeOH): ee 100%, Rt = 2.76 minutes.

[0904] Compound 97-B-E2 LC / MS ESI 522 (M+H) + . 1H NMR (400MHz, MeOD) δ7.68-7.66(m, 1H), 7.54-7.52(m, 1H), 7.44-7.34(m, 3 H), 6.49(d, J=7.2Hz, 1H), 5.02-4.90(m, 2H), 4.16-4.14(m, 1H), 3.92-3.90 (m, 2H), 3.70-3.20(m, 8H), 2.70-2.68(m, 2H), 2.54-2.52(m, 2H), 2.10-2. 07(m, 2H), 1.90-1.50(m, 9H), 1.31-1.29(m, 1H), 1.20(s, 3H), 1.05(s, 3H). Chiral SFC H (40% MeOH): ee 100%, Rt = 3.85 min.

[0905] [Example 28]: Preparation of 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 98-A-E1, 98-A-E2 and 98-B)

[0906] Step 1: Cyanomethyl 2-bromo-4-fluorobenzoate

[0907] [ka]

[0908] To a solution of 2-bromo-4-fluorobenzoic acid (5.0 g, 0.23 mol) in anhydrous DCM (20 mL), triethylamine (9.2 g, 0.69 mol) and chloroacetonitrile (3.5 g, 0.46 mol) were added at 0°C. The reaction mixture was heated under reflux and stirred overnight. After cooling to room temperature, the reaction mixture was washed sequentially with aqueous HCl (2 M, 20 mL) and saturated NaHCO3 solution (20 mL). The organic phase was dehydrated with anhydrous MgSO4 and concentrated under reduced pressure to obtain the desired product, cyanomethyl 2-bromo-4-fluorobenzoate, as a pale yellow oil (4.0 g). Yield 68% (ESI 258 / 260 [M+H]). + ).

[0909] Stage 2: 1-(2-bromo-4-fluorophenyl)-5-hydroxypentane-1,4-dione

[0910] [ka]

[0911] To a solution of cyanomethyl 2-bromo-4-fluorobenzoate (3.4 g, 13.2 mmol) and Ti(OiPr)4 (4.15 g, 14.6 mmol) in Et2O (70 mL), EtMgBr (28 mL, 28 mmol, in 1 M THF solution) was added dropwise under argon at 0°C. After adding the Grignard reagent, the mixture was heated to room temperature and stirred for 1 hour. The turbid yellow mixture was stopped with water (10 mL), 1 M HCl (30 mL) was added, and the mixture was extracted with SiO2 (3 times with 50 mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and dehydrated (MgSO4). After removing the solvent, the residue was purified by silica gel column chromatography (petroleum ether: SiO₂ 3:1) to obtain the desired product, 1-(2-bromo-4-fluorophenyl)-5-hydroxypentane-1,4-dione (901 mg), as a colorless oil. Yield 25% (ESI 289 / 271 [M+H]). + ).

[0912] Stage 3: 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol

[0913] [ka]

[0914] To a solution of 1-(2-bromo-4-fluorophenyl)-5-hydroxypentan-1,4-dione (900 mg, 3.13 mmol) in DCM (40 mL), boron trifluoride (diethyl ether complex, 1110 mg, 7.8 mmol) was added dropwise at 0°C. After addition, triethylsilane (910 mg, 7.8 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. The reaction reaction was stopped with saturated NaHCO3 (20 mL) and extracted with DCM (twice with 50 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA 3:1) to obtain the desired product 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol as a colorless oil (650 mg). Yield 80% (ESI 275 / 277[M+H]) + ).

[0915] Stage 4: 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one

[0916] [ka]

[0917] To a solution of 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol (100 mg, 0.37 mmol) in DCM (5 mL), dess-martin periodonan (150 mg, 0.50 mmol) was added in several portions. After addition, the reaction mixture was stirred at room temperature for 2 hours and stopped with saturated NaHCO3 solution (5 mL). The organic layer was washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one as a colorless oil (20 mg). Yield 20% (ESI 273 / 275[M+H]) + ).

[0918] Stage 5: 2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran

[0919] [ka]

[0920] To a solution of methyltriphenylphosphonium bromide (134 mg, 0.52 mmol) in THF (3 mL) at 0°C, n-BuLi (solution in 2.5 M hexane, 0.21 mL, 0.52 mmol) was added, and the reaction mixture was stirred at 0°C for 30 minutes. Next, a solution of 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one (70 mg, 0.26 mmol) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 12 hours, the reaction was stopped with saturated NH4Cl aqueous solution, and the mixture was extracted by DCM (twice with 10 mL). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: siRNA 10:1) to obtain the desired product 2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran as a colorless oil (51 mg, yield 70%). 1 H NMR (400MHz, CDCl3) δ7.52-7.50(m, 1H), 7.27-7.25(m, 1H), 7.05-7.01(m, 1H), 4.89-4.88(m, 2H), 4.75-4. 73(m, 1H), 4.37-4.34(m, 1H), 4.20-4.17(m, 1H), 2.50-2.46(m, 2H), 2.15-2.10(m, 1H), 1.52-1.50(m, 1H).

[0921] Stage 6: 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane

[0922] [ka]

[0923] TFA (690 mg, 6.0 mmol) was added to a solution of ZnEt2 (1 M THF solution, 6 mL, 6.0 mmol) in DCM (20 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, and then CH2I2 (1.7 g, 6.0 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 0.5 hours, and then 2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran (280 mg, 1.0 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, the reaction was stopped with saturated NaHCO3 solution (20 mL), and the DCM layer was dehydrated with Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 50:1) to obtain the desired product 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane as a yellow oil (250 mg). Yield 80% (ESI 267 / 269[M+H-H2O]). + ).

[0924] Step 7: tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate

[0925] [ka]

[0926] A mixture of 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane (250 mg, 0.88 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution in 0.5 M THF (10 mL, 5 mmol), Pd2(dba)3 (40 mg, 0.05 mmol), and Q-phos (31 mg, 0.05 mmol) in THF (2 mL) was stirred at 80°C for 2 hours. Next, the mixture was added to saturated NaHCO3 solution (50 mL) and  (60 mL). The mixture was filtered, the organic layer was washed with brine, dehydrated with Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO2 10:1) to obtain the desired product tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl) acetate as a red oil (160 mg). Yield 53% (ESI 343[M+Na] + ).

[0927] Step 8: tert-butyl 2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate

[0928] [ka]

[0929] To a solution of tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl) acetate (160 mg, 0.5 mmol) in THF (5 mL), lithium diisopropylamide solution in THF / hexane (0.62 mL, 1.25 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, then chlorotrimethylsilane (135 mg, 1.25 mmol) in THF (1 mL) was added, and the reaction mixture was stirred at -78°C for another 30 minutes. Next, NBS (221 mg, 1.25 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl) acetate, as a colorless oil (130 mg). Yield 60% (ESI 419 / 421[M+Na] + ).

[0930] Stage 9: tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolizin-1-yl)acetate

[0931] [ka]

[0932] A mixture of tert-butyl 2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl) acetate (130 mg, 0.33 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (101 mg, 0.33 mmol), DIPEA (126 mg, 0.99 mmol), and NaI (50 mg) in acetonitrile (10 mL) was stirred at 40°C for 12 hours. The mixture was diluted with water (8 mL) and ethyl acetate (25 mL). The organic phase was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl)acetate, as a colorless oil (101 mg). Yield = 52% (ESI 595[M+H] + ).

[0933] Step 10: 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 98-A-E1, 98-A-E2 and 98-B)

[0934] [ka]

[0935] A solution of tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate (210 mg, 0.35 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 15 hours. The solution was then concentrated and purified by preparative HPLC A (40% to 70% MeCN) to obtain 98-A (106 mg) and 98-B (16 mg). 98-A was separated by preparative chiral SFC C to obtain products 98-A-E1 (35 mg) and 98-A-E2 (31 mg) as white solids.

[0936] Compound 98-A-E1 LC / MS ESI 538(M+H) + . 1 H NMR (500MHz, MeOD) δ7.64-7.61(m, 1H), 7.49-7.46(m, 1H), 7.18-7.16(m, 2H), 6.39(d, J=7.5Hz, 1H), 4.93(s , 1H), 4.82-4.85(m, 1H), 4.19(brs, 1H), 4.12-4.10(m, 1H), 3.61(m, 1H), 3.49(t, J=6.5Hz, 2H), 3.341-3.38( m, 3H), 3.23(d, J=12.5H, 1H), 3.11-3.09(m, 2H), 2.72(t, J=6.0Hz, 2H), 2.56(t, J=7.5Hz, 2H), 2.3-2.2-(m, 1 H), 2.11-2.00(m, 4H), 1.90-1.88(m, 2H), 1.74-1.72(m, 2H), 1.65-1.63(m, 2H), 1.2(m, 1H), 0.6-0.3(m, 4H). Chiral SFC C(20%EtOH): ee100%, Rt=1.29 min.

[0937] Compound 98-A-E2 LC / MS ESI 538(M+H) + . 1H NMR (400MHz, MeOD) δ7.63-7.61(m, 1H), 7.50-7.48(m, 1H), 7.22-7.16(m, 2H), 6.39(d, J=7.6Hz, 1H), 4.82-4.80(m, 1H) ), 4.20-4.12(m, 2H), 3.60-3.32(m, 6H), 3.30-3.05(m, 4H), 2.75-2.55(m, 4H), 2.25-1.58(m, 12H), 0.58-0.30(m, 4H). Chiral SFC C(20%EtOH): ee100%, Rt=2.17 min.

[0938] Compound 98-B (mixture of two stereoisomers) LC / MS ESI 538(M+H) + . 1 H NMR (400MHz, MeOD) δ7.41-7.32(m, 2H), 7.08-6.98(m, 2H), 6.28-6.22(m, 1H), 4.80-4.75(m, 1H), 4.05-3.85(m, 2H), 3.60-3.32(m, 6H), 3.10-2.85(m, 4H), 2.62-2.58(m, 2H), 2.47-2.41(m, 2H), 2.21-1.40(m, 12H), 0.55-0.20(m, 4H).

[0939] [Example 29]: Preparation of 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 99-E1 and 99-E2)

[0940] Stage 1: 1-(2-bromo-4-fluorophenyl)cyclopropanol

[0941] [ka]

[0942] To a solution of 1-(2-bromo-4-fluorophenyl)ethanone (5.0 g, 23.1 mmol) and Et3N (3.51 g, 34.7 mmol) in DCM (50 mL), TMSOTf (6.17 g, 27.8 mmol) was added dropwise over 10 minutes using a syringe under nitrogen at 0°C. The reaction mixture was stirred overnight at room temperature, and the reaction was stopped with saturated NaHCO3 aqueous solution (20 mL). The aqueous solution was extracted with DCM (twice with 30 mL). The combined organic phases were washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain crude ether. The crude ether was dissolved in anhydrous DCM (50 mL), diiodomethane (25.0 g, 92.4 mmol) was added, the mixture was cooled to 0°C, and diethylzinc (1 M THF solution, 93 mL, 93 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, stopped with saturated NH4Cl solution (30 mL), and extracted by DCM (twice with 50 mL). The combined organic phase was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in MeOH (20 mL), then K2CO3 (3.2 g, 23.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, H2O (20 mL) was added, and the mixture was extracted with ELISA (twice with 40 mL). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ELISA 5:1) to obtain the desired product 1-(2-bromo-4-fluorophenyl)cyclopropanol as a colorless oil (3.1 g). Yield 86% (ESI 213 / 215[M+H]) + ).

[0943] Step 2: Ethyl 5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate

[0944] [ka]

[0945] A mixture of 1-(2-bromo-4-fluorophenyl)cyclopropanol (100 mg, 0.44 mmol), ethyl 2-bromo-2,2-difluoroacetate (351 mg, 1.74 mmol), CuI (8.2 mg, 0.044 mmol), phenanthroline (17.2 mg, 0.088 mmol), and K2CO3 (120 mg, 0.88 mmol) in MeCN (5 mL) was stirred at 90°C for 17 hours. The reaction was stopped with water (10 mL), and the mixture was extracted with ethyl acetate (three times with 10 mL). The combined organic layers were washed with brine, dehydrated with Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: HCl 5:1) to obtain the desired product, ethyl 5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate, as a colorless oil (81 mg). Yield 53% (ESI 353 / 355[M+H]). + ).

[0946] Stage 3: 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran

[0947] [ka]

[0948] To a solution of ethyl 5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate (100 mg, 0.28 mmol) in MeOH (5 mL), NaBH4 (44 mg, 1.12 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure, H2O (10 mL) was added, and the mixture was extracted with DCM (three times with 10 mL). The combined organic phases were dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (3 mL), and trifucal acid (100 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, the reaction was stopped with saturated NaHCO3 aqueous solution (5 mL), and the mixture was extracted with DCM (twice with 10 mL). The combined organic layers were washed with brine, dehydrated with Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: siRNA 10:1) to obtain the desired product, 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran, as a colorless oil (40 mg). Yield 47% (ESI 297 / 299[M+H]). + ).

[0949] Stage 4: tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl) acetate

[0950] [ka]

[0951] A mixture of 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran (800 mg, 2.93 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (30 mL, 15 mmol in 0.5 M THF), Pd2(dba)3 (152 mg, 0.15 mmol), and Q-phos (105 mg, 0.15 mmol) in THF (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was then added to saturated NaHCO3 solution (20 mL) and  (30 mL). The mixture was filtered, the organic layer was washed with brine, dehydrated with Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl) acetate as a red oil (703 mg). Yield 78% (ESI 275[M+H-tBu]) + ).

[0952] Stage 5: tert-butyl 2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate

[0953] [ka]

[0954] To a solution of tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl) acetate (703 mg, 2.12 mmol) in THF (5 mL), lithium diisopropylamide solution (2 M, 2.65 mL, 5.3 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, and a solution of chlorotrimethylsilane (573 mg, 5.3 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (944 mg, 5.3 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product, tert-butyl 2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl) acetate, as a red oil (816 mg). Yield 66% (ESI 352 / 354[M+H-tBu]). + ).

[0955] Step 6: tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0956] [ka]

[0957] A mixture of tert-butyl 2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl) acetate (816 mg, 2.0 mmol), (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine (660 mg, 2.0 mmol), DIPEA (821 mg, 6.0 mmol), and NaI (50 mg) in acetonitrile (20 mL) was stirred at 40°C for 6 hours. The mixture was diluted with water (8 mL) and ethyl acetate (25 mL). The organic phase was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (DCM:MeOH 20:1) to obtain the desired product, tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate, as a colorless oil (710 mg). Yield 58% (ESI 604[M+H]). + ).

[0958] Step 7: 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 99-E1 and 99-E2)

[0959] [ka]

[0960] To a solution of tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl) acetate (710 mg, 1.2 mmol) in DCM (10 mL), TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. Next, it was concentrated and purified by preparative HPLC A (40% to 70% MeCN) to obtain 99 as a white solid (400 mg, yield 63%). The racemic product was separated by preparative chiral SFC A to obtain diastereomer products 99-E1 (74 mg) and 99-E2 (88 mg) as white solids.

[0961] Compound 99-E1 LC / MS ESI 548(M+H) + . 1 H NMR (400MHz, MeOD) δ7.61-7.59(m, 1H), 7.51-7.48(m, 1H), 7.22-7.13(m, 2H), 6. 41(d, J=7.2Hz, 1H), 4.99-4.90(m, 1H), 4.80(s, 1H), 4.19-4.17(m, 1H), 4.01-3.8 0(m, 2H), 3.50-3.35(m, 6H), 3.20-3.18(m, 1H), 3.02-2.98(m, 1H), 2.81-2.79(m, 2H), 2.62-2.59(m, 2H), 2.30-2.01(m, 6H), 1.82-1.80(m, 2H), 1.75-1.60(m, 4H). Chiral SFC A (40%MeOH): ee100%, Rt=1.92 min.

[0962] Compound 99-E2 LC / MS ESI 548(M+H) + . 1H NMR (400MHz, MeOD) δ7.62-7.60(m, 1H), 7.53-7.51(m, 1H), 7.28(d, J=7.6Hz, 1H), 7.17-7.14(m, 1H), 6.44(d, J=7.2Hz, 1H), 4.99-4.90(m, 1H), 4.79(s, 1H), 4.19-4. 17(m, 1H), 4.01-3.80(m, 2H), 3.60-3.35(m, 6H), 3.20-3.18(m, 2H), 2.81-2.79(m , 2H), 2.62-2.59(m, 2H), 2.30-2.01(m, 6H), 1.82-1.80(m, 2H), 1.75-1.60(m, 4H). Chiral SFC A (40%MeOH): ee98%, Rt=2.47 min.

[0963] [Example 30]: Preparation of 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 100-E1 and 100-E2)

[0964] Step 1: Ethyl 3-(2-bromophenyl)acrylate

[0965] [ka]

[0966] To a solution of 2-bromobenzaldehyde (5.00 g, 27.0 mmol) in THF (30 mL), ethyl 2-(triphenyl-15-phosphaneylidene) acetate (9.89 g, 28.4 mmol) was added, and the mixture was stirred overnight at 60°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product as a yellow oily substance (6.51 g). Yield 93%. 1 H NMR (400MHz, CDCl3) δ8.06(d, 1H), 7.61(m, 2H), 7.24-7.19(m, 2H), 6.40(d, 1H), 4.31-4.08(m, 2H), 1.36-1.15(m, 3H).

[0967] Stage 2: 3-(2-bromophenyl)propa-2-en-1-ol

[0968] [ka]

[0969] 3-(2-bromophenyl)acrylate (6.5 g, 30.7 mmol) was dissolved in THF (anhydrous, 50 mL) at 0°C, and DIBAL-H (1 M, 61.3 mL, 61.3 mmol) was added dropwise. The mixture was stirred at 0°C for 30 minutes, then heated and allowed to cool to room temperature for 1 hour. The reaction solvent was added to aqueous HCl (1 N, 200 mL) and stirred overnight at room temperature. The mixture was extracted with ethyl acetate (3 times with 50 mL). The combined organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: HCl 10:3) to obtain the desired product as a light yellow oil (5.10 g). Yield 89%. 1 H NMR (400MHz, CDCl3) δ7.59-7.30(m, 3H), 7.18-7.08(m, 2H), 6.34-6.30(m, 1H), 4.37-4.27(m, 2H).

[0970] Stage 3: 1-Bromo-2-(3-bromopropa-1-enyl)benzene

[0971] [ka]

[0972] To a solution of 3-(2-bromophenyl)propa-2-en-1-ol (4.80 g, 22.64 mmol) in diethyl ether (anhydrous, 50 mL), phosphorus tribromide (1.27 mL, 9.06 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, the reaction was stopped with saturated NaHCO3, and the mixture was extracted with diethyl ether (twice with 50 mL). The combined organic layers were washed with brine, anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product, 1-bromo-2-(3-bromopropa-1-enyl)benzene, as a yellow oil (5.20 g). Yield 79%. 1 H NMR (400MHz, CDCl3) δ7.56-7.46(m, 2H), 7.34-7.26(m, 2H), 6.36-6.34(m, 1H), 4.18-4.03(m, 2H).

[0973] Stage 4: Methyl 5-(2-bromophenyl)-2,2-dimethylpenta-4-enoate

[0974] [ka]

[0975] To a solution of methyl isobutyrate (2.13 g, 20.88 mmol) in THF (anhydrous, 40 mL), LDA (1 M, 20.88 mL, 20.88 mmol) was added dropwise at -78°C. The mixture was stirred at -78°C for 30 minutes, and a solution of 1-bromo-2-(3-bromopropa-1-en-1-yl)benzene (5.20 g, 18.98 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes, then the temperature was raised and the mixture was allowed to rise to room temperature for another hour. The reaction was stopped with saturated NH4Cl, and the mixture was extracted with siRNA (three times with 50 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: siRNA 5:1) to obtain the desired product as a yellow oil (4.36 g, 78% yield). 1H NMR (400MHz, CDCl3) δ7.58-7.46(m, 2H), 7.23-7.09(m, 2H), 6.74-6.51(m, 1H) , 6.10-6.02(m, 1H), 3.69-3.64(m, 3H), 2.48-2.40(m, 2H), 1.24-1.15(m, 6H).

[0976] Stage 5: 5-(2-bromophenyl)-2,2-dimethylpenta-4-en-1-ol

[0977] [ka]

[0978] To a solution of methyl 5-(2-bromophenyl)-2,2-dimethylpenta-4-enoate (4.36 g, 14.53 mmol) in THF (anhydrous, 20 mL), a solution of lithium aluminum hydride in tetrahydrofuran (2.4 M, 6.66 mL, 11.80 mmol) was added dropwise at -78°C. The mixture was stirred at -78°C for 3 hours, and the reaction was stopped with 1 M HCl (approximately 100 mL, added dropwise at the start). The reaction mixture was extracted with HCl (three times with 50 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: HCl 10:3) to obtain the desired product as a yellow oil (3.74 g, 93% yield). ESI: 267(M+H) + .

[0979] Step 6: Ethyl 3-(2-bromophenyl)acrylate

[0980] [ka]

[0981] To a solution of 5-(2-bromophenyl)-2,2-dimethylpenta-4-en-1-ol (3.74 g, 13.95 mmol) in dichloroethane (20 mL), tetrabutylammonium hexafluorophosphate (0.27 g, 0.70 mmol) and calcium(II) bis(trifluoromethanesulfonyl)imide (0.22 g, 0.70 mmol) were added. The mixture was stirred at 90°C for 20 hours, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: siRNA 10:1) to obtain the desired product, ethyl 3-(2-bromophenyl)acrylate, as a yellow oil (1.50 g, yield 40%). 1 H NMR (400MHz, CDCl3) δ7.54(d, J=6.8Hz,2H), 7.33(t, J=8.0Hz,1H), 7.10(t, J=7.2Hz, 1H), 4.56(d, J=9.6Hz, 1H) , 3.3(d, J=11.2Hz, 1H), 3.38(d, J=11.2Hz, 1H), 1.88-1.84(m, 1H), 1.59-1.53(m, 4H), 1.13(s, 3H), 0.88(s, 3H).

[0982] Step 7: Butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate

[0983] [ka]

[0984] To a mixture of ethyl 3-(2-bromophenyl)acrylate (1.50 g, 5.60 mmol), tris(dibenzylideneacetone)dipalladium (0.29 g, 0.28 mmol), and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (0.20 g, 0.28 mmol) in THF (10 mL), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide (1 M THF solution, 28 mL, 28 mmol) was added. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was added to saturated NaHCO3 (100 mL) and extracted with ethyl (three times in 50 mL increments). The combined organic layer was washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: SiO₂ 10:1) to obtain the desired product as a red oily substance (1.21 g, 71% yield). ESI: 249 (M-C₄H₇+H) +

[0985] Step 8: tert-butyl 2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)acetate

[0986] [ka]

[0987] To a solution of tert-butylbutyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate (1.21 g, 3.17 mmol) in THF (10 mL), a 2.0 M lithium diisopropylamide solution in THF / hexane (4.0 mL, 8.0 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, chlorotrimethylsilane (864 mg, 8.0 mmol) was added, and the reaction mixture was stirred at -78°C for another 30 minutes. Next, a solution of NBS (1.43 g, 8.0 mmol) in THF (10 mL) was added, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was stopped with MeOH (2 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO 10:1) to obtain the desired product, tert-butyl 2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate, as a yellow oil (1.31 g, yield 85%). ESI: 327(M-C4H9+H) + .

[0988] Stage 9: tert-butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0989] [ka]

[0990] (S)-7-(4,4-difluoro-5-(pyrroridine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (200 mg, 0.65 mmol, 2-bromo-2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl) acetate (220 mg, 0.65 mmol), DIEA (252 mg, 1.95 mmol), and NaI (19.5 mg, 0.13 mmol) were mixed in acetonitrile (10 mL) and stirred at 50°C for 6 hours. The solvent was removed under reduced pressure, and the residue was collected by silica gel column (DCM:MeOH). Purification by 20:1) yielded the desired product, tert-butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate, as a yellow oil (150 mg, yield 45%). ESI: 578(M+H) + .

[0991] Step 10: tert-butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 100-E1 and 100-E2)

[0992] [ka]

[0993] tert-butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)pyrrolidine-1-yl) acetate (150 mg, 0.26 mmol) was treated overnight at 25°C with a mixture of DCM (3 mL) and TFA (3 mL). The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC A (30% to 65% MeCN) to obtain the desired product, tert-butyl 2-(2-(5,5-dimethyltetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 100), as a white solid (96 mg, 70%). The racemic product was separated by preparative chiral SFC H to obtain diastereomer products 100-E1 (29 mg) and 100-E2 (26 mg) as white solids.

[0994] Compound 100-E1 LC / MS ESI 522.7(M+H) + . 1 H NMR (400MHz, MeOD) δ7.68(d, J=8.0Hz, 1H), 7.59(d, J=8.0Hz, 1H), 7.45-7.38(m, 2 H), 7.15(d, J=8.0Hz, 1H), 6.37(d, J=7.2Hz, 1H), 4.93(s, 1H), 4.73(d, J=8.0Hz, 1H) ), 4.19(s, 1H), 3.56-3.36(m, 7H), 3.22-3.05(m, 3H), 2.70(t, J=6.0Hz, 2H), 2.57 (t, J=6.0Hz,2H), 2.14-1.92(m, 6H), 1.76-1.61(m, 6H), 1.15(s, 3H), 0.95(s, 3H). Chiral SFC H(45%MeOH): ee98%, Rt=1.54 min.

[0995] Compound 100-E2 LC / MS ESI 522.7(M+H) + . 1H NMR (400MHz, MeOD) δ7.68(d, J=8.0Hz, 1H), 7.59(d, J=8.0Hz, 1H), 7.45-7.38( m, 2H), 7.15(d, J=8.0Hz, 1H), 6.37(d, J=7.2Hz, 1H), 4.81-4.78(m, 2H), 4.17( s, 1H), 3.58-3.32(m, 8H), 3.22-3.15(m, 2H), 2.70(t, J=6.0Hz, 2H), 2.55(t, J =6.0Hz,2H), 2.18-1.92(m, 6H), 1.76-1.61(m, 6H), 1.12(s, 3H), 0.89(s, 3H). Chiral SFC H(45%MeOH): ee100%, Rt=2.35 min.

[0996] [Example 31]: Preparation of 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomer compounds 101-A-E1, 101-A-E2, 101-B-E1 and 101-B-E2)

[0997] Stage 1: 4-(2,6-dichloropyridine-3-yl)buta-3-en-2-one

[0998] [ka]

[0999] A mixture of 2,6-dichloronicotinaldehyde (25 g, 143.5 mmol) and 1-(triphenylphosphoranylidene)-2-propanone (57.2 g, 179.6 mmol) in toluene (180 mL) was stirred at 110 °C for 16 hours. The mixture was cooled to room temperature, H₂O (40 mL) was added, and the mixture was extracted with ethyl acetate (three times with 50 mL each). The combined organic layer was dehydrated with Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: siRNA 1:1) to obtain the desired product as a yellow solid (13.3 g). Yield 43% (ESI 216.0 (M+H)). + ).

[1000] Stage 2: 4-(2,6-dichloropyridine-3-yl)butan-2-amine

[1001] [ka]

[1002] A mixture of 4-(2,6-dichloropyridine-3-yl)buta-3-en-2-one (12 g, 55.8 mmol), NH4OAc (21.5 g, 279.1 mmol), and NaBH3CN (10.6 g, 167.4 mmol) in MeOH (100 mL) was stirred at 30°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (DCM:MeOH 40:1) to obtain the desired product as a yellow oil (7.94 g). Yield 58% (ESI 219.0 (M+H)). + ).

[1003] Stage 3: (R)-7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine and (S)-7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine

[1004] [ka]

[1005] A mixture of 4-(2,6-dichloropyridine-3-yl)butan-2-amine (7 g, 32.1 mmol) and Cs2CO3 (52 g, 160.6 mmol) in DMF (120 mL) was stirred at 140°C for 16 hours. The mixture was cooled to room temperature, siRNA (100 mL) was added, and the mixture was washed with H2O (three times with 100 mL). The organic layer was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:siRNA 1:1) to obtain the desired product as a yellow oil (1.9 g). Yield 32% (ESI 183.0 (M+H)). +The racemic product was separated by preparative chiral SFC B to obtain stereoisomer A (870 mg) and stereoisomer B (890 mg) as a yellow oily substance.

[1006] Stage 4: (R)-tert-butyl 7-chloro-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A

[1007] [ka]

[1008] A mixture of 7-chloro-2-methyl-1,2,3,4-tetrahydro-1,8-naphthirizine stereoisomer A (870 mg, 4.75 mmol), (Boc)2O (3.13 g, 14.35 mmol), and DMAP (1.75 g, 14.35 mmol) in THF (40 mL) was stirred at 60°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (petroleum ether: SiO2 10:1) to obtain the desired product as a yellow solid (1.2 g). Yield 89% (ESI 283.0 (M+H)). + ).

[1009] Stage 5: tert-butyl 7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yloxy)butyl)-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A

[1010] [ka]

[1011] (R)-tert-butyl 3-(buta-3-enyloxy)pyrrolidine-1-carboxylate (512 mg, 2.13 mmol) was added to a solution of (R)-tert-butyl 3-(buta-3-enyloxy)pyrrolidine-1-carboxylate (anhydrous, 5 mL) in THF (anhydrous), under Ar, with 9-BBN (0.5 M THF solution, 8.5 mL, 4.25 mmol). The reaction mixture was stirred at 50°C for 2 hours, cooled to room temperature, and then tert-butyl 7-chloro-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A (600 mg, 2.13 mmol), tricyclohexylphosphine (60 mg, 0.21 mmol), Pd(OAc)2 (47 mg, 0.21 mmol), and NaOH (127 mg, 3.19 mmol) were added. The mixture was stirred at 70°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: SiO₂ 8:1) to obtain the desired product as a yellow solid (988 mg). Yield 95% (ESI 490.0(M+H)). + ).

[1012] Stage 6: 2-methyl-7-(4-((R)-pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine stereoisomer A

[1013] [ka]

[1014] 1.2 g, 2.45 mmol of tert-butyl 7-(4-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yloxy)butyl)-2-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A was treated with HCl / 1,4-dioxane (4 M, 8 mL) at 25 °C for 16 hours. The solvent was removed under reduced pressure to obtain the desired product (781.7 mg) as a white solid. Yield 88% (ESI 290.0 (M+H)). + ).

[1015] Step 7: tert-butyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-((R)-3-(4-(7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)pyrrolidine-1-yl)acetate stereoisomer A

[1016] [ka]

[1017] A mixture of 2-methyl-7-(4-((R)-pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthirizine stereoisomer A (200 mg, 0.55 mmol), tert-butyl 2-bromo-2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl) aceta...

Claims

1. A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising, as an active compound, an αvβ6 integrin inhibitor having the structure of formula (I) below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 【Chemistry 1】 [In the formula, A is 【Chemistry 2】 And R １ In either case, it is H; B is, 【Transformation 3】 Selected from the group consisting of; q is 0, 1, 2, or 3; p is 0, 1, or 2; C is, 【Chemistry 4】 And n is 0; R ２ teeth 【Transformation 5】 And R ２ n in this case is 1; R ４ These are independently alkyl, -C(F ２ )CH ３ Selected from cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is substituted or unsubstituted, and if substituted, is substituted with a halogen, alkyl, or alkoxy; R ５ is F; R ａ is H; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

2. B 【Transformation 6】 The pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 2, wherein q is 2.

4. A 【Transformation 7】 The pharmaceutical composition according to claim 3.

5. R ４ The pharmaceutical composition according to claim 4, wherein R is cycloalkyl.

6. R ４ The pharmaceutical composition according to claim 4, wherein is a heterocycloalkyl group.

7. R ４ The pharmaceutical composition according to claim 4, wherein is -O-alkylene-cycloalkyl.

8. R ４ but 【Transformation 8】 A pharmaceutical composition according to claim 4, selected from the above.

9. R ４ but 【Chemistry 9】 The pharmaceutical composition according to claim 1.

10. R ４ but 【Chemistry 10】 The pharmaceutical composition according to claim 1.

11. R ４ but 【Chemistry 11】 The pharmaceutical composition according to claim 1.

12. R ４ but 【Chemistry 12】 The pharmaceutical composition according to claim 1.

13. A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising, as an active compound, an αvβ6 integrin inhibitor having the structure of formula (I) below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 【Chemistry 13】 [In the formula, A is, 【Chemistry 14】 And R １ In either case, it is H; B is, 【Chemistry 15】 Selected from the group consisting of; q is 2; C is, 【Chemistry 16】 And n is 0; R ２ teeth, 【Chemistry 17】 And R ２ n in this case is 0; R ４ It is a heterocycloalkyl; R ａ is H; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

14. A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising, as an active compound, an αvβ6 integrin inhibitor having the structure of formula (I) below or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Chemistry 18] [In the formula, A is, 【Chemistry 19】 And R １ In either case, it is H; B is, 【Chemistry 20】 Selected from the group consisting of; q is 0, 1, 2, or 3; p is 0, 1, or 2; C is 【Chemistry 21】 And n is 0; R ２ teeth 【Chemistry 22】 And R ２ In this case, m is either 0 or 1; R ４ These are independently alkyl, -C(F ２ )CH ３ Selected from cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; R ５ is F; R ａ is H; The absolute configuration of any stereocenter is R, S, or a mixture thereof.

15. B 【Chemistry 23】 And q is 2; C 【Chemistry 24】 And n is 0, R ４ is a cycloalkyl; R ａ H is; The pharmaceutical composition according to claim 14, wherein the absolute configuration of any stereocenter is R, S, or a mixture thereof.

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