Inhibitors of alpha v beta 6 integrin

Abstract

Disclosed are small molecule inhibitors of αvβ6 integrin, and methods of using the same to treat a number of diseases and conditions.

Description

[0001] This application is a divisional application of the invention patent application filed on February 27, 2018, with Chinese national application number 201880028013.6, entitled "Inhibitor of αvβ6 integrin".

[0002] Related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 464,693, filed on February 28, 2017. Background Technology

[0004] The heterodimeric integrase family of receptors regulates cell shape and cell adhesion to extracellular substrates in response to extrinsic and intrinsic cues.

[0005] Integral signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.

[0006] Integrin receptors can specifically signal cells bidirectionally, both "inside-out" and "outside-in." Therefore, they mediate cell migration and regulate cytoskeleton organization to achieve the shape changes required during cell migration through extracellular substrate-to-cytoskeleton transfer. RGD-binding integrins can bind to and activate TGF-β and have recently been associated with fibrotic diseases.

[0007] Integrins are present on the surface of most human cells. Their pathology contributes to a variety of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidneys, macular degeneration, and various autoimmune and chronic inflammatory diseases.

[0008] The role of integrins as drug targets has long been recognized, and a total of six injectable integrin inhibitors have been approved by the Food and Drug Administration for the treatment of various therapeutic indications, including inflammatory bowel disease. Multiple sclerosis Psoriasis and acute coronary syndrome However, there has been a significant lack of successful treatment using oral bioavailable integrin inhibitors.

[0009] Of the 24 known integrin heterodimers, at least half are associated with inflammation, fibrosis, tumors, and vascular diseases. There is a need for novel classes of integrin inhibitors. Summary of the Invention

[0010] In some embodiments, the present invention relates to compounds of formula I:

[0011] ABC(I)

[0012] in:

[0013] A is

[0014] B represents alkylene, -alkylene-(O), -alkylene-N(R)C(O)-, -alkylene-(heterocyclic)-C(O)-, -alkylene-C(O)N(R)-, -alkylene-C(O)-, -alkylene-N(R)-, -alkylene-N(R)C(O)N(R)-, -alkylene-N(R)SO2-, -alkylene-(aryl)-, -alkylene-(heterocyclic)-, -alkylene -(heterocyclic)-alkylene-, -aryl-alkylene-N(R)C(O)-, -aryl-C(O)N(R)-, -aryl-N(R)C(O)-, -(heterocyclic)-alkylene-, -heterocyclic-alkylene-N(R)C(O)-, -heterocyclic-C(O)N(R)-, -O-heterocyclic-, -alkylene-O-, -heterocyclic-C(O)-, cycloalkylene or cycloalkylene-O-;

[0015] C is

[0016] R is H, alkyl, or aryl;

[0017] R1 can be independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R or NH2;

[0018] R2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkylene-aryl, or heterocycloalkyl;

[0019] It is a 3- to 12-membered heterocyclic alkylene group that is unsubstituted or substituted by one or more instances of R1;

[0020] X is C(R) c ) or N;

[0021] Two Rs a Examples include H, which may form bonds together, or (C1-C4) alkylene bridges;

[0022] R b It is H or (C1-C6) alkyl; and

[0023] R c It can be H, alkyl, aryl, OH or a halide;

[0024] Or its pharmaceutically acceptable salt;

[0025] The limiting condition is that the compound is not a

[0026] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0038]

[0039] In some embodiments, the present invention relates to a method for treating diseases or conditions selected from the group consisting of: idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary cholangitis, primary sclerosing cholangitis, solid tumors, hematologic malignancies, organ transplantation, Allport 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 myocardial fibrosis, the method comprising the step of administering a therapeutically effective amount of any of the compounds described herein to an individual in need. Attached Figure Description

[0040] Figure 1 A table outlining the inhibition of αvβ6 integrin by example compounds in fluorescence polarization assays. Detailed Implementation

[0041] In some embodiments, the present invention relates to compounds that inhibit αvβ6 integrin. In some embodiments, the compounds selectively target αvβ6 integrin.

[0042] The compounds can be used to treat idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary cholangitis, primary sclerosing cholangitis, solid tumors, hematologic malignancies, organ transplantation, Allport 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 myocardial fibrosis.

[0043] definition

[0044] For convenience, certain terms used in this specification, examples, and appended claims are collected herein before further description of the invention. These definitions should be read according to the remainder of the invention and as understood by one of ordinary skill in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0045] To facilitate understanding of the invention, certain terms and phrases are defined below and throughout this specification.

[0046] In this text, the article “a / an” refers to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one or more elements.

[0047] As used in this specification and claims, the phrase “and / or” should be understood to mean “any one or two” of the elements so combined, that is, elements that exist together in some cases and separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those specifically identified elements. Thus, as a non-limiting example, reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising,” may in one embodiment mean only A (optionally including elements other than B); in another embodiment, only B (optionally including elements other than A); in yet another embodiment, both A and B (optionally including other elements); and so on.

[0048] As used herein in this specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, i.e., including many elements or at least one of the elements in the list, but also including more than one, and, optionally, additional unlisted items. Only terms explicitly indicating the opposite, such as “only one of” or “exactly one of”, or, when used in the claims, “consisting of” will refer to including many elements or exactly one of the elements in the list. Generally, as used herein, when preceding exclusive terms (e.g., “or,” “one of,” “only one of,” or “exactly one of”), the term “or” should only be interpreted as indicating an exclusive option (i.e., “one or the other, but not both”). “Substantially consisting of”, when used in the claims, should have its usual meaning as used in the field of patent law.

[0049] As used herein and in the claims, the phrase "at least one" referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the element list, but does not necessarily include each of the elements specifically listed in the element list and at least one of each element, and does not exclude any combination of elements in the element list. This definition also allows the phrase "at least one" to mean that, in addition to the elements specifically identified in the element list, elements may optionally exist, whether related to or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B", or, equivalently, "at least one of A and / or B") may, in one embodiment, mean at least one, optionally including more than one A, with no B (and optionally including elements other than B); in another embodiment, mean at least one, optionally including more than one B, with no A (and optionally including elements other than A); in yet another embodiment, mean at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0050] It should also be understood that, unless explicitly indicated to the contrary, in any method described herein that involves more than one step or action, the order of the steps or actions of the method is not required to limit the order of the steps or actions of the method described herein.

[0051] In the claims, and in the above description, all transitional phrases (such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "constituting," etc.) will be understood as open-ended, meaning that they include but are not limited to. Only the transitional phrases "constituting of" and "constituting substantially of" should be closed or semi-closed transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0052] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention covers all such compounds comprising cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof falling within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included within the present invention.

[0053] If, for example, a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, wherein the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed using a suitable optically active acid or base, and the diastereomeric salt thus formed by fractional crystallization or chromatographic methods well known in the art is then eluted, and the pure enantiomer is subsequently recovered.

[0054] The structures described in this article also refer to different compounds containing only one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by using... 13 C- or 14 Compounds prepared by replacing carbon with C-concentrated carbon are within the scope of this invention.

[0055] As used herein, the term "prodrug" encompasses compounds that, under physiological conditions, are converted into therapeutically activating agents. Common methods for preparing prodrugs involve hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted via the enzymatic activity of a host animal.

[0056] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or medium (such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance) that involves the transport or delivery of a target chemical from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense of being compatible with the other components of the formulation, harmless to the patient, and substantially nonpyrogenic. Some examples of substances that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil and cottonseed oil. Oils, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic and compatible substances used in pharmaceutical formulations. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free, i.e., do not cause a significant temperature rise when administered to a patient.

[0057] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic addition salt of a compound to an inorganic or organic acid. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free base form, with a suitable organic or inorganic acid and isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucono-p-ethyl, lacturonate, and laurylsulfonate, etc. (See, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.)

[0058] In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and thus be able to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these examples, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic, or organic base addition salt of the compound. These salts can be prepared in situ during the final isotopeing and purification of the compound, or by reacting the purified compound, in its free acid form, with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine alone. Representative bases or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., above).

[0059] The "therapeutic effective amount" (or "effective amount") of a compound relative to its use in treatment refers to the amount of the compound in a formulation that, when administered as part of a desired dosage regimen (to mammals, preferably humans), is clinically acceptable or cosmetically intended to alleviate symptoms, improve conditions, or slow the onset of a disease condition, based on the criteria for treatment or for any reasonable benefit / risk ratio suitable for any medical treatment.

[0060] The term "preventive or therapeutic" refers to a treatment that is technically approved and involves the administration of one or more targeted compositions to a host. A treatment is preventive if it is administered before the clinical manifestation of an unwanted symptom (e.g., a disease or other unwanted condition in the host animal), i.e., it protects the host from developing the unwanted symptom; however, a treatment is therapeutic if it is administered after the manifestation of the unwanted symptom, i.e., it is intended to reduce, improve, or stabilize the existing unwanted symptom or its side effects.

[0061] The term "patient" refers to a mammal that requires specific treatment. In some embodiments, the patient is a primate, canine, feline, or equine animal. In some embodiments, the patient is a human.

[0062] Aliphatic chains include alkyl, alkenyl, and alkynyl groups as defined below. Straight-chain aliphatic chains are limited to unbranched carbon chain portions. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group containing saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0063] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or, if not specified, up to 30 carbon atoms. For example, alkyl groups with 1 to 8 carbon atoms refer to groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those groups that are positional isomers of these groups. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., for straight-chain C1-C1). 30 For branch chain C3-C 30 ), and more preferably 20 or fewer. The alkyl groups may be substituted or unsubstituted.

[0064] 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) and containing two connecting sites on its longest carbon chain that are attached to the remainder of the compound. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or unbranched carbon chain groups, and may optionally be substituted with one or more substituents.

[0065] "Cycloalkyl" means a monocyclic, bicyclic, bridged, or spirocyclic ring, or a polycyclic saturated carbon ring, having 3 to 12 carbon atoms. Preferably, the cycloalkyl group has 3 to 10 carbon atoms in its ring structure, and more preferably 3 to 6 carbon atoms in its ring structure. The cycloalkyl group may be substituted or unsubstituted.

[0066] Unless the number of carbons is otherwise specified, as used herein, "low carbon number alkyl" means an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "low carbon number alkenyl" and "low carbon number alkynyl" have similar chain lengths. Throughout this application, alkyl groups are preferably low carbon number alkyl groups. In some embodiments, substituents specified herein, such as alkyl groups, are low carbon number alkyl groups.

[0067] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain group having a specified number of carbon atoms, or, if the specified number of carbon atoms is not limited, up to 26 carbon atoms; and having one or more double bonds in the group. Examples of alkenyl groups with 6 to 26 carbon atoms are as follows: hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, dodecenyl, tridecenyl, and dodecenyl, wherein the unsaturated bonds may be located at any position in the group and may have (Z) or (E) configurations with respect to the double bonds.

[0068] "Alkyne" refers to the hydrocarbon group in the alkenyl range, but with one or more triple bonds in the portion.

[0069] The term "alkathioyl" refers to an alkyl group as defined above, having a thio group attached thereto. In some embodiments, the "alkathioyl" group is composed of -(S)-alkyl, -(S)-alkenyl, -(S)-ynyl, and -(S)-(CH2). m -R 1 One of the representations, where m and R 1 The definitions are as follows. Representative alkathioyl groups include methylthio, ethylthio, etc. As used herein, the term "alkoxy" refers to an alkyl group as defined above, having an oxygen moiety attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. An "ether" is two hydrocarbons covalently linked by oxygen. Therefore, the substitution of the alkyl group for an ether is either alkyl or similar to an alkoxy group, such as -O-alkyl, -O-alkenyl, -O-ynyl, -O-(CH2). m -R 10 One of the representations, where m and R 10 The description is as follows.

[0070] The terms "amine" and "amino" are technically recognized and refer to both unsubstituted and substituted amines, for example, portions that can be represented by the following formula:

[0071]

[0072] Where R 11 R 12 and R 13 Each can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , or R 11 and R 12 Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure; R 10This represents an alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclic, or polycyclic group; and m is an integer in the range of 0 or 1 to 8. In some embodiments, R 11 Or R 12 Only one of them can be a carbonyl group, for example, R 11 R 12 It does not form an imide with nitrogen. In even more specific embodiments, R 11 and R 12 (and optional R) 13 Each of these can independently represent hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 Therefore, as used herein, the term "alkylamine" means an amino group as defined above, having a substituted or unsubstituted alkyl group attached thereto, i.e., R 11 and R 12 At least one of them is an alkyl group. In some embodiments, the amino or alkylamine is basic, meaning it has a pK... a Conjugate acids with a pK value >7.00, meaning that the protonated forms of these functional groups have a pK value greater than 7.00 relative to water. a .

[0073] As used in this article, the term "amide" refers to a group.

[0074]

[0075] Among them, each R 14 Independently representing a hydrogen or hydrocarbon group, or two Rs 14 Together with the N atom it is attached to, it forms a heterocycle with 4 to 8 atoms in the ring structure.

[0076] As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl comprises 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. 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, wherein the ring structure comprises 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0077] As used herein, the terms “halogen,” “halide,” or “halogen” mean halogen and include, for example, but not limited to, fluorine, chlorine, bromine, iodine, etc., which are in both radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0078] The term "heterocyclyl group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, wherein the ring structure comprises 1 to 4 heteroatoms. The heterocycle can be a monocyclic, bicyclic, spirocyclic, or polycyclic ring. Heterocyclic groups include, for example, thiophene, thiathrone, furan, piperan, isobenzofuran, chromene, oxanthracene, phenoxthia, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxoline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, phenanthroxoline, phenazine, phenpyrazine, phenothiazine, furazine, phenothiazine, pyrrolidine, oxopentane, oxopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as azacyclobutanone and pyrrolidone), sulfonamide, sulfonyllactone, etc. The heterocyclic ring may be substituted at one or more positions with the substituents described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, hydrogen sulfide, imino, amide, phosphate ester, phosphonate ester, phosphonite ester, carbonyl, carboxyl, silyl, aminosulfonyl, thionyl, ether, alkyl sulfonyl, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic group, -CF3, -CN, etc.

[0079] The term "carbonyl" is technically recognized and includes groups that can be represented by the following formula:

[0080]

[0081] Where X' is a bond or represents oxygen or sulfur, and R 15 Indicates hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Or a pharmaceutically acceptable salt, R 16 Indicates hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , where m and R 10 As defined above. When X' is oxygen and R... 15 Or R 16 In the absence of hydrogen, the formula represents "ester". When X' is oxygen and R... 15 As defined above, the group referred to herein is called a carboxyl group, and more specifically, when R... 15 When X' is hydrogen, the formula represents "carboxylic acid". When X' is oxygen and R... 16When X' is hydrogen, the formula represents "formate ester". Generally, when the oxygen atom in the above formula is replaced by sulfur, the formula represents "thiocarbonyl". When X' is sulfur and R... 15 Or R 16 In the absence of hydrogen, the formula represents a "thioester" group. When X' is sulfur and R... 15 When X' is hydrogen, the formula represents a "thiocarboxylic acid" group. When X' is sulfur and R... 16 In the case of hydrogen, the formula represents a "thiocarbamate" group. On the other hand, when X' is a bond and R... 15 When the hydrogen atom is not hydrogen, the above formula represents a "ketone" group. When X' is a bond and R... 15 In the case of hydrogen, the above formula represents the "aldehyde" group.

[0082] As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, said permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Illustrative substituents include, for example, those described above herein. The permissible substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of this invention, the heteroatom of nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compound described herein that satisfy the chemical valence of the heteroatom. This invention is not intended to be limited in any way by the permissible substituents of organic compounds. It should be understood that "substituted" or "substituted via" includes an implicit limiting clause that the substitution is based on the permissible valence of the substituted atom and the substituent, and that said substitution results in a stable compound, for example, which does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.).

[0083] As used herein, the term “nitro” means -NO2; the term “halogen” indicates -F, -Cl, -Br or -I; the term “thiohydrogen” means -SH; the term “hydroxyl” means -OH; the term “sulfonyl” means -SO2-; the term “azido” means -N3; ​​the term “cyano” means -CN; the term “isocyanate” means -NCO; the term “thiocyanate” means -SCN; the term “isothiocyanate” means -NCS; and the term “cyanate” means -OCN.

[0084] The term "aminosulfonyl" is technically recognized and includes a group that can be represented by the following formula:

[0085]

[0086] Where R 11 and R 12 As defined above.

[0087] The term "sulfate" is technically recognized and includes groups that can be represented by the following formula:

[0088]

[0089] Where R 15 As defined above.

[0090] The term "sulfonamide" is technically recognized and includes a group that can be represented by the following formula:

[0091]

[0092] Where R 11 and R 16 As defined above.

[0093] The term "sulfonate" is technically recognized and includes groups that can be represented by the following formula:

[0094]

[0095] Where R 54 It can be an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0096] As used herein, the terms "sulfonyl" or "sulfinyl" refer to a group that can be represented by the following formula:

[0097]

[0098] Where R 17 Choose from the following groups: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aralkyl, or aryl.

[0099] The term "urea" is technically recognized and can be represented by the following general formula:

[0100]

[0101] Among them, each R 18 Independently representing hydrogen or a hydrocarbon group (such as an alkyl group), or any R that appears. 18 It forms a heterocycle with 4 to 8 atoms in a ring structure together with another atom and an intervening atom.

[0102] As used herein, the definitions of each expression (e.g., alkyl, m, n, etc.) are intended to be independent of their definitions elsewhere in the same structure when they appear more than once in any structure.

[0103] For the purposes of this invention, chemical elements are identified according to the periodic table (CAS version), Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0104] Exemplary compounds of the present invention

[0105] In some embodiments, the present invention relates to compounds of formula I:

[0106] ABC(I)

[0107] in:

[0108] A is

[0109] B represents alkylene, -alkylene-(O), -alkylene-N(R)C(O)-, -alkylene-(heterocyclic)-C(O)-, -alkylene-C(O)N(R)-, -alkylene-C(O)-, -alkylene-N(R)-, -alkylene-N(R)C(O)N(R)-, -alkylene-N(R)SO2-, -alkylene-(aryl)-, -alkylene-(heterocyclic)-, -alkylene -(heterocyclic)-alkylene-, -aryl-alkylene-N(R)C(O)-, -aryl-C(O)N(R)-, -aryl-N(R)C(O)-, -(heterocyclic)-alkylene-, -heterocyclic-alkylene-N(R)C(O)-, -heterocyclic-C(O)N(R)-, -O-heterocyclic-, -alkylene-O-, -heterocyclic-C(O)-, cycloalkylene or cycloalkylene-O-;

[0110] C is

[0111] R is H, alkyl, or aryl;

[0112] R1 can be H, alkyl, halide, alkoxy, CF3, OH, NO2, -N(H)R or NH2 independently;

[0113] R2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkylene-aryl, or heterocycloalkyl;

[0114] It is a 3- to 12-membered heterocyclic alkylene group that is unsubstituted or substituted by one or more instances of R1;

[0115] X is C(R) c ) or N;

[0116] Two Rs a Examples are H, or together forming a bond, or a (C1-C4) alkylene bridge; R6 is H or a (C1-C6) alkyl group; and

[0117] R c It can be H, alkyl, aryl, OH or a halide;

[0118] Or its pharmaceutically acceptable salt;

[0119] The limiting condition is that the compound is not a

[0120]

[0121] In some embodiments, the present invention relates to any of the above-described compounds, wherein A is... In some embodiments, the present invention relates to any of the above-described compounds, wherein A is... In some embodiments, the present invention relates to any of the above-described compounds, wherein A is... In some embodiments, the present invention relates to any of the above-described compounds, wherein A is...

[0122] In some embodiments, the present invention relates to any of the above-described compounds, wherein R1 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2. In some embodiments, the present invention relates to any of the above-described compounds, wherein R1 is independently alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, or NH2. In some embodiments, the present invention relates to any of the above-described compounds, wherein R1 is alkyl, halide, OMe, OH, alkylene-OH, or NH2. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one example of R1 is alkyl. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one example of R1 is methyl. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one example of R1 is alkylene-OH. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one example of R1 is CH2OH. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one example of R1 is H. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of R1 is a halide. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of R1 is iodine, bromine, chlorine, or fluorine. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of R1 is iodine, bromine, chlorine, or fluorine, and other instances of R1 are hydrogen. In some embodiments, the present invention relates to any of the above-described compounds, wherein all instances of R1 are hydrogen.

[0123] In some embodiments, the present invention relates to any of the above-described compounds, wherein R is H, alkyl, or aryl. In some embodiments, the present invention relates to any of the above-described compounds, wherein R is H. In some embodiments, the present invention relates to any of the above-described compounds, wherein R is methyl. In some embodiments, the present invention relates to any of the above-described compounds, wherein R is phenyl.

[0124] In some embodiments, the present invention relates to any of the above-described compounds, wherein B is alkylene, -alkylene-(O), -alkylene-N(R)C(O)-, -alkylene-(heterocyclic)-C(O)-, -alkylene-C(O)N(R)-, -alkylene-C(O)-, -alkylene-N(R)-, -alkylene-N(R)C(O)N(R)-, -alkylene-N(R)SO2-, -alkylene-(aryl)-, -alkylene -(heterocyclic)-, -alkylene-(heterocyclic)-alkylene-, -aryl-alkylene-N(R)C(O)-, -aryl-C(O)N(R)-, -aryl-N(R)C(O)-, -(heterocyclic)-alkylene-, -heterocyclic-alkylene-N(R)C(O)-, -heterocyclic-C(O)N(R)-, -O-heterocyclic-, -alkylene-O-, -heterocyclic-C(O)-, cycloalkylene or cycloalkylene-O-.

[0125] In some embodiments, the present invention relates to any of the compounds described above, wherein B is selected from the group consisting of:

[0126]

[0127] m is 0, 1, 2 or 3; n is 0 or 1; and p is 0, 1 or 2.

[0128] In some embodiments, the present invention relates to any of the above-described compounds, wherein It is a 3- to 12-membered heterocyclic alkylene group substituted with one or more instances of R1.

[0129] In some embodiments, the present invention relates to any of the above-described compounds, wherein It is an unsubstituted 3- to 12-membered heterocyclic alkylene group. In some embodiments, the present invention relates to any of the above-described compounds, wherein... It is a 3- to 12-membered heterocyclic alkylene group substituted with one or more instances of R1, wherein R1 is...

[0130] In some embodiments, the present invention relates to any of the above-described compounds, wherein X is N.

[0131] In some embodiments, the present invention relates to any of the above-described compounds, wherein R aTwo instances of are H.

[0132] In some embodiments, the present invention relates to any of the above-described compounds, wherein R b H. In some embodiments, the present invention relates to any of the above-described compounds, wherein R b It is (C1-C6) alkyl. In some embodiments, the present invention relates to any of the above-described compounds, wherein R b It is methyl. In some embodiments, the present invention relates to any of the above-described compounds, wherein R b It is an ethyl group.

[0133] In some embodiments, the present invention relates to any of the compounds described above, wherein C is selected from the group consisting of:

[0134] In some embodiments, the present invention relates to any of the above-described compounds, wherein X is C(R) c ).

[0135] In some embodiments, the present invention relates to any of the above-described compounds, wherein R c It is H, alkyl, aryl, OH, or a halide. In some embodiments, the present invention relates to any of the above-described compounds, wherein R c For H.

[0136] In some embodiments, the present invention relates to any of the above-described compounds, wherein the two Rs a Examples of them together form bonds, or (C1-C4)-alkylene bridges.

[0137] In some embodiments, the present invention relates to any of the above-described compounds, wherein C is...

[0138] In some embodiments, the present invention relates to any of the above-described compounds, wherein C represents In some embodiments, the present invention relates to any of the above-described compounds, wherein C represents

[0139] In some embodiments, the present invention relates to any of the above-described compounds, wherein R2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, alkylene-alkoxy, alkylene-aryl, or heterocycloalkyl.

[0140] In some embodiments, the present invention relates to any of the above-described compounds, wherein R2 is H, (C1-C4)alkyl, cyclopropyl, CH2OMe, phenyl, -CH2Ph, pyridyl, or indole.

[0141] In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is H. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is Me. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is an unsubstituted phenyl. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is a substituted phenyl. In some embodiments, the invention relates to any of the above-described compounds, wherein the substituted phenyl is substituted with one or more independent examples of an alkoxy, a halide, -C(O)NH2, or -C(O)alkyl. In some embodiments, the invention relates to any of the above-described compounds, wherein the substituted phenyl is substituted with at least one halide. In some embodiments, the invention relates to any of the above-described compounds, wherein the halide is Cl. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is an unsubstituted pyridyl. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is a substituted pyridyl. In some embodiments, the invention relates to any of the above-described compounds, wherein the substituted pyridyl is substituted with NH2 or OH. In some embodiments, the invention relates to any of the above-described compounds, wherein R2 is...

[0142] In some embodiments, the present invention relates to any of the above-described compounds, wherein R3 is H, a halide, CF3, an alkyl group, an alkylene-alkoxy group, an aryl group, a hydroxyl group, or an alkoxy group.

[0143] In some embodiments, the present invention relates to any of the above-described compounds, wherein R3 is H, a halide, Me, OMe, or Ph. In some embodiments, the present invention relates to any of the above-described compounds, wherein R3 is iodine, bromine, chlorine, or fluorine. In some embodiments, the present invention relates to any of the above-described compounds, wherein R3 is H.

[0144] In some embodiments, the present invention relates to any of the above-described compounds, wherein R6 is H, a halide, CF3, an alkyl group, an alkylene-alkoxy group, an aryl group, a hydroxyl group, or an alkoxy group. In some embodiments, the present invention relates to any of the above-described compounds, wherein R6 is H. In some embodiments, the present invention relates to any of the above-described compounds, wherein R6 is OMe. In some embodiments, the present invention relates to any of the above-described compounds, wherein R6 is Me.

[0145] In some embodiments, the present invention relates to any of the above-described compounds, wherein R7 is H, a halide, CF3, an alkyl group, an alkylene-alkoxy group, an aryl group, a hydroxyl group, or an alkoxy group.

[0146] In some embodiments, the present invention relates to any of the above-described compounds, wherein R7 is H. In some embodiments, the present invention relates to any of the above-described compounds, wherein R7 is OMe. In some embodiments, the present invention relates to any of the above-described compounds, wherein R7 is Me. In some embodiments, the present invention relates to any of the above-described compounds, wherein R7 is CH2OH.

[0147] In some embodiments, the present invention relates to any of the above-described compounds, wherein R3 is H or F, R6 is H, and R7 is H or CH2OH.

[0148] In some embodiments, the present invention relates to any of the above-described compounds, wherein only one instance of n' is 0. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of n' is 0. In some embodiments, the present invention relates to any of the above-described compounds, wherein both instances of n' are 0. In some embodiments, the present invention relates to any of the above-described compounds, wherein only one instance of n' is 1. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of n' is 1. In some embodiments, the present invention relates to any of the above-described compounds, wherein both instances of n' are 1. In some embodiments, the present invention relates to any of the above-described compounds, wherein only one instance of n' is 2. In some embodiments, the present invention relates to any of the above-described compounds, wherein at least one instance of n' is 2. In some embodiments, the present invention relates to any of the above-described compounds, wherein both instances of n' are 2. In some embodiments, the present invention relates to any of the above-described compounds, wherein one instance of n' is 0 and one instance of n' is 1.

[0149] In some embodiments, the present invention relates to any of the compounds described above, wherein C is selected from the group consisting of:

[0150]

[0151] In some embodiments, the present invention relates to any of the compounds described above, wherein optional substituents (when present) are selected from the group consisting of: alkoxy, alkyl ester, alkyl carbonyl, hydroxyalkyl, cyano, halogen, amino, amide, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, alkyl, alkylthio, and cyanoalkyl.

[0152] In some embodiments, the present invention relates to any of the above-described compounds, wherein said compounds are pharmaceutically acceptable salts.

[0153] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0164]

[0165]

[0166]

[0167] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0168]

[0169]

[0170]

[0171] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0172]

[0173]

[0174] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0175]

[0176]

[0177]

[0178] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0179] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0180]

[0181]

[0182]

[0183]

[0184] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0185]

[0186]

[0187]

[0188]

[0189] In some embodiments, the present invention relates to compounds selected from the group consisting of:

[0190]

[0191]

[0192]

[0193]

[0194] Exemplary pharmaceutical compositions

[0195] In some embodiments, the present invention relates to a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier.

[0196] Patients (including, but not limited to, humans) may be treated by administration of an effective amount of the active compound or a pharmaceutically acceptable prodrug or its salt (in the presence of a pharmaceutically acceptable carrier or diluent). The active substance may be administered via any suitable route, for example, orally, non-enterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.

[0197] The concentration of the active compound in a pharmaceutical composition will depend on the rates of absorption, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary with the severity of the symptom to be alleviated. It should be further understood that any particular individual, specific dosage regimen, should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely illustrative and not intended to limit the scope or practice of the composition. The active ingredient may be administered once or divided into many smaller doses administered at varying time intervals.

[0198] In some embodiments, the active compound is administered orally. Oral compositions generally include an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into lozenges. For oral therapeutic application, the active compound may be incorporated with excipients and used in lozenge, sublingual, or capsule form. Pharmaceutically compatible binders and / or excipients may be included as part of the composition.

[0199] Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders (such as microcrystalline cellulose, tragacanth gum, or gelatin), excipients (such as starch or lactose), disintegrants (such as alginate, sodium hydroxyacetate (Primogel), or corn starch), lubricants (such as magnesium stearate or sterote), gliding agents (such as colloidal silica), sweeteners (such as sucrose or saccharin), or flavoring agents (such as peppermint, methyl salicylate, or orange flavoring). When the unit dosage form is a capsule, in addition to the above types of substances, it may contain a liquid carrier (such as fatty oil). Furthermore, the unit dosage form may contain various other substances in physical form that modify the dosage unit, such as sugar, shellac coatings, or other intestinal preparations.

[0200] The compound can be applied as a component of elixirs, suspensions, syrups, tablets, chewing gum, etc. In addition to the active compound, syrups may contain sucrose or sweeteners as sweeteners, and certain preservatives, dyes and pigments, and flavorings.

[0201] Compounds or pharmaceutically acceptable prodrugs or their salts may also be mixed with other active substances that do not impair the desired effect or with substances that complement the desired effect (such as antibiotics, antifungals, anti-inflammatory drugs, or other antiviral agents (including but not limited to nucleoside compounds)). Solutions or suspensions intended for non-enteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents, such as water for injection, saline solutions, fixative oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, and phosphates; and osmotic modifiers, such as sodium chloride or dextran. Parent formulations may be sealed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0202] If administered intravenously, the carriers include normal saline and phosphate-buffered saline (PBS).

[0203] In some embodiments, active compounds, such as controlled-release formulations, are prepared using a carrier that protects the compound from rapid elimination by the body. These include, but are not limited to, implants and microcapsule delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. For example, intestinal coating compounds can be used for protection against breakdown by gastric acid. Methods for preparing these formulations will be apparent to those skilled in the art. Suitable substances are also commercially available.

[0204] Liposome suspensions (including, but not limited to, liposomes targeting infected cells with monoclonal antibodies against viral antigens) are also preferably used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art (e.g., as described in U.S. Patent No. 4,522,811, incorporated herein by reference). For example, liposome formulations can be prepared by dissolving suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, and cholesterol) in an inorganic solvent, then evaporating the solvent, leaving a film of dried lipids on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then vortexed by hand to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0205] Exemplary methods of the present invention

[0206] In some embodiments, the present invention relates to a method for treating diseases or conditions selected from the group consisting of: idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary cholangitis, primary sclerosing cholangitis, solid tumors, hematologic malignancies, organ transplantation, Allport 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 myocardial fibrosis, the method comprising the step of administering a therapeutically effective amount of any one of the above compounds to an individual in need.

[0207] In some embodiments, the applied compound is selected from the group consisting of:

[0208]

[0209] In some embodiments, the present invention relates to any of the methods described above, wherein the disease or symptom is a solid tumor (sarcoma, carcinoma, and lymphoma). Exemplary tumors treatable according to the present invention include, for example, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, myeloma, 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, colon carcinoma, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal cancer, stomach cancer, and gastric cancer. Cancer), gliomas (e.g., adult and pediatric brainstem, pediatric cerebral astrocytoma, pediatric visual pathway and hypothalamus), glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body, cervical cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, brain cancer (e.g., brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), lips and oral cavity and pharynx, larynx, small intestine, melanoma. Venereal adenoma, villous colonic adenoma, tumor formation, epithelial tumor formation, lymphoma (e.g., AIDS-related, Burkitt's, cutaneous T-cell, Hodgkin's, non-Hodgkin's, and primary central nervous system), breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, neoplastic diseases containing solid tumors, tumors of the neck or head, polycythemia vera, idiopathic thrombocythemia, myelofibrosis with bone marrow tissue deformities, Waldenstrom's macroglobulinemia. Macroglobulinemia), adrenocortical carcinoma, AIDS-related cancers, pediatric cerebellar astrocytoma, extrahepatic bile duct carcinoma, malignant fibrous histiocytoma, bone cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, primary central nervous system cancer, cerebellar astrocytoma, childhood cancer, extracranial germ cell tumor, gonadal germ cell tumor, intraocular melanoma ocular cancer, retinoblastoma ocular cancer, gallbladder cancer, germ cell tumors (e.g.,Extracranial, extragonadal, and ovarian cancers include: gestational trophoblastic tumors, hepatocellular carcinoma, hypopharyngeal carcinoma, hypothalamic and visual pathway gliomas, islet cell carcinoma (endocrine pancreas), laryngeal cancer, malignant fibrous histiocytoma / osteosarcoma of bone, mesothelioma, primary occult metastatic squamous neck cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumors, mycosis fungoides, nasal and sinus carcinomas, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oropharyngeal carcinoma, ovarian epithelial carcinoma, ovarian germ cell tumors, low-potency ovarian tumors, islet cell pancreatic cancer, parathyroid carcinoma, pheochromocytoma, pineal blastoma, pituitary adenoma, pleural pulmonary blastoma, ureteral transitional cell carcinoma, retinoblastoma, salivary gland cancer, Sezary syndrome, non-melanoma skin cancer, Merkel cell carcinoma, testicular cancer, thymoma, and Wilms' tumor. ,

[0210] In some embodiments, the present invention relates to any of the methods described above, wherein the disease or symptom is a hematologic malignancy. Exemplary hematologic malignancies treatable according to the present invention include, for example, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma.

[0211] In some embodiments, the present invention relates to any of the methods described above, wherein the disease or symptom is selected from the group consisting of: idiopathic pulmonary fibrosis, systemic sclerosis associated with interstitial lung disease, myositis associated with interstitial lung disease, systemic lupus erythematosus associated with interstitial lung disease, and rheumatoid arthritis associated with interstitial lung disease.

[0212] In some embodiments, the present invention relates to any of the methods described above, wherein the disease or symptom is selected from the group consisting of: diabetic nephropathy, focal segmental glomerulosclerosis, and chronic kidney disease.

[0213] In some embodiments, the present invention relates to any of the methods described above, wherein the disease or symptom is selected from the group consisting of: non-alcoholic steatohepatitis, primary cholangitis, and primary sclerosing cholangitis.

[0214] In some embodiments, the present invention relates to any of the methods described above, wherein the individual is a mammal. In some embodiments, the present invention relates to any of the methods described above, wherein the individual is a human.

[0215] Example

[0216] The invention will now be generally described, and will be more readily understood by reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0217] General reaction diagrams and procedures for preparing the compounds of the present invention

[0218] Groups R and R1 are suitable ester protecting groups; R2, R3, R4, R5 and R6 are H or suitable substituents; and L is a suitable linker.

[0219] The term indicates a substituted 3- to 12-membered heterocyclic alkylene group, including piperidine, piperazine, piperazine ketone, pyrrolidine, and aziridine.

[0220] This indicates that either substituted tetrahydronaphthyl or 2-aminopyridine is suitable.

[0221] General reaction diagram for the synthesis of αvβ6 inhibitors

[0222]

[0223]

[0224] General Procedure

[0225] Reductive amination:

[0226]

[0227] A mixture containing amine (1 equivalent), aldehyde or ketone (1 to 1.2 equivalents), NaBH(OAc)3 (2 to 3 equivalents), and HCl or acetic acid (0.1 to 2 equivalents) in DCM or DCE (5 to 10 mL / mmol amine) is stirred at room temperature for 1 to 16 hours until complete by LC / MS. The reaction is concentrated or treated under vacuum (diluted with water and extracted with DCM; the combined extracts are dried over Na2SO4, filtered, and concentrated), and the residue is purified by silica gel column chromatography to obtain the desired amine product.

[0228] Amide bond formation:

[0229]

[0230] A mixture of carboxylic acids (1 equivalent), amines (0.5 to 2 equivalents), HATU (1 to 2 equivalents), and DIEA (2 to 5 equivalents) contained in DMF or DCM (5 to 10 mL / mmol amine) was stirred at room temperature for 16 hours or until complete by LC / MS. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography to obtain the desired amide product.

[0231] Urea formation:

[0232]

[0233] At 0°C, triphosgene (0.4 to 0.5 equivalents) is added to a solution of amine 1 (1 equivalent) and triethylamine (3 to 5 equivalents) contained in DCM (5 to 10 mL / mmol amine 1). The reaction is stirred for 30 minutes to 1 hour, and then amine 2 (0.5 to 1.5 equivalents) contained in DCM (1 to 2 mL / mmol amine 1) is added. The reaction is stirred at room temperature for 2 to 16 hours, and then concentrated under vacuum. The residue is purified by silica gel column chromatography to obtain the desired urea.

[0234] Boc protection:

[0235]

[0236] At room temperature, Boc-protected amines (1 equivalent) are treated with HCl (5 to 20 equivalents) in dioxane (5 to 20 mL / mmol amine) for 1 to 4 hours. The reaction is concentrated under vacuum, and the amine product is used as a crude product or after purification by silica gel column chromatography.

[0237] Amine alkylation:

[0238]

[0239] A mixture of amine (1 equivalent), bromoacetate (1 to 1.5 equivalents), and K₂CO₃ (2 to 5 equivalents) contained in MeCN or DMF (3 to 10 mL / mmol amine) was stirred at room temperature for 4 to 16 hours. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography to obtain the desired glycine.

[0240] Saponification:

[0241]

[0242] At room temperature, the ester (1 equivalent) was treated with LiOH-H2O (3 to 5 equivalents) in MeOH (3 to 10 mL / mmol ester) and water (3 to 10 mL / mmol ester) for 1 to 16 hours. The reaction was concentrated under vacuum, and the residue was purified by preparative HPLC to obtain the desired carboxylic acid product.

[0243] Petasis reaction:

[0244]

[0245] As an alternative to the amine alkylation / saponification sequence, the Petasis reaction can be used to prepare certain aryl analogs: a mixture of an amine (1 eq.) in MeCN or DMF (2 to 10 mL / mmol amine), aryl dihydroxyboronic acid or aryl dihydroxyboronic ester (1 to 1.5 eq.), and 2-oxoacetic acid (1.5 to 2 equivalents) is stirred for 2 to 16 hours at 50 to 80 °C. The reaction is concentrated under vacuum, and the residue is purified by preparative HPLC to obtain the desired glycine.

[0246] Analytical methods

[0247] LCMS analysis method

[0248] The final compounds were analyzed using LC / MS conditions with a UV detector monitored at 214 nm and 254 nm, and mass spectra scanned from 110 to 800 amu in ESI+ ionization mode.

[0249] LC / MS A: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: A: water (10 mM ammonium bicarbonate), B: CH3CN; Gradient: 5% to 95% B over 1.4 min, then hold for 1.6 min; Flow rate: 1.8 mL / min; Oven temperature: 50 °C.

[0250] LC / MS B: Column: SunFire C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: A water (0.01% TFA), B CH3CN; Gradient: 5% to 95% B over 1.5 min, then hold for 1.5 min; Flow rate: 2.0 mL / min; Oven temperature: 50 °C.

[0251] LC / MS C: Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN; Gradient: 5% to 95% B over 1.5 min, then hold for 1.5 min; Flow rate: 1.8 mL / min; Oven temperature: 50 °C.

[0252] LC / MS D: Column: Poroshell 120EC-C138, 4.6 x 30 mm, 2.7 μm; Mobile phase: A. Water (0.01% TFA), B. CH3CN (0.01% TFA); Gradient: 5% to 95% B over 1.2 min, then hold for 1.8 min; Flow rate: 2.2 mL / min; Oven temperature: 50 °C.

[0253] LC / MS E: Column: XBridge C18, 3.0 x 30 mm, 2.5 μm; Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN; Gradient: 5% to 95% B over 1.5 min, then hold for 0.6 min; Flow rate: 1.5 mL / min; Oven temperature: 50 °C.

[0254] LC / MS F: Column: Agilent poroshell 120EC-C18, 4.6 x 50 mm, 2.7 μm: A water (0.1% formic acid), B CH3CN (0.1% formic acid); gradient 5% to 95% B over 4.0 min, then hold for 6.0 min; flow rate 0.95 mL / min; oven temperature 50 °C.

[0255] Preparative-HPLC method

[0256] The crude sample was dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument (detection wavelength 214 nm).

[0257] Preparative HPLC A: Column: XBridge C18, 21.2*250mm, 10μm; Mobile phase: A. Water (10mM ammonium bicarbonate), B. CH3CN; Gradient elution as described in the text; Flow rate: 20mL / min.

[0258] Preparative HPLC B: Column: XBridge C18, 21.2*250mm, 10μm; Mobile phase: A (water (10mM formic acid)), BCH3CN; Gradient elution as described in the text; Flow rate: 20mL / min.

[0259] Preparative HPLC C: Column: XBridge OBD C18, 19*100mm, 5μm; Mobile phase: A water, B CH3CN; Gradient elution as described in the text; Flow rate: 20mL / min.

[0260] Preparative chiral SFC method

[0261] Racemic products were separated into individual enantiomers using a chiral preparative SFC with an SFC-80 (Thar, Waters) instrument (detection wavelength 214 nm):

[0262] Preparative chiral SFC A: Column: (R,R)-Whelk-O1, 20*250mm, 5μm (Decial), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution) = 60 / 40, flow rate: 80g / min, back pressure: 100 bar.

[0263] Preparative chiral SFC B: Column: AD 20*250mm, 10μm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution) = 60 / 40, flow rate: 80g / min, back pressure: 100 bar.

[0264] Preparative chiral SFC C: Column: AS 20*250mm, 10μm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution) = 60 / 40, flow rate: 80g / min, back pressure: 100 bar.

[0265] Analytical chiral SFC method

[0266] Chiral products were analyzed using an SFC-80 (Thar, Waters) instrument (detection wavelength 214 nm) via chiral SFC:

[0267] Chiral SFC A: Column: (R,R)-Whelk-O1, 4.6*100mm, 5μm (Decial), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0268] Chiral SFC B: Column: AD 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0269] Chiral SFC C: Column: AS 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0270] Chiral SFC D: Column: OD 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0271] Chiral SFC E: Column: Cellulose-SC 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0272] Chiral SFC F: Column: OZ 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0273] Chiral SFC G: Column: IC 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol in ammonia solution), elution at the same concentration as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0274] Chiral SFC H: Column: AD 4.6*250mm, 5μm (SHIMADZU), column temperature: 40℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), elution with equal concentration as described in the text, flow rate: 1mL / min.

[0275] Chiral SFC I: Column: IC 4.6*250mm, 5μm (SHIMADZU), column temperature: 40℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), elution at the same concentration as described in the text, flow rate: 1mL / min.

[0276] 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), elution with equal concentration as described in the text, flow rate: 1mL / min.

[0277] Chiral SFC K: Column: OZ-H 4.6*250mm, 5μm (SHIMADZU), column temperature: 40℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), elution with equal concentration as described in the text, flow rate: 1mL / min.

[0278] 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), elution with equal concentration as described in the text, flow rate: 1mL / min.

[0279] Example 1: Preparation of 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetic acid (compound 1)

[0280] Step 1: tert-butyl 4-(1,8-naphthid-2-yl)piperidin-1-carboxylate

[0281]

[0282] A mixture containing 2.0 g (8.80 mmol) of 4-acetylpiperidin-1-carboxylic acid tert-butyl ester, 1.1 g (8.80 mmol) of 2-aminonicotinaldehyde, and 2.0 g (17.60 mmol) of L-proline in EtOH (20 mL) was heated to reflux overnight. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 1:1) to give 0.8 g of 4-(1,8-naphthid-2-yl)piperidin-1-carboxylic acid tert-butyl ester as a colorless oil. Yield 30% (100% purity, UV = 214 nm, ESI 314.2 (M+H)). + ).

[0283] Step 2: tert-butyl 4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidine-1-carboxylate

[0284]

[0285] 4-(1,8-naphthid-2-yl)piperidin-1-carboxylic acid tert-butyl ester (0.8 g, 2.56 mmol) was hydrogenated overnight at room temperature in EtOH (20 mL) under balloon hydrogen atmosphere. The reaction was filtered through diatomaceous earth and concentrated to give crude 4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-carboxylic acid tert-butyl ester (800 mg) as a colorless oil, which was used directly in the next step. Yield 98% (95% purity, UV = 214 nm, ESI 318.2 (M+H)). + ).

[0286] Step 3: 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride

[0287]

[0288] 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride (800 mg, 2.52 mmol) was treated with a solution of HCl in 1,4-dioxane (4 N, 4 mL) for 2 hours at room temperature. The solvent was removed under vacuum to give crude 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride (750 mg) as a white solid. Yield 95% (100% purity, UV = 214 nm, ESI 218.2 (M+H)). + The crude product is used directly in the next step.

[0289] Step 4: 4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester

[0290]

[0291] Under a nitrogen atmosphere, at room temperature, a mixture of 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride (300 mg, 1.04 mmol) and tert-butyl 4-formylpiperidin-1-carboxylate (220.6 mg, 1.03 mmol) in DCE (5 mL) was stirred for 15 minutes. NaBH(OAc)3 (437 mg, 2.06 mmol) was added at room temperature. The reaction mixture was stirred for another hour, diluted with water (10 mL), and extracted with DCM (20 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to give tert-butyl 4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-carboxylate (148 mg, yield: 35%) as a colorless oil (90% purity, UV = 214 nm, ESI 415.1 (M+H)). + ).

[0292] Step 5: 7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride

[0293]

[0294] 4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (148 mg, 0.36 mmol) was treated with a solution of HCl in 1,4-dioxane (4 N, 2 mL) for 2 hours at room temperature. The solvent was removed under vacuum to give crude 7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthidium dihydrochloride (135 mg crude) as a white solid. Yield 95% (ESI 315.2 (M+H)). + The crude product is used directly in the next step.

[0295] Step 6: 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl acetate

[0296]

[0297] A mixture of 7-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyl dihydrochloride (135 mg crude), methyl 2-bromoacetate (64 mg, 0.42 mmol), and K₂CO₃ (138 mg, 1.0 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 5 hours. The reaction was filtered and concentrated under vacuum. The residue was purified by preparative-HPLC A (33 to 65% MeCN) to give methyl 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthyl-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetate (54 mg, 52% yield) as a white solid. (91% purity, UV = 254 nm, ESI 387.2 (M+H)) + ).

[0298] Step 7: 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetic acid (compound 1)

[0299]

[0300] 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetate (54 mg, 0.14 mmol) was treated with LiOH (21 mg, 0.5 mmol) in MeOH (3 mL) and H₂O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give compound 1 (15 mg, 29% yield) as a white solid. LC / MS D: 100% purity, UV = 214 nm, Rt = 0.38 min, ESI 373.3 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.43(d,J=7.4Hz,1H),6.55(d,J=7.4Hz,1H),3.75-3.61(m,4H),3.53(d,J=11.9Hz,2H),3.49-3.42(m,2H),3.06(t, J=11.8Hz,2H),2.92(d,J=6.5Hz,2H),2.85(s,3H),2.79(t,J=6.2Hz,2H),2.08-2.01(m,7H),1.98-1.90(m,2H),1.68(d,J=12.2Hz,2H).

[0301] Example 2: Preparation of 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperazin-1-yl)acetic acid (compound 2)

[0302] Step 1: 4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester

[0303]

[0304] At 0 °C, NaH (60% contained in mineral oil, 1.20 g, 30.0 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (5.00 g, 25.0 mmol) in DMF (50 mL). The mixture was stirred for 30 min, and then methyl 2-bromoacetate (2.60 mL, 27.5 mmol) was added. The reaction was stirred at room temperature for 16 h, then stopped with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 5:1 to 2:1) to give the desired compound (4.0 g) as a colorless oil. Yield 59% (86% purity, UV = 214 nm, ESI 217.0 (M+H)+).

[0305] Step 2: Methyl 2-(2-oxopiperazin-1-yl)acetate

[0306]

[0307] 4-(2-methoxy-2-oxoethyl)-3-oxopiperazin-1-carboxylic acid tert-butyl ester (2.50 g, 9.18 mmol) was treated with a solution of HCl / EtOAc (4.0 M, 20 mL) for 2 h at room temperature. The solvent was removed under vacuum to give the desired product, methyl 2-(2-oxopiperazin-1-yl)acetate (1.50 g), as a grayish-white solid. Yield 98% (88% purity, UV = 214 nm, ESI 173.1(M+H)+).

[0308] Step 3: 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)piperazin-1-yl)methyl acetate

[0309]

[0310] Triphosgene (111 mg, 0.37 mmol) was added to a mixture of 7-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (200 mg, 0.75 mmol) and triethylamine (300 mg, 2.96 mmol) contained in DCM (10 mL) at 0 °C. The mixture was stirred for 30 min, and then methyl 2-(2-oxopiperazin-1-yl)acetate (187 mg, 0.90 mmol) contained in DCM (5.0 mL) was added. The mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product (300 mg) as a grayish-white solid. Yield 93% (81% purity, UV = 214 nm, ESI 430.3(M+H)+).

[0311] Step 4: 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperazin-1-yl)acetic acid (compound 2)

[0312]

[0313] 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperazin-1-yl)methyl acetate (300 mg, 0.70 mmol) was treated with LiOH-H2O (117 mg, 2.79 mmol) in THF / MeOH / water (5 mL / 5 mL / 5 mL) for 16 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC-B (30 to 55% MeCN) to give compound 2 (88 mg) as a white solid, yield 23%. LC / MS D: 100% purity, UV = 214 nm, Rt = 0.939 min, ESI 416.1 (M+H)+. 1 H NMR(400MHz,DMSO-d6)δ8.15(0.25H,HCOOH),7.05(d,J=7.2Hz,1H),6.55(s,1H),6.24(d,J=7.2Hz,1H),4.00(s,2H),3.78(s,2H),3.58-3.54(m,2H) ,3.39-3.38(m,4H),3.24(s,2H),2.71-2.65(m,2H),2.62-2.59(m,2H),2. 37-2.39(m,2H),1.80-1.73(m,3H),1.56-1.53(m,2H),1.15-1.06(m,2H).

[0314] Example 3: Preparation of 2-(2-oxo-4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (compound 3)

[0315] Step 1: Methyl 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylate

[0316]

[0317] At 0 °C, NaH (60% contained in mineral oil, 886 mg, 22.1 mmol) was added to a solution of methyl 2-oxopiperidine-4-carboxylate (2.90 g, 18.4 mmol) in DMF (30 mL). The mixture was stirred for 30 min, and then tert-butyl 2-bromoacetate (4.32 g, 22.1 mmol) was added. The reaction was stirred at room temperature for 16 h, then stopped with water (20 mL), and extracted with EtOAc (50 mL x 5). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give methyl 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylate (1.5 g) as a colorless oil. Yield 30% (90% purity, UV = 214nm, ESI 216.1(M+H)+).

[0318] Step 2: 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylic acid

[0319]

[0320] Methyl 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylic acid (1.00 g, 3.68 mmol) was treated with LiOH-H2O (201 mg, 4.79 mmol) in THF / MeOH / water (20 mL / 20 mL / 20 mL) for 16 h at room temperature. The mixture was adjusted to pH ~5 with aqueous HCl (3.0 M, 10 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product, 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidine-4-carboxylic acid (900 mg), as a pale yellow oil. Yield 95% (85% purity, UV = 214 nm, ESI 202.0(M+H)+).

[0321] Step 3: 2-(2-oxo-4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)piperidin-1-yl)tert-butyl acetate

[0322]

[0323] At 50 °C, a mixture containing 1-(2-tert-butoxy-2-oxoethyl)-2-oxopiperidin-4-carboxylic acid (150 mg, 0.58 mmol) and 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthylidine (178 mg, 0.70 mmol), DIEA (500 mg, 3.87 mmol), and HATU (450 mg, 1.18 mmol) in DMF (5.0 mL) was stirred for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product (150 mg) as a pale yellow oil. Yield 56% (86% purity, UV = 214 nm, ESI 457.4(M+H)+).

[0324] Step 4: 2-(2-oxo-4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (compound 3)

[0325]

[0326] 2-(2-oxo-4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)piperidin-1-carbonyl)piperidin-1-yl)tert-butyl acetate (150 mg, 0.33 mmol) was treated with LiOH-H2O (69 mg, 1.64 mmol) in THF / MeOH / water (5 mL / 5 mL / 5 mL) for 16 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC B (33 to 50% MeCN) to give the desired product compound 3 (20 mg, 15% yield) as a white solid. LC / MS D: 96% purity, UV = 214 nm, Rt = 1.373 min, ESI 401.1(M+H)+. 1H NMR(400MHz,DMSO-d6)δ8.14(0.15H,HCOOH),7.10(d,J=7.2Hz,1H),6.38-6.36(m,1H ),6.31(d,J=7.2Hz,1H),4.51-4.48(m,1H),4.11-4.04(m,2H),3.87-3.83(m,1H),3. 43-3.40(m,2H),3.29-3.24(m,5H),3.13-3.06(m,1H),2.69-2.57(m,4H),2.40-2.26 (m,2H),1.91-1.88(m,1H),1.78-1.73(m,5H),1.61-1.55(m,1H),1.47-1.44(m,1H).

[0327] Example 4: Preparation of 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compound 4)

[0328] Step 1: Methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate

[0329]

[0330] Add tert-butyl bromoacetate (1.95 g, 1 mmol) to a solution containing methyl piperidine-4-carboxylate (1.43 g, 1 mmol) and triethylamine (2.02 g, 2 mmol) in THF (20 mL). Heat the resulting mixture under reflux overnight. Remove the solvent under vacuum, and purify the residue by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product, methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (0.77 g), as a colorless oil. Yield: 30%. 1 H NMR (400MHz, CDCl3) δ3.68(s,3H),3.11(s,2H),2.95-2.87(m,2H),2.33-2.21(m,3H),1.94-1.77(m,4H),1.46(s,9H).

[0331] Step 2: 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid

[0332]

[0333] A mixture of methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid (0.77 g, 3.0 mmol) was treated overnight at room temperature with LiOH-H2O (126 mg, 3.0 mmol) in MeOH (10 mL), THF (5 mL), and H2O (5 mL). The organic solvent was removed under vacuum; then an aqueous HCl solution (1 N) was added to pH ~5. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the desired product, 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid (590 mg), as a colorless oil. Yield 81% (ESI 244(M+H)+).

[0334] Step 3: 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)butyl acetate

[0335]

[0336] At 50 °C, a mixture containing 3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl-1-amine hydrochloride (140 mg, 0.62 mmol), 1-(2-tert-butoxy-2-oxoethyl)piperidin-4-carboxylic acid (100 mg, 0.41 mmol), EDCI (118 mg, 0.62 mmol), and DIPEA (159 mg, 1.23 mmol) in DMF (4 mL) was stirred overnight. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)butyl acetate (120 mg), as a yellow oil. Yield 70% (95% purity, UV = 254nm, ESI 417.2(M+H)+).

[0337] Step 4: 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compound 4)

[0338]

[0339] 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)butyl acetate (120 mg, 0.29 mmol) was treated with LiOH-H2O (59 mg, 1.40 mmol) in MeOH (4 mL), THF (2 mL), and H2O (2 mL) for 2 h at 40 °C. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 4 (40 mg, 39% yield) as a white solid. LC / MS C: 100% purity, UV = 214 nm, Rt = 1.36 min, ESI 361(M+H)+. 1 H NMR (500MHz, CD3OD) δ7.16(d,J=7.0Hz,1H),6.39(d,J=7.0Hz,1H),3.66-3.55(m,4H),3.39(t,J=5.5Hz,2H),3.22( t,J=7.0Hz,2H),3.04-2.96(m,2H),2.72(t,J=6.5Hz,2H),2.58-2.43(m,3H),2.05-1.98(m,4H),1.92-1.80(m,4H).

[0340] Example 5: Preparation of 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl)acetic acid (compound 5)

[0341] Step 1: 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl)ethyl acetate

[0342]

[0343] At 0 °C, triphosgene (157 mg, 0.52 mmol) was added to a mixture of 3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl-1-amine hydrochloride (200 mg, 0.88 mmol) and triethylamine (177 mg, 1.75 mmol) contained in DCM (6 mL). The mixture was stirred for 30 minutes, and then ethyl 2-(piperazin-1-yl)acetate (151 mg, 0.88 mmol) contained in DCM (2 mL) was added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 10:1) to give the desired product (226 mg) as a white solid. Yield 66% (ESI 390.1(M+H)+).

[0344] Step 2: 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl)acetic acid (compound 5)

[0345]

[0346] At room temperature, 200 mg (0.51 mmol) of ethyl 2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl)ethyl acetate was treated overnight with LiOH-H2O (100 mg, 2.38 mmol) in MeOH (4 mL), THF (2 mL), and H2O (2 mL). The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 5 (MRT-A0034) (45 mg) as a white solid, in 24% yield. LC / MS B: 100% purity, UV = 214 nm, Rt = 0.794 min, ESI 362.1 (M+H)+. 1 H NMR (400MHz, CD3OD) δ7.18(d,J=7.2Hz,1H),6.41(d,J=7.2Hz,1H),3.48-3.41(m,4H),3.39(t,J=5.6Hz ,2H),3.19(t,J=6.8Hz,2H),3.12(s,2H),2.75-2.65(m,6H),2.56(t,J=7.6Hz,2H),1.91-1.80(m,4H).

[0347] Example 6: Preparation of (S)-2-(3-(hydroxymethyl)-2-oxo-4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)piperazin-1-yl)acetic acid (compound 6)

[0348] Step 1: Ethyl 2-(2,2-dimethoxyethylamino)acetate

[0349]

[0350] A mixture containing 2,2-dimethoxyethylamine (5.0 g, 47.55 mmol), ethyl 2-bromoethylamine (7.9 g, 47.30 mmol), and K₂CO₃ (6.64 g, 48.04 mmol) in DMF (40 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, ethyl 2-(2,2-dimethoxyethylamino)ethylamine (6.5 g), as a colorless oil. Yield 71% (ESI 191.0 (M+H)). + ).

[0351] Step 2: (S)-2-(3-(benzyloxy)-2-(tert-butoxycarbonylamino)-N-(2,2-dimethoxyethyl)propionylamino)ethyl acetate

[0352]

[0353] A mixture of ethyl 2-(2,2-dimethoxyethylamino)acetate (1.0 g, 5.23 mmol), (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propionic acid (1.54 g, 5.23 mmol), HATU (2.98 g, 7.84 mmol), and DIEA (2.02 g, 15.68 mmol) in MeCN (10 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:1) to give the desired product (S)-2-(3-(benzyloxy)-2-(tert-butoxycarbonylamino)-N-(2,2-dimethoxyethyl)propionylamino)acetate (1.9 g) as a colorless oil. Yield 77% (ESI 468 (M+H)). + ).

[0354] Step 3: (S)-2-(benzyloxymethyl)-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-tert-butyl formate

[0355]

[0356] A mixture of ethyl (S)-2-(3-(benzyloxy)-2-(tert-butoxycarbonylamino)-N-(2,2-dimethoxyethyl)propionylamino)acetate (1.5 g, 3.2 mmol) and CF3COOH (1.09 g, 9.6 mmol) in DCM (10 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product (S)-2-(benzyloxymethyl)-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylic acid tert-butyl ester (700 mg) as a colorless oil. Yield 72% (ESI 404(M+H)+). 1H NMR(500MHz,CD3OD)δ7.20(d,J=3.8Hz,6H),6.36-6.13(m,1H),5.63(dd,J=49.5,6.0Hz,1H),4.92-4.81(m,1H),4.51-4.33(m, 3H), 4.17 (d, J = 4.8Hz, 2H), 4.12-4.02 (m, 2H), 3.72-3.62 (m, 1H), 3.57-3.46 (m, 1H), 1.41-1.32 (m, 10H), 1.15 (t, J = 7.1Hz, 4H).

[0357] Step 4: (S)-4-(2-ethoxy-2-oxoethyl)-2-(hydroxymethyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester

[0358]

[0359] Under H2 balloon conditions at room temperature, a mixture of (S)-2-(benzyloxymethyl)-4-(2-ethoxy-2-oxoethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-tert-butyl carboxylate (700 mg, 2.3 mmol) and Pd / C (140 mg, 20 wt%) in MeOH (10 mL) was stirred overnight. The suspension was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH (10 mL × 2). The combined filtrates were concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product (S)-4-(2-ethoxy-2-oxoethyl)-2-(hydroxymethyl)-3-oxo-piperazine-1-carboxylate (540 mg) as a colorless oil. Yield 99% (ESI 316(M+H)+).

[0360] Step 5: (S)-2-(3-(hydroxymethyl)-2-oxo-4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)piperazin-1-yl)ethyl acetate

[0361]

[0362] At 0°C, a mixture containing 3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl-1-amine (212 mg, 1.11 mmol), triphosgene (137 mg, 0.46 mmol), and triethylamine (562 mg, 5.55 mmol) in DCM (8 mL) was stirred for 1 hour. At 0°C, a solution containing (S)-4-(2-ethoxy-2-oxoethyl)-2-(hydroxymethyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol) in DCM (2 mL) was added dropwise using a syringe. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:CH3OH 20:1) to give the desired product (S)-2-(3-(hydroxymethyl)-2-oxo-4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl)ethyl acetate (250 mg) as a colorless oil. Yield 63% (ESI 433(M+H) + ).

[0363] Step 6: (S)-2-(3-(hydroxymethyl)-2-oxo-4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)piperazin-1-yl)acetic acid (compound 6)

[0364]

[0365] At room temperature, ethyl acetate (250 mg, 0.58 mmol) of (S)-2-(3-(hydroxymethyl)-2-oxo-4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperazin-1-yl) was treated with LiOH-H2O (97 mg, 2.31 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC (30 to 65% MeCN) to give compound 6 (25 mg, 11% yield) as a white solid. LC / MS B: 100% purity, UV = 214 nm, Rt = 0.58 min, ESI 405.5(M+H)+. 1H NMR (500MHz, MeOD) δ7.49(d,J=7.3Hz,1H),6.55(d,J=7.4Hz,1H),4.59(d,J=16.6Hz,2H),4.09(dd,J=11.5,7.1Hz,2H),3.92(dd,J=11.6,3.5 Hz,1H),3.78(dd,J=11.7,4.1Hz,1H),3.68(d,J=11.6Hz,1H),3.49-3.35(m,4H),3.20(d,J=8.1Hz,2H),2.80-2.60(m,4H),1.97-1.70(m,4H).

[0366] Example 7: Preparation of 2-(3-(1-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)ureo)-2-oxopyrrolidine-1-yl)acetic acid (compounds 7-E1 and 7-E2)

[0367] Step 1: (R)-2-(tert-Butoxycarbonylamino)succinic acid 1-benzyl ester 4-methyl ester

[0368]

[0369] A mixture containing (R)-4-(benzyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutyric acid (11.0 g, 34.0 mmol), K₂CO₃ (17.0 g, 123 mmol), and MeI (6.50 mL, 104 mmol) in acetone (500 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, diluted with water, and extracted with EtOAc (200 mL x 5). The combined organic extracts were washed with brine and dried over Na₂SO₄, filtered, and concentrated under vacuum to give (R)-2-(tert-butoxycarbonylamino)succinate 1-benzyl ester 4-methyl ester (11.0 g) as a yellow solid. Yield 98% (94% purity, UV = 214 nm, ESI 238.1(M+H)+).

[0370] Step 2: (R)-2-(tert-Butoxycarbonyl(methyl)amino)succinate 1-benzyl ester 4-methyl ester

[0371]

[0372] At 0 °C, NaH (60% contained in mineral oil, 533 mg, 13.3 mmol) was added to a solution of (R)-2-(tert-butoxycarbonyl(methyl)amino)succinate 1-benzyl 4-methyl ester (3.00 g, 8.89 mmol) and MeI (1.50 mL, 24.1 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 1 hour, then diluted with water (20 mL) and extracted with EtOAc (50 mL x 5). The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and concentrated under vacuum to give (R)-2-(tert-butoxycarbonyl(methyl)amino)succinate 1-benzyl 4-methyl ester (3.00 g) as a yellow oil. Yield 98% (88% purity, UV = 214 nm, ESI 252.3(M+H)+).

[0373] Step 3: (R)-2-(tert-Butoxycarbonyl(methyl)amino)-4-oxobutyrate benzyl ester

[0374]

[0375] At -78°C, DIBAL-H (1.0 M, 17.0 mL) was added dropwise to a solution of (R)-2-(tert-butoxycarbonyl(methyl)amino)succinate 1-benzyl ester 4-methyl ester (3.00 g, 8.54 mmol) contained in anhydrous Et₂O (150 mL). The mixture was stirred at -78°C for 1 hour, then stopped with a saturated aqueous solution of NH₄Cl (20 mL). The mixture was stirred at room temperature for 1 hour, then filtered and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum to give the desired product (2.5 g) as a pale yellow oil. Yield 92% (80% purity, UV = 214 nm, ESI 222.4(M+H)+).

[0376] Step 4: 2-(3-(tert-Butoxycarbonyl(methyl)amino)-2-oxopyrrolidine-1-yl)ethyl acetate

[0377]

[0378] A mixture of ethyl 2-aminoacetate (4.42 g, 31.7 mmol), triethylamine (7.5 mL, 54.1 mmol), NaBH(OAc)3 (4.00 g, 18.8 mmol), acetic acid (catalytic amount (cat)), and (R)-2-(tert-butoxycarbonyl(methyl)amino)-4-oxobutyrate benzyl ester (1.61 g, 5.01 mmol) in DCM (100 mL) was stirred at room temperature for 16 hours. The reaction was stopped with water (20 mL) and extracted with DCM (50 mL x 3). The combined organic extracts were concentrated under vacuum, and the residue was purified by passing through a reverse-phase C18 column (35% to 50% MeCN / H2O (0.5% NH4HCO3)) to give the desired product (410 mg) as a pale yellow oil. Yield 18% (95% purity, UV = 214nm, ESI 201.3(M+H)+).

[0379] Step 5: Ethyl 2-(3-(methylamino)-2-oxopyrrolidine-1-yl)ethyl acetate

[0380]

[0381] Ethyl 2-(3-(tert-Butoxycarbonyl(methyl)amino)-2-oxopyrrolidine-1-yl)ethyl acetate (410 mg, 1.36 mmol) was treated with a dioxane solution of HCl (4.0 M, 10 mL) for 2 h at room temperature. The reaction was concentrated under vacuum to give the desired product (340 mg) as a pale yellow solid. Yield 95% (95% purity, UV = 214 nm, ESI 201.3(M+H)+).

[0382] Step 6: 2-(3-(1-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)ureo)-2-oxopyrrolidine-1-yl)ethyl acetate

[0383]

[0384] At 0 °C, triphosgene (250 mg, 0.85 mmol) was added to a mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)but-1-amine (375 mg, 1.55 mmol) and triethylamine (1.00 mL) contained in DCM (20 mL). The mixture was stirred for 30 minutes, and then ethyl 2-(3-(methylamino)-2-oxopyrrolidine-1-yl)acetate (340 mg, 1.68 mmol) contained in DCM (5 mL) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, ethyl 2-(3-(1-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)ureo)-2-oxopyrrolidine-1-yl)ethyl acetate (300 mg), as a pale yellow solid. Yield 45% (82% purity, UV = 214 nm, ESI 432.4(M+H)+).

[0385] Step 7: 2-(3-(1-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)ureo)-2-oxopyrrolidine-1-yl)acetic acid (compounds 7-E1 and 7-E2)

[0386]

[0387] Ethyl 2-(3-(1-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyl)ureido)-2-oxopyrrolidine-1-yl)ethyl acetate (300 mg, 0.70 mmol)) was treated with LiOH-H2O (292 mg, 6.95 mmol) in MeOH (7.5 mL) and water (2.5 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC-A (35 to 65% MeCN) to give racemic compound 7 (245 mg, 85% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 7-E1 (118 mg) and 7-E2 (95 mg) as white solids.

[0388] Compound 7-E1 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.376 min, ESI 404.3(M+H)+. 1HNMR(400MHz,D2O)δ7.02(d,J=6.8Hz,1H),6.38(m,2),6.25(d,J=7.2Hz,1H),4.90(m,1H),3.94-3.81(m,2H),3.22(m,4H),3.02-2.97( m,2H),2.60(m,4H),2.43-2.40(m,3H),2.14-2.08(m,1H),1.89-1.84(m,1H),1.75-1.71(m,2H),1.56-1.53(m,2H),1.41-1.40(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt=1.91 min.

[0389] Compound 7-E2 LC / MS A: 99.5% purity, UV = 214 nm, Rt = 1.37 min, ESI 404.4(M+H)+. 1 H NMR (400MHz, CD3OD) δ7.02(d,J=6.8Hz,1H),6.38(m,2),6.25(d,J=7.2Hz,1H),4.90(m,1H),3.94-3.81(m,2H),3.22(m,4H),3.02-2.97 (m,2H),2.60(m,4H),2.43-2.40(m,3H),2.14-2.08(m,1H),1.89-1.84(m,1H),1.75-1.71(m,2H),1.56-1.53(m,2H),1.41-1.40(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt=4.02 min.

[0390] Example 8: Preparation of 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)acetic acid (compounds 8-E1 and 8-E2)

[0391] Step 1: 4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidine-1-carboxylic acid tert-butyl ester

[0392]

[0393] A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyric acid (500 mg, 2.27 mmol), tert-butyl 4-aminopiperidin-1-carboxylate (454 mg, 2.27 mmol), HATU (1296 mg, 3.41 mmol), and DIEA (879 mg, 6.81 mmol) in DMF (6 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, tert-butyl 4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-carboxylate (620 mg), as a yellow oil. Yield 68% (98% purity, UV = 214 nm, ESI 402.0 (M+H)). + ).

[0394] Step 2: N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyramide

[0395]

[0396] 4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-carboxylic acid tert-butyl ester (620 mg, 1.54 mmol) was treated overnight with HCl (4 mL, 15.4 mmol) in 5 mL of 1,4-dioxane. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 40:1) to give the desired product N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyramide (440 mg) as a yellow oil. Yield 95% (100% purity, UV = 214 nm, ESI 302 (M+H)). + ).

[0397] Step 3: 2-Phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)ethyl acetate

[0398]

[0399] A mixture containing N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyramide (200 mg, 0.66 mmol), ethyl 2-bromo-2-phenylacetate (192 mg, 0.79 mmol), DIEA (255 mg, 1.98 mmol), and K₂CO₃ (273 mg, 1.98 mmol) in MeCN (4 mL) was stirred for 3 hours at 50 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, ethyl 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)acetate (160 mg), as a yellow oil. Yield 52% (100% purity, UV = 214 nm, ESI 464 (M+H)). + ).

[0400] Step 4: 2-Phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)acetic acid (compounds 8-E1 and 8-E2)

[0401]

[0402] At room temperature, ethyl 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)ethyl acetate (160 mg, 0.34 mmol) was treated with LiOH-H2O (58 mg, 1.38 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give racemic compound 8 (65 mg, 44% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 8-E1 (32 mg) and 8-E2 (31 mg) as white solids.

[0403] Compound 8-E1 LC / MS A: 95% purity, UV = 214 nm, Rt = 1.44 min, ESI 436(M+H)+. 1HNMR (400MHz, CD3OD) δ7.59-7.58(m,2H),7.42-7.41(m,3H),7.19(d,J=7.0Hz,1H),6.39(d,J=7.5Hz,1H),4.33(s,1H ),3.82(m,1H),3.39-3.32(m,4H),2.96-2.69(m,6H),2.56(t,J=7.5Hz,2H),2.20(t,J=7.5Hz,2H),1.86-1.28(m,6H). Chiral SFC A (45% MeOH): ee 100%, Rt = 2.09 min.

[0404] Compound 8-E2 LC / MS A: 95.8% purity, UV = 214 nm, Rt = 1.45 min, ESI 436(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.59-7.58(m,2H),7.42-7.41(m,3H),7.19(d,J=7.0Hz,1H),6.39(d,J=7.5Hz,1H),4.33(s,1H ),3.82(m,1H),3.39-3.32(m,4H),2.96-2.69(m,6H),2.56(t,J=7.5Hz,2H),2.20(t,J=7.5Hz,2H),1.86-1.28(m,6H). Chiral SFC A (45% MeOH): ee 100%, Rt=3.8 min.

[0405] Example 9: Preparation of 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butylamino)piperidin-1-yl)propionic acid (compound 9)

[0406] Step 1: Methyl 2-(4-oxopiperidin-1-yl)propionate

[0407]

[0408] A mixture containing piperidine-4-one hydrochloride (1.0 g, 7.38 mmol), methyl 2-bromopropionate (1.85 g, 11.06 mmol), and K₂CO₃ (3.06 g, 22.13 mmol) in MeCN (20 mL) was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product (1.2 g) as a colorless oil. Yield 88% (80% purity, UV = 214 nm, ESI 186.1(M+H)+).

[0409] Step 2: Methyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butylamino)piperidin-1-yl)propionate

[0410]

[0411] Triethylamine (145 mg, 1.44 mmol) was added to a solution of 4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)but-1-amine hydrochloride (200 mg, 0.72 mmol) in DCM (5 mL) at room temperature. The mixture was stirred for 10 minutes, and then methyl 2-(4-oxopiperidin-1-yl)propionate (213 mg, 0.86 mmol), NaBH(OAc)3 (457 mg, 2.16 mmol), and one drop of HOAc were added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product (240 mg) as a colorless oil. Yield 89% (100% purity, UV = 254 nm, ESI 375.3(M+H)+).

[0412] Step 3: 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butylamino)piperidin-1-yl)propionic acid (compound 9)

[0413]

[0414] Methyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butylamino)piperidin-1-yl)propionate (100 mg, 0.27 mmol) was treated with LiOH-H2O (42 mg, 1.0 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 9 (as a white solid (35 mg, yield 36%). LC / MS C: 97.2% purity, UV = 214 nm, Rt = 1.166 min, ESI 361.4 (M+H)+). 1 H NMR (400MHz, CD3OD) δ7.14(d,J=7.2Hz,1H),6.38(d,J=7.6Hz,1H),3.39-3.18(m,4H),2.91-2.83(m,3 H), 2.72-2.53 (m, 6H), 2.15-2.02 (m, 2H), 1.89-1.84 (m, 2H), 1.75-1.59 (m, 6H), 1.36 (d, J = 6.8Hz, 3H).

[0415] Example 10: Preparation of 2-phenyl-2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compounds 10-E1 and 10-E2)

[0416] Step 1: 4-(2-methoxy-2-oxo-1-phenethyl)piperazine-1-carboxylic acid tert-butyl ester

[0417]

[0418] A mixture containing tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol), methyl 2-bromo-2-phenylacetate (2.21 g, 9.66 mmol), and K₂CO₃ (3.33 g, 24.15 mmol) in MeCN (30 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:2) to give the desired product (1.6 g) as a colorless oil. Yield 60% (ESI 235 (M+H-100)). + ).

[0419] Step 2: 2-Phenylacetic-2-(piperazin-1-yl)methyl acetate hydrochloride

[0420]

[0421] 4-(2-methoxy-2-oxo-1-phenethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.50 mmol) was treated with a solution of HCl / dioxane (2.0 M, 10 mL) for 2 hours at room temperature, and then concentrated under vacuum to give the desired product (389 mg) as a white solid. Yield 96% (ESI 235(M+H)+).

[0422] Step 3: Methyl 2-phenyl-2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetate

[0423]

[0424] At room temperature, triethylamine (112 mg, 1.11 mmol) was added to a solution of methyl 2-phenyl-2-(piperazin-1-yl)acetate hydrochloride (150 mg, 0.55 mmol) in DCM (5 mL). The mixture was stirred for 10 minutes, and then 5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanal (120 mg, 0.55 mmol), NaBH(OAc)3 (350 mg, 1.65 mmol), and one drop of HOAc were added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 10:1) to give the desired product (130 mg) as a colorless oil. Yield 54% (100% purity, UV = 254 nm, ESI 437.3(M+H)+).

[0425] Step 4: 2-Phenyl-2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compounds 10-E1 and 10-E2)

[0426]

[0427] Methyl 2-phenyl-2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetate (130 mg, 0.30 mmol) was treated with LiOH-H2O (63 mg, 1.50 mmol) in MeOH (5.0 mL) and H2O (1.0 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give racemic compound 10 (70 mg, 55% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 10-E1 (21 mg) and 10-E2 (18 mg) as white solids.

[0428] Compound 10-E1 LC / MS A: 95% purity, UV = 214 nm, Rt = 1.53 min, ESI 423.4(M+H)+. 1HNMR (400MHz, CD3OD) δ7.43-7.41(m,2H),7.24-7.18(m,3H),7.05(d,J=7.6Hz,1H),6.26(d,J=7.2Hz,1H),3 .76(s,1H),3.27-3.24(m,2H),2.86-2.39(m,14H),1.80-1.72(m,2H),1.60-1.43(m,4H),1.29-1.17(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 1.93 min.

[0429] Compound 10-E2 LC / MS A: 95% purity, UV = 214 nm, Rt = 1.53 min, ESI 423.4(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.43-7.41(m,2H),7.24-7.18(m,3H),7.05(d,J=7.6Hz,1H),6.26(d,J=7.2Hz,1H),3 .76(s,1H),3.27-3.24(m,2H),2.86-2.39(m,14H),1.80-1.72(m,2H),1.60-1.43(m,4H),1.29-1.17(m,2H). Chiral SFC A (45% MeOH): ee 95%, Rt = 2.72 min.

[0430] Example 11: Preparation of 2-phenyl-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-piperidin-1'-yl)acetic acid (compounds 11-E1 and 11-E2)

[0431] Step 1: Methyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate

[0432]

[0433] A mixture containing piperidine-4-one hydrochloride (1.0 g, 7.38 mmol), methyl 2-bromo-2-phenylacetate (2.53 g, 11.06 mmol), and K₂CO₃ (3.06 g, 22.13 mmol) in MeCN (30 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to give the desired product, methyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate (1.3 g), as a colorless oil. Yield 71% (98% purity, UV = 214 nm, ESI 248.0 (M+H)). + ).

[0434] Step 2: Methyl 2-phenyl-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-bipiperidin-1'-yl)acetate

[0435]

[0436] A mixture of 7-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (152 mg, 0.66 mmol), methyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate (195 mg, 0.79 mmol), and NaBH(OAc)3 (418 mg, 1.97 mmol) in DCM (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, methyl 2-phenyl-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidine-2-yl)methyl)-1,4'-bipiperidin-1'-yl)acetate (110 mg), as a colorless oil. Yield 36% (100% purity, UV = 214 nm, ESI 463 (M+H)). + ).

[0437] Step 3: 2-Phenylacetyl-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-piperidin-1'-yl)acetic acid (compounds 11-E1 and 11-E2)

[0438]

[0439] 2-Phenylacetyl-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-bipiperidin-1'-yl)acetate (110 mg, 0.24 mmol) was treated with LiOH-H2O (42 mg, 1.0 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give racemic compound 11 (55 mg, 52% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 11-E1 (12 mg) and 11-E2 (15 mg) as white solids.

[0440] Compound 11-E1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.5 min, ESI 449.5(M+H)+. 1HNMR (400MHz, CD3OD) δ7.54-7.52(m,2H),7.34-7.32(m,3H),7.13(d,J=7.2Hz,1H),6.35(d,J=7.2H z,1H),3.92(br,1H),3.58-3.20(m,5H),2.90-2.32(m,9H),2.22-1.64(m,10H),1.44-1.25(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt = 2.98 min.

[0441] Compound 11-E2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.5 min, ESI 449.5(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.54-7.52(m,2H),7.34-7.32(m,3H),7.13(d,J=7.2Hz,1H),6.35(d,J=7.2H z,1H),3.95(br,1H),3.58-3.20(m,5H),2.90-2.32(m,9H),2.22-1.64(m,10H),1.44-1.25(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt = 4.15 min.

[0442] Example 12: Preparation of 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butoxy)piperidin-1-yl)acetic acid (compounds 12-E1 and 12-E2)

[0443] Step 1: 6-Bromohexan-2-one

[0444]

[0445] At 0 °C, a mixture of 1-methylcyclopentanol (4.00 g, 39.94 mmol) and K₂CO₃ (33.11 g, 239.6 mmol) in CHCl₃ (130 mL) was stirred for 15 min, and then bromine (10.23 mL, 199.7 mmol) was added. The reaction mixture was stirred at 0 °C for 2.5 h, and then slowly poured into ice-cold saturated aqueous solution of Na₂S₂O₃ (100 mL). The organic layer was separated, washed with water (2 x 100 mL), dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 3:1) to give the desired product 6-bromohexane-2-one (4 g) as a colorless oil. Yield 56% (98% purity, UV = 214 nm, ESI not detected). 1H-NMR (400MHz, CDCl3) δ1.66-1.80 (m, 2H), 1.82-1.93 (m, 2H), 2.15 (s, 3H), 2.48 (t, J = 7.3Hz, 2H), 3.41 (t, J = 6.5Hz, 2H).

[0446] Step 2: 2-(4-bromobutyl)-2-methyl-1,3-dioxolane

[0447]

[0448] In a flame-dried round-bottom flask equipped with a magnetic stir bar and a Dean-Stark valve, under N2, a solution containing 6-bromo-hexane-2-one (2.0 g, 11.17 mmol), ethylene glycol (6.93 g, 111.7 mmol), and TsOH (384 mg, 0.22 mmol) in toluene (40 mL) was heated to reflux for 3 hours. The reaction was allowed to cool to room temperature, and saturated aqueous NaHCO3 solution (60 mL) and ethyl acetate (100 mL) were added. The organic layer was separated, washed with water (2 x 100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product 2-(4-bromobutyl)-2-methyl-1,3-dioxolane (1.6 g) as a colorless oil. Yield 64% (98% purity, UV = 214nm, not detected by ESI). 1 H-NMR (400MHz, CDCl3) δ1.34 (s, 3H), 1.50-1.65 (m, 2H), 1.65-1.75 (m, 2H), 1.84-1.98 (m, 2H), 3.43 (t, J = 6.8Hz, 2H), 3.90-4.04 (m, 4H).

[0449] Step 3: 4-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)piperidine-1-carboxylic acid tert-butyl ester

[0450]

[0451] At 0 °C, a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (866 mg, 4.31 mmol) and NaH (287 mg, 7.18 mmol) in DMF (10 mL) was stirred for 1 hour. At 0 °C, a solution of 2-(4-bromobutyl)-2-methyl-1,3-dioxolane (800 mg, 3.59 mmol) in DMF (5 mL) was added dropwise to the above mixture, and the reaction mixture was stirred overnight at 100 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product, tert-butyl 4-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)piperidine-1-carboxylate (420 mg), as a colorless oil. Yield 36% (98% purity, UV = 214 nm, ESI 243 (M+H)). + ).

[0452] Step 4: 6-(piperidin-4-yloxy)hexane-2-one

[0453]

[0454] 4-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)piperidin-1-carboxylic acid tert-butyl ester (420 mg, 1.22 mmol) was treated with 4M HCl (3.1 mL, 12.2 mmol) in 10 mL of 1,4-dioxane for 2 hours at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:2) to give the desired product 6-(piperidin-4-yloxy)hexane-2-one (290 mg) as a colorless oil. Yield 97% (98% purity, UV = 214 nm, ESI 243 (M+H)). + ).

[0455] Step 5: Methyl 2-(4-(5-oxohexyloxy)piperidin-1-yl)-2-phenylacetate

[0456]

[0457] A mixture containing 290 mg (1.19 mmol) of 6-(piperidin-4-yloxy)hexane-2-one, 493 mg (3.57 mmol) of K₂CO₃, and methyl 2-bromo-2-phenylacetate (409 mg, 1.79 mmol) in acetonitrile (8 mL) was stirred for 3 hours at 50 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:2) to give the desired product, methyl 2-(4-(5-oxohexyloxy)piperidin-1-yl)-2-phenylacetate (340 mg), as a colorless oil. Yield 82% (98% purity, UV = 214 nm, ESI 347 (M+H)). + ).

[0458] Step 6: Methyl 2-(4-(4-(1,8-naphthid-2-yl)butoxy)piperidin-1-yl)-2-phenylacetate

[0459]

[0460] A mixture of methyl 2-(4-(5-oxohexyloxy)piperidin-1-yl)-2-phenylacetate (340 mg, 0.98 mmol), 2-aminonicotinaldehyde (155 mg, 1.27 mmol), and pyrrolidine (90 mg, 1.27 mmol) in ethanol (8 mL) was refluxed overnight. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 40:1) to give the desired product, methyl 2-(4-(4-(1,8-naphthidin-2-yl)butoxy)piperidin-1-yl)-2-phenylacetate (220 mg), as a colorless oil. Yield 51% (98% purity, UV = 254 nm, ESI 434.5(M+H)+).

[0461] Step 7: Methyl 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)piperidin-1-yl)acetate

[0462]

[0463] Under balloon hydrogen atmosphere at room temperature, a mixture of methyl 2-(4-(4-(1,8-naphthid-2-yl)butoxy)piperidin-1-yl)-2-phenylacetate (220 mg, 0.51 mmol) and Pd / C (10%, 20 mg) in EtOAc (30 mL) was stirred for 16 hours. The mixture was filtered and concentrated to give the desired product (220 mg) as a colorless oil. Yield 99% (92% purity, UV = 214 nm, ESI 438.4(M+H)+).

[0464] Step 8: 2-Phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butoxy)piperidin-1-yl)acetic acid (compounds 12-E1 and 12-E2) (MRT-B0103)

[0465]

[0466] Methyl 2-(4-(4-(1,8-naphthid-2-yl)butoxy)piperidin-1-yl)-2-phenylacetate (220 mg, 0.51 mmol) was treated with LiOH-H2O (86 mg, 2.04 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 hours at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give racemic compound 12 (42 mg, 19% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 12-E1 (17 mg) and 12-E2 (20 mg) as white solids.

[0467] Compound 12-E1 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.61 min, ESI 423.5(M+H)+. 1 H-NMR (400MHz, MeOD) δ7.61-7.50(m,2H),7.48-7.38(m,3H),7.14(d,J=7.3Hz,1H),6.36(d,J=7.3Hz,1H),4.46(s,1H),3.57(s,1H),3.46(t,J =6.2Hz,2H),3.41-3.35(m,2H),3.14(s,1H),2.85(s,1H),2.71(t,J=6 .2Hz,2H),2.53(t,J=7.5Hz,2H),2.19-1.79(m,7H),1.56-1.63(m,5H). Chiral SFC A (45% MeOH): ee 96.2%, Rt=1.88 min.

[0468] Compound 12-E2 LC / MS A: 97% purity, UV = 214 nm, Rt = 1.61 min, ESI 423.5(M+H)+. 1H-NMR (400MHz, MeOD) δ7.61-7.50(m,2H),7.48-7.38(m,3H),7.14(d,J=7.3Hz,1H),6.36(d,J=7.3Hz,1H),4.46(s,1H),3.57(s,1H),3.46(t,J =6.2Hz,2H),3.41-3.35(m,2H),3.14(s,1H),2.85(s,1H),2.71(t,J=6 .2Hz,2H),2.53(t,J=7.5Hz,2H),2.19-1.79(m,7H),1.56-1.63(m,5H). Chiral SFC A (45% MeOH): ee 99.6%, Rt=3.05 min.

[0469] Example 13: Preparation of 2-phenyl-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-yl)acetic acid (compounds 13-E1 and 13-E2)

[0470] Step 1: (R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0471]

[0472] A mixture containing (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (124.7 mg, 0.58 mmol), 3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl-1-amine (100 mg, 0.52 mmol), HATU (331 mg, 0.87 mmol), and DIPEA (374 mg, 2.9 mmol) in DMF (5.0 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 10:1) to give the desired product (R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg) as a yellow oil. Yield 49% (ESI 389(M+H)+).

[0473] Step 2: (R)-N-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)pyrrolidine-3-carboxamide

[0474]

[0475] (R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 0.29 mmol) was treated with a solution of HCl / dioxane (4.0 M, 2 mL) for 2 h at room temperature. The solvent was removed under vacuum to give the desired product (80 mg) as a brown oil. Yield 98% (ESI 289.2(M+H)+).

[0476] Step 3: 2-Phenyl-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-yl)ethyl acetate

[0477]

[0478] A mixture containing (R)-N-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)pyrrolidine-3-carboxamide (80 mg, 0.28 mmol), ethyl 2-bromo-2-phenylacetate (68.6 mg, 0.28 mmol), and K₂CO₃ (116 mg, 0.84 mmol) in MeCN (2.5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, ethyl 2-phenyl-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-yl)acetate (70 mg), as a colorless oil. Yield 71% (ESI 451.3 (M+H)). + ).

[0479] Step 4: 2-Phenyl-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-yl)acetic acid (compounds 13-E1 and 13-E2)

[0480]

[0481] Ethyl 2-phenyl-2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)pyrrolidine-1-yl)ethyl acetate (70 mg, 0.16 mmol)) was treated with LiOH-H2O (65.1 mg, 1.55 mmol) in MeOH (2.0 mL) and H2O (0.5 mL) for 2 hours at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give two diastereomers, 13-E1 (6.1 mg) and 13-E2 ​​(6.5 mg), as white solids.

[0482] Compound 13-E1 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.23 min, ESI 423.7(M+H)+. 1 H NMR (400MHz, MeOD) δ7.55-7.46(m,2H),7.45-7.29(m,3H),7.24(d,J=7.2Hz,1H),6.42(d,J=7.2Hz,1H),4. 17(s,1H),3.43-3.37(m,3H),3.25-3.12(m,2H),2.97-2.50(m,8H),2.31-2.19(m,1H),2.05-1.73(m,5H).

[0483] Compound 13-E2 ​​LC / MS B: 97% purity, UV = 214 nm, Rt = 1.23 min, ESI 423.7(M+H)+. 1 HNMR(400MHz,MeOD)δ7.54-7.53(m,2H),7.39-7.24(m,3H),7.16(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),4.04(s,1H),3 .38(t,J=5.6Hz,2H),3.28-3.18(m,2H),3.05-2.83(m,4H),2.71(t,J=6.2Hz,2H),2.58-2.52(m,3H),2.09-1.87(m,6H).

[0484] Example 14: 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanyl)pyrrolidine-1-yl)acetic acid (compound 14)

[0485] Step 1: Ethyl 2-((R)-3-(tert-Butoxycarbonylamino)pyrrolidine-1-yl)-2-phenylacetate

[0486]

[0487] A mixture containing (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (200 mg, 1.07 mmol), ethyl 2-bromo-2-phenylacetate (390 mg, 1.60 mmol), and K₂CO₃ (445 mg, 3.22 mmol) in MeCN (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 3:1) to give the desired product, ethyl 2-((R)-3-(tert-butoxycarbonylamino)pyrrolidine-1-yl)-2-phenylacetate (335 mg), as a yellow oil. Yield 89% (ESI 349.0 (M+H)). + ).

[0488] Step 2: Ethyl 2-((R)-3-aminopyrrolidone-1-yl)-2-phenylacetate

[0489]

[0490] Ethyl 2-((R)-3-(tert-Butoxycarbonylamino)pyrrolidine-1-yl)-2-phenylacetate (335 mg, 0.96 mmol) was treated with a solution of HCl / dioxane (4.0 M, 4 mL) for 2 hours at room temperature, followed by solvent removal under vacuum to give the desired product, ethyl 2-((R)-3-aminopyrrolidine-1-yl)-2-phenylacetate (234 mg), as a brown oil. Yield 98% (ESI 249.2(M+H)+).

[0491] Step 3: 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanyl)pyrrolidine-1-yl)ethyl acetate

[0492]

[0493] A mixture of ethyl 2-((R)-3-aminopyrrolidone-1-yl)-2-phenylacetate (234 mg, 0.94 mmol), 4-(5,6,7,8-tetrahydro-1,8-naphthidone-2-yl)butyraldehyde (191 mg, 0.94 mmol), and NaBH(OAc)3 (598 mg, 2.82 mmol) in DCM (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 15:1) to give the desired ethyl 2-phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidone-2-yl)butanamino)pyrrolidone-1-yl)acetate (180 mg) as a colorless oil. Yield 44% (ESI 437(M+H)+).

[0494] Step 4: 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)pyrrolidine-1-yl)acetic acid (compound 14)

[0495]

[0496] Ethyl 2-phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanyl)pyrrolidine-1-yl)ethyl acetate (180 mg, 0.41 mmol)) was treated with LiOH-H2O (86 mg, 2.05 mmol) in MeOH (5.0 mL) and H2O (1.0 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 14 (52 mg) as a yellow solid. LC / MS E: 98% purity, UV = 214 nm, Rt = 1.03 min, ESI 409.2(M+H)+. 1 H NMR (400MHz, MeOD) δ7.61-7.54(m,2H),7.54-7.20(m,3H),7.15(d,J=7.3Hz,1H),6.42-6.38(m,1H),3.81-3 .77(m,1H),3.62-3.51(m,1H),3.43-3.34(m,2H),3.24-3.20(m,1H),2.94-2.20(m,9H),1.88-1.57(m,8H).

[0497] Example 15: Preparation of 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (compound 15)

[0498] Step 1: 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0499]

[0500] A mixture containing 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (132 mg, 0.66 mmol), HATU (251 mg, 0.66 mmol), 7-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydro-1,8-naphthylidine hydrochloride (200 mg, 0.66 mmol), and triethylamine (0.4 mL, 2.64 mmol) in DMF (2 mL) was stirred overnight. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 0:100) to give tert-butyl 3-(4-((5,6,7,8-tetrahydro-1,8-naphthyl-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid (210 mg) as a pale yellow solid. Yield 77% (100% purity, UV = 214nm, ESI 415(M+H)) + ).

[0501] Step 2: Azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-yl)methyl ketone

[0502]

[0503] 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester (210 mg, 0.51 mmol) was treated overnight with HCl (2 mL, 8 mmol) in dioxane (2 mL). The solvent was removed under vacuum to give a pale yellow solid, azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl ketone (189 mg). Yield 100% (100% purity, UV = 214 nm, ESI 315 (M+H)). + ).

[0504] Step 3: 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)ethyl acetate

[0505]

[0506] At room temperature, NaBH3CN (103 mg, 6.63 mmol) was added to a stirred mixture containing aziridine-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl ketone (158 mg, 0.41 mmol) and 2-oxoethyl acetate (0.1 mL, 0.12 mmol) in DCE. The resulting mixture was stirred for 2 hours, then diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were washed with water and brine, dried, and concentrated to give 150 mg of 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)aziridine-1-yl)ethyl acetate as a pale yellow oil. Yield 92% (100% purity, UV = 214nm, ESI 401(M+H)) + ).

[0507] Step 4: 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (compound 15)

[0508]

[0509] At room temperature, ethyl acetate (163 mg, 0.41 mmol) of 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl) was treated with LiOH-H2O (34 mg, 0.81 mmol) in THF (4 mL) and H2O (2 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give compound 15 (15 mg) as a white solid. Yield 10% (LC / MS A: 100% purity, UV = 214 nm, Rt = 1.44 min, ESI 373 (M+H)). + ). 1H NMR(500MHz,MeOD)δ7.05(d,J=7.2Hz,1H),6.25(d,J=7.2Hz,1H),4.36(d, J=13.1Hz,1H),4.21-4.03(m,3H),3.88-3.77(m,1H),3.63(s,2H),3.48(d, J=13.2Hz,1H),3.32-3.24(m,2H),2.90(t,J=13.1Hz,1H),2.63-2.49(m,3H ), 2.36 (d, J = 7.2Hz, 2H), 1.78 (m, 3H), 1.58 (d, J = 13.1Hz, 2H), 1.05 (m, 2H).

[0510] Example 16: Preparation of 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compound 16)

[0511] Step 1: Methyl 6-oxo-heptanoate

[0512]

[0513] Concentrated H₂SO₄ (0.2 mL) was added to a stirred solution of 6-oxo-heptanic acid (10 g, 69 mmol) contained in DCE / MeOH (50 mL / 20 mL). The mixture was stirred overnight at 90 °C. The solution was cooled to room temperature and concentrated. The residue was diluted with DCM (200 mL), washed with saturated NaHCO₃ solution, water, and brine, dried, and concentrated to give methyl 6-oxo-heptanic acid (8.4 g) as a pale yellow liquid (76% yield, 100% purity, UV = 214 nm, ESI 159 (M+H)). + ).

[0514] Step 2: Methyl 5-(1,8-naphthid-2-yl)valerate

[0515]

[0516] A mixture containing methyl 6-oxo-heptanoate (11 g, 69.53 mmol), 2-aminonicotinaldehyde (8.5 g, 69.53 mmol), and L-proline (4 g, 34.77 mmol) in MeOH (100 mL) was stirred overnight at 90 °C. The mixture was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (EtOAc) to give methyl 5-(1,8-naphthid-2-yl)valerate (7 g) as a pale yellow solid. Yield 65% (100% purity, UV = 214 nm, ESI 245 (M+H)). + ). 1H NMR (400MHz, CDCl3) δ9.08(dd,J=4.2,1.9Hz,1H),8.16(dd,J=8.1,1.9Hz,1H),8.10(d,J=8.3Hz,1H),7.44(dd,J=8 .1,4.3Hz,1H),7.39(d,J=8.3Hz,1H),3.66(s,3H),3.11-3.02(m,2H),2.39(m,2H),1.96(m,2H),1.81-1.70(m,2H).

[0517] Step 3: Methyl 5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)valerate

[0518]

[0519] Under balloon H2, at room temperature, a mixture of methyl 5-(1,8-naphthid-2-yl)valerate (5 g, 20.47 mmol) and Pd / C (500 mg) in MeOH (50 mL) was stirred overnight. The mixture was filtered and concentrated to give methyl 5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)valerate (4.2 g) as a light brown oil. Yield 83% (100% purity, UV = 214 nm, ESI 249(M+H)). + ).

[0520] Step 4: tert-butyl 7-(5-methoxy-5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-formate

[0521]

[0522] A mixture of methyl 5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)valerate (2.4 g, 9.7 mmol) and Boc₂O (11 g, 8 mmol) in dioxane (20 mL) was stirred for 16 hours at 80 °C. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give tert-butyl 7-(5-methoxy-5-oxopentyl)-3,4-dihydro-1,8-naphthid-1(2H)-carboxylate (1.8 g) as a pale yellow oil, in 53% yield (100% purity, UV = 214 nm, ESI 349 (M+H)). + ).

[0523] Step 5: tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-formate

[0524]

[0525] At 75 °C, a mixture containing 740 mg (2.12 mmol) of tert-butyl 7-(5-methoxy-5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate and 93 mg (4.24 mmol) of LiBH4 in 10 mL of THF was stirred for 2 hours. The solution was cooled to room temperature and concentrated, diluted with 20 mL of EtOAc, washed with water and brine, dried, and concentrated to give 500 mg of tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate as a pale yellow oil. Yield 73% (100% purity, UV = 214 nm, ESI 321(M+H)). + ).

[0526] Step 6: tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-formate

[0527]

[0528] IBX (1.22 g, 4.36 mmol) was added to DMSO (15 mL) and stirred until the solution became clear. Tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (700 mg, 2.18 mmol) contained in DMSO (5 mL) was added dropwise to the solution, and the resulting mixture was stirred at room temperature for 16 hours, then diluted with water (80 mL) and extracted with DCM (300 mL). The combined organic extracts were washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc 1:1) to give tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (498 mg) as a pale yellow oil in 72% yield (100% purity, UV = 214 nm, ESI 319(M+H)). + ).

[0529] Step 7: 7-(5-(4-(2-ethoxy-2-oxoethyl)piperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-formate tert-butyl ester

[0530]

[0531] At room temperature, NaBH3CN (79 mg, 1.26 mmol) was added to a stirred mixture of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (100 mg, 0.31 mmol) and ethyl 2-(piperazin-1-yl)carboxylate (81 mL, 0.47 mmol). The resulting mixture was stirred for 2 hours, then diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were washed with water and brine, dried, and concentrated to give tert-butyl 7-(5-(4-(2-ethoxy-2-oxoethyl)piperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (98 mg) as a pale yellow oil. Yield 65% (100% purity, UV = 214nm, ESI 475(M+H)) + ).

[0532] Step 8: 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)ethyl acetate

[0533]

[0534] 7-(5-(4-(2-ethoxy-2-oxoethyl)piperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester (20 mg, 0.04 mmol) was treated overnight with HCl (3 mL, 9 mmol) in dioxane (2 mL). The solvent was removed under vacuum to give ethyl acetate (10 mg) of 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthyl-2-yl)pentyl)piperazin-1-yl) as a pale yellow solid. Yield 63% (100% purity, UV = 214 nm, ESI 375 (M+H)). + ).

[0535] Step 9: 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compound 16)

[0536]

[0537] At room temperature, ethyl acetate (10 mg, 0.03 mmol) of 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl) was treated with LiOH-H2O (3.4 mg, 0.09 mmol) in THF (4 mL) and H2O (2 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 16 (5 mg) as a white solid. Yield 54% (LC / MS A: 100% purity, UV = 214 nm, Rt = 1.45 min, ESI 347 (M+H)). + ). 1 H NMR(500MHz,MeOD)δ7.14(d,J=7.3Hz,1H),6.38(d,J=7.3Hz,1H),3.42-3.36(m,2H),3.10(s,2H),2.81-2.56(m,10H), 2.53(t,J=7.6Hz,2H),2.46-2.40(m,2H),1.92-1.83(m,2H),1.71-1.62(m,2H),1.61-1.51(m,2H),1.40-1.30(m,2H).

[0538] Example 17: 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compound 17)

[0539] Step 1: 7-(5-(4-(2-ethoxy-2-oxoethyl)-3-oxopiperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-formate tert-butyl ester

[0540]

[0541] At room temperature, NaBH3CN (79 mg, 1.24 mmol) was added to a stirred mixture of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (100 mg, 0.31 mmol) and ethyl 2-(2-oxopiperazin-1-yl)carboxylate (175 mg, 0.93 mmol) contained in DCE. The resulting mixture was stirred for 2 hours, then diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were washed with water and brine, dried, and concentrated to give tert-butyl 7-(5-(4-(2-ethoxy-2-oxoethyl)-3-oxopiperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (50 mg) as a pale yellow oil. Yield 32% (100% purity, UV = 214nm, ESI 489(M+H)) + ).

[0542] Step 2: 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)ethyl acetate

[0543]

[0544] At room temperature, tert-butyl 7-(5-(4-(2-methoxy-2-oxoethyl)-3-oxopiperazin-1-yl)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (50 mg, 0.11 mmol) was treated overnight with HCl (3 mL, 9 mmol) in dioxane (2 mL). The solvent was removed under vacuum to give ethyl acetate (34 mg) of 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthidine-2-yl)pentyl)piperazin-1-yl) as a pale yellow solid. Yield 87% (100% purity, UV = 214 nm, ESI 389(M+H)). + ).

[0545] Step 3: 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)acetic acid (compound 17)

[0546]

[0547] At room temperature, ethyl acetate (38 mg, 0.10 mmol) of 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl) was treated with LiOH-H2O (13 mg, 0.30 mmol) in THF (4 mL) and H2O (2 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give compound 17 (18 mg) as a white solid. Yield 48% (LC / MS A: 100% purity, UV = 214 nm, Rt = 0.95 min, ESI 361 (M+H)). + ). 1 H NMR (500MHz, MeOD) δ7.46(d,J=7.3Hz,1H),6.52(d,J=7.3Hz,1H),3.98(s,2H),3.52(t,J=5.7Hz,2H),3.49-3.43(m,2H),3.30(s,2H),3.00(t,J =5.7Hz,2H),2.79(t,J=6.1Hz,2H),2.77-2.70(m,2H),2.69-2.61(m,2H ),1.98-1.87(m,2H),1.77-1.67(m,2H),1.67-1.58(m,2H),1.54(m,2H).

[0548] Example 18: Preparation of 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)acetic acid (compound 18)

[0549] Step 1: 2-(4-oxopiperidin-1-yl)ethyl acetate

[0550]

[0551] A mixture containing piperidine-4-one hydrochloride (120 mg, 0.88 mmol), K₂CO₃ (245 mg, 1.76 mmol), and ethyl 2-bromoacetate (147 mg, 0.88 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated to give ethyl 2-(4-oxopiperidin-1-yl)acetate (140 mg, 85% yield) as a yellow oil. (89% purity, UV = 214 nm, ESI 186.2 (M+H)) + ).

[0552] Step 2: 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)ethyl acetate

[0553]

[0554] To a solution of ethyl 2-(4-oxopiperidin-1-yl)acetate (140 mg, 0.75 mmol) in DCE (2 mL) and MeOH (2 mL), 4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)but-1-amine (155 mg, 0.75 mmol) and acetic acid (1 drop) were added. The reaction mixture was stirred at room temperature for 1 hour. Then, NaBH3CN (190 mg, 3 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc = 1:5) to give ethyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanoamino)piperidin-1-yl)acetate (120 mg, 42% yield) as a yellow oil. (100% purity, UV = 214 nm, ESI = 375.3 (M+H)) + ).

[0555] Step 3: 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)acetic acid (compound 18)

[0556]

[0557] Ethyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)ethyl acetate (120 mg, 0.32 mmol)) was treated with LiOH (23 mg, 0.96 mmol) in THF (4 mL) and water (2 mL) for 2 h at room temperature. The reaction mixture was neutralized with 6N HCl and concentrated under vacuum, and the residue was purified by preparative HPLC A (35 to 69% MeCN) to give compound 18 (57 mg) as a white solid. LC / MS A: 100% purity, UV = 214 nm, Rt = 1.47 min, ESI 347.3 (M+H) + . 1H NMR (500MHz, CD3OD) δ7.18(d,J=7.2Hz,1H),6.42(d,J=7.2Hz,1H),3.38-3.33(m,2H),3.33-3.32(m,4H),3.01-2.9 6(m,3H),2.69(t,J=6Hz,2H),2.56(t,J=7.2Hz,2H),2.46(t,J=11.6Hz,2H),2.08(m,2H),1.86(m,2H),1.67(m,6H)

[0558] Example 19: Preparation of 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)acetic acid (compound 19)

[0559] Step 1: 4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidine-1-carboxylic acid tert-butyl ester

[0560]

[0561] To a solution of 4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyric acid (100 mg, 0.46 mmol) in DMF (4 mL), tert-butyl 4-aminopiperidin-1-carboxylate (110 mg, 0.55 mmol), EDCI (104 mg, 0.55 mmol), HOBT (73 mg, 0.55 mmol), and DIEA (117 mg, 0.92 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (15 mL, 3 times). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum to give tert-butyl 4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-carboxylate (120 mg, 66% yield) as a yellow oil. (80% purity, UV = 254nm, ESI 403.2(M+H)) + ).

[0562] Step 2: N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyramide

[0563]

[0564] TFA (4 mL) was added to a solution of tert-butyl 4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-carboxylate (120 mg, 0.29 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under vacuum, and the residue was purified by preparative HPLC A (30 to 60% MeCN) to give N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyramide (87 mg, 98% yield) as a yellow oil. (100% purity, UV = 254 nm, ESI 303.3 (M+H)) + ).

[0565] Step 3: 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)ethyl acetate

[0566]

[0567] A mixture of N-(piperidin-4-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyramide (87 mg, 0.29 mmol), ethyl 2-bromoacetate (52 mg, 0.32 mmol), and K₂CO₃ (47 mg, 0.32 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (15 mL, 3x). The combined organic phases were washed with brine, dried over Na₂SO₄, concentrated under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc = 5:1) to give ethyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)acetate (70 mg, 62% yield) as a yellow oil. (100% purity, UV = 254nm, ESI 389.1(M+H)) + ).

[0568] Step 4: 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)acetic acid (compound 19)

[0569]

[0570] Ethyl 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyrylamino)piperidin-1-yl)ethyl acetate (70 mg, 0.18 mmol)) was treated with LiOH (21 mg, 0.9 mmol) in EtOH (4 mL) and water (2 mL) for 2 h at room temperature. The reaction mixture was neutralized with 6N HCl. The resulting mixture was concentrated under vacuum, and the residue was purified by preparative HPLC A (35 to 69% MeCN) to give compound 19 (47.3 mg) as a white solid. LC / MS A: 100% purity, UV = 214 nm, Rt = 1.47 min, ESI 361.3(M+H)+. 1 H NMR(500MHz,MeOD)δ7.18(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),3.99-3.85(m,1H),3.61-3.49(m,4H),3.41(dd,J=14.9,9.4Hz ,2H),3.10(t,J=11.0Hz,2H),2.73-2.70(m,2H),2.56(t,J=7.6Hz,2H),2.32-2.18(m,2H),2.10-2.07(m,2H),2.00-1.74(m,6H).

[0571] Example 20: Preparation of 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-yl)acetic acid (compound 20)

[0572] Step 1: 4-Allylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

[0573]

[0574] At -78°C, LiHMDS (25.3 mL, 1 M / L in THF, 25.3 mmol) was added to a solution of 4-ethyl 1-tert-butyl piperidine-1,4-dicarboxylate (5 g, 19.5 mmol) in THF (50 mL). The reaction mixture was stirred at -78°C for 1 hour. Then, 3-bromoprop-1-ene (3.5 g, 29.3 mmol) was added at -78°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1) to give 4-ethyl 1-tert-butyl piperidine-1,4-dicarboxylate (5 g, 86% yield) as a colorless oil. (86% purity, UV=214nm, ESI 242.2(M-55)) + ).

[0575] Step 2: 4-(2-oxoethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

[0576]

[0577] A solution of 4-(2-oxoethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (1 g, 3.36 mmol) in water (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, a solution of NaIO4 (1.44 g, 6.72 mmol) in water (8 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was extracted with DCM (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum to give 4-(2-oxoethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (1 g, 100% crude yield) as a black oil. (36% purity, UV = 214 nm, ESI 200.2 (M-99)) + ).

[0578] Step 3: 1-Oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0579]

[0580] Triethylamine (383 mg, 3.8 mmol) and 4-(2-oxoethyl)piperidin-1,4-dicarboxylic acid tert-butyl 4-ethyl ester (454 mg, 1.52 mmol) were added to a suspension of 3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl-1-amine dihydrochloride (400 mg, 1.52 mmol) in DCE (10 mL). The reaction mixture was stirred at room temperature for 1 hour. Then NaBH(OAc)3 (644 mg, 3.04 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (EtOAc:MeOH = 4:1) to give tert-butyl 1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 46% yield) as a yellow oil. (60% purity, UV = 254 nm, ESI 429.3 (M+H)) + ).

[0581] Step 4: 2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-1-one dihydrochloride

[0582]

[0583] At 0 °C, HCl (6 mL, 4 M, 24 mmol) containing 1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (300 mg, 0.7 mmol) in 1,4-dioxane (4 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was concentrated under vacuum to give 2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-1-one dihydrochloride (400 mg, 100% yield) as a yellow oil. (83% purity, UV = 254 nm, ESI 329.4 (M+H)) + ).

[0584] Step 5: 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-yl)ethyl acetate

[0585]

[0586] Triethylamine (300 mg, 3 mmol) and ethyl 2-bromoacetate (193 mg, 0.75 mmol) were added to a solution of 2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-1-one dihydrochloride (400 mg, 1 mmol) in ACN (7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was separated by silica gel column chromatography (MeOH:EtOAc = 1:5) to give ethyl 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-yl)acetate (180 mg, 45% yield) as a yellow solid. (75% purity, UV = 254nm, ESI 415.4(M+H)) + ).

[0587] Step 6: 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-yl)acetic acid (compound 20)

[0588]

[0589] Ethyl 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2,8-diazaspiro[4.5]decane-8-yl) (180 mg, 0.43 mmol) was treated with LiOH (92 mg, 2.17 mmol) in EtOH (4 mL) and water (2 mL) for 2 h at room temperature. The reaction was neutralized with 2N HCl and concentrated under vacuum, and the residue was purified by preparative HPLC A (35 to 65% MeCN) to give compound 20 (70 mg) as a white solid. LC / MS A: 100% purity, UV = 214 nm, Rt = 1.45 min, ESI 387.4 (M+H) + . 1 H NMR (500MHz, CD3OD) δ7.14(d,J=7Hz,1H),6.39(d,J=7Hz,1H),3.50-3.33(m,10H),3.01(br,2H),2. 71(t,J=6.5Hz,2H),2.51(t,J=7Hz,2H),2.09-2.01(m,4H),1.91-1.86(m,4H),1.69(d,J=13Hz,2H).

[0590] Example 21: Preparation of 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-yl)acetic acid (compound 21)

[0591] Step 1: 3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-carboxylic acid tert-butyl ester

[0592]

[0593] A mixture containing 100 mg (0.45 mmol) of 4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyric acid, 78.2 mg (0.45 mmol) of tert-butyl 3-aminoazacyclobutane-1-carboxylate, 123 mg (0.72 mmol) of EDCI, 48.6 mg (0.36 mmol) of HOBT, and 290 mg (2.25 mmol) of DIEA in DMF (2 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc1:10) to give the desired product, tert-butyl 3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-carboxylate (80 mg), as a yellow oil. Yield 47% (98% purity, UV = 214nm, ESI 375(M+H)) + ).

[0594] Step 2: N-(azacyclobutane-3-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butyramide

[0595]

[0596] 3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-carboxylic acid tert-butyl ester (80 mg, 0.21 mmol) was treated overnight with TFA (3 mL, 1.06 mmol) in DCM (3 mL). The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 40:1) to give the desired product N-(azacyclobutane-3-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyramide (205 mg) as a yellow oil. Yield 98% (98% purity, UV = 214 nm, ESI 275 (M+H)). + ).

[0597] Step 3: 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-yl)ethyl acetate

[0598]

[0599] A mixture containing N-(azacyclobutan-3-yl)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyramide (60 mg, 0.20 mmol), ethyl 2-oxoethyl acetate (82 mg, 0.80 mmol), acetic acid (0.12 mg, 0.002 mmol), and NaBH(OAc)3 (127.2 mg, 0.60 mmol) in DCM (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutan-1-yl)ethyl acetate (30 mg), as a colorless oil. Yield 38% (98% purity, UV = 214 nm, ESI 361 (M+H)). + ).

[0600] Step 4: 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-yl)acetic acid (compound 21)

[0601]

[0602] At room temperature, ethyl acetate (30 mg, 0.083 mmol) of 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-yl) was treated with LiOH-H2O (14 mg, 0.33 mmol) in MeOH (1 mL) and H2O (1 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give compound 21 (10 mg) as a white solid. Yield: 33%. LC / MS A: 98% purity, Rt = 1.46 min, ESI 333 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.16(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),4.55(p,J=7.3Hz,1H),4.23-4.15(m,2H),3.78(dd,J=10 .4,7.0Hz,2H),3.43-3.37(m,2H),2.72(t,J=6.2Hz,2H),2.56(t,J=7.5Hz,2H),2.24(t,J=7.5Hz,2H),2.00-1.85(m,4H).

[0603] Example 22: 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanyl)azacyclobutan-1-yl)acetic acid (compound 22)

[0604] Step 1: 7-(5-(1-(2-ethoxy-2-oxoethyl)azacyclobutane-3-ylamino)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0605]

[0606] At room temperature, NaBH3CN (59 mg, 0.94 mmol) was added to a stirred mixture of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (100 mg, 0.31 mmol) and ethyl acetate 2-(3-aminoazacyclobutane-1-yl)carboxylate hydrochloride (73 mg, 0.38 mmol). The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were washed with water and brine, dried, and concentrated to give tert-butyl 7-(5-(1-(2-ethoxy-2-oxoethyl)azacyclobutane-3-ylamino)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (102 mg) as a pale yellow oil. Yield 71% (100% purity, UV = 214nm, ESI 461(M+H)) + ).

[0607] Step 2: 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanyl)azacyclobutane-1-yl)ethyl acetate

[0608]

[0609] At room temperature, tert-butyl 7-(5-(1-(2-ethoxy-2-oxoethyl)azacyclobutane-3-ylamino)pentyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (35 mg, 0.08 mmol) was treated overnight with HCl (3 mL, 9 mmol) in dioxane (2 mL). The solvent was removed under vacuum to give ethyl acetate (20 mg) of 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyl-2-yl)pentylamino)azacyclobutane-1-yl) as a pale yellow solid. Yield 73% (100% purity, UV = 214 nm, ESI 361(M+H)). + ).

[0610] Step 3: 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentanyl)azacyclobutan-1-yl)acetic acid (compound 22)

[0611]

[0612] At room temperature, ethyl acetate (25 mg, 0.07 mmol) of 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanamino)azacyclobutan-1-yl) was treated with LiOH-H2O (9 mg, 0.21 mmol) in THF (2 mL) and H2O (2 mL) for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC B (33 to 65% MeCN) to give compound 22 (5 mg) as a white solid in 26% yield (LC / MS A: 100% purity, UV = 214 nm, Rt = 1.47 min, ESI 333 (M+H)). + ). 1 H NMR (500MHz, MeOD) δ8.45(s,2H),7.52(d,J=7.3Hz,1H),6.56(d,J=7.3Hz,1H),4.37-4.21(m,2H),4.00-3.91(m,2H),3.88(m,1H),3.78(s,2H),3. 52-3.41(m,2H),2.81(t,J=6.1Hz,2H),2.70(dd,J=16.0,8.2Hz,4H),2.0 3-1.87(m,2H),1.81-1.65(m,2H),1.67-1.52(m,2H),1.51-1.37(m,2H).

[0613] Example 23: 2-Phenyl-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compounds 23-E1 and 23-E2)

[0614] Step 1: 4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester

[0615]

[0616] A mixture containing 3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl-1-amine (200 mg, 0.76 mmol), 1-(tert-butyloxycarbonyl)piperidin-4-carboxylic acid (173 mg, 0.76 mmol), EDCI (234.2 mg, 1.22 mmol), HOBT (82.1 mg, 0.61 mmol), and DIEA (490.2 mg, 3.8 mmol) in DMF (4 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc 1:10) to give the desired product, tert-butyl 4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)piperidin-1-carboxylic acid (133 mg), as a yellow oil. Yield 43% (98% purity, UV = 214nm, ESI 403.0 (M+H)) + ).

[0617] Step 2: N-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)piperidin-4-carboxamide

[0618]

[0619] 4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-carboxylic acid tert-butyl ester (133 mg, 0.33 mmol) was treated overnight with TFA (5 mL, 1.65 mmol) in DCM (5 mL). The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 40:1) to give the desired product N-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)piperidin-4-carboxamide (100 mg) as a yellow oil. Yield 99% (98% purity, UV = 214 nm, ESI 303 (M+H)). + ).

[0620] Step 3: 2-Phenyl-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)ethyl acetate

[0621]

[0622] A mixture of N-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)piperidin-4-carboxamide (200 mg, 0.66 mmol), ethyl 2-bromo-2-phenylacetate (192 mg, 0.79 mmol), and DIEA (255 mg, 1.98 mmol) in MeCN (4 mL) was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, ethyl 2-phenyl-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propylcarbamoyl)piperidin-1-yl)acetate (200 mg), as a yellow oil. Yield 65% (98% purity, UV = 214 nm, ESI 465 (M+H)). + ).

[0623] Step 4: 2-Phenylacetyl-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compounds 23-E1 and 23-E2) (MRT-C0123)

[0624]

[0625] Ethyl 2-phenyl-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)ethyl acetate (200 mg, 0.43 mmol)) was treated with LiOH-H2O (88.3 mg, 2.15 mmol) in MeOH (4 mL) and H2O (2 mL) for 3 h at 50 °C. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give racemic compound 23 (150 mg, 44% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give enantiomers 23-E1 (40 mg) and 23-E2 (44 mg) as white solids.

[0626] Compound 23-E1 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.48 min, ESI 437 (M+H) + . 1HNMR(500MHz,MeOD)δ7.59(dd,J=6.5,2.8Hz,2H),7.49-7.41(m,3H),7.16(d,J=7.3H z,1H),6.39(d,J=7.3Hz,1H),4.43(s,1H),3.77(s,1H),3.41-3.36(m,2H),3.20(t,J =6.9Hz,2H),3.06(s,1H),2.95(t,J=10.0Hz,1H),2.82(s,1H),2.70(dd,J=13.8,7.5 Hz,2H),2.57-2.51(m,2H),2.48-2.38(m,1H),2.10-1.93(m,3H),1.92-1.79(m,5H). Chiral S,S-Whelk-O1 A (45% MeOH): ee 100%, Rt = 2.17 min.

[0627] Compound 23-E2 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.48 min, ESI 437 (M+H) + . 1 HNMR(500MHz,MeOD)δ7.59(dd,J=6.4,2.8Hz,2H),7.48-7.41(m,3H),7.17(d,J=7.3Hz,1 H),6.39(d,J=7.3Hz,1H),4.43(s,1H),3.76(s,1H),3.42-3.36(m,2H),3.20(t,J=6.9Hz ,2H),3.06(d,J=11.6Hz,1H),2.94(t,J=10.5Hz,1H),2.80(s,1H),2.71(t,J=6.2Hz,2H) ,2.58-2.51(m,2H),2.48-2.38(m,1H),2.01(tt,J=22.5,11.2Hz,3H),1.92-1.79(m,5H). Chiral S,S-Whelk-O1 A (45% MeOH): ee 100%, Rt = 3.04 min.

[0628] Example 24: Preparation of 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)acetic acid (compounds 24-E1 and 24-E2)

[0629] Step 1: Ethyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate

[0630]

[0631] A mixture containing piperidine-4-one hydrochloride (1.0 g, 7.38 mmol), ethyl 2-bromo-2-phenylacetate (2.53 g, 11.06 mmol), and K₂CO₃ (3.06 g, 22.13 mmol) in DMF (30 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to give the desired product, ethyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate (1.0 g), as a colorless oil. Yield 92% (98% purity, UV = 214 nm, ESI 262.0 (M+H)). + ).

[0632] Step 2: 2-Phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanyl)piperidin-1-yl)ethyl acetate

[0633]

[0634] A mixture of 4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)but-1-amine (261 mg, 1.28 mmol), ethyl 2-(4-oxopiperidin-1-yl)-2-phenylacetate (400 mg, 1.5 mmol), and NaBH3CN (245 mg, 3.84 mmol) in DCM (10 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, ethyl 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanoamino)piperidin-1-yl)acetate (180 mg), as a colorless oil. Yield 45% (98% purity, UV = 214 nm, ESI 451 (M+H)). + ).

[0635] Step 3: 2-Phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butanyl)piperidin-1-yl)acetic acid (compounds 24-E1 and 24-E2)

[0636]

[0637] Ethyl 2-phenyl-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butanyl)piperidin-1-yl)ethyl acetate (50 mg, 0.11 mmol) was treated with LiOH-H2O (23.4 mg, 0.56 mmol) in EtOH (2 mL) and H2O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 24 (30 mg, 60% yield) as a white solid. The racemic product was separated by preparative chiral SFC B to give the enantiomers compound 24-E1 (2.2 mg) and compound 24-E2 (5.7 mg) as white solids.

[0638] Compound 24-E1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.623 min, ESI 423 (M+H) +1 HNMR(500MHz,MeOD)δ7.52(d,J=7.0Hz,2H),7.34(dt,J=14.1,7.1Hz,3H),7.18(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),3.80(s,1H) ,3.38-3.34(m,3H),3.04-2.91(m,3H),2.78(s,1H),2.69(t,J=6.2Hz,2H),2.56(t,J=7.0Hz,2H),2.25(s,1H),2.08-1.63(m,11H). Chiral AD-HA (40% MeOH): ee22.5%, Rt=2.49min

[0639] Compound 24-E2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.51 min, ESI 423 (M+H) +1 H NMR(500MHz,MeOD)δ7.53(d,J=7.0Hz,2H),7.32(dt,J=21.7,7.0Hz,3H),7.17(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),3.80(s,1H),3.41-3.3 4(m,3H),3.05-2.88(m,3H),2.79(d,J=11.1Hz,1H),2.69(t,J=6.2Hz,2H),2.56(t,J=7.1Hz,2H),2.25(t,J=11.1Hz,1H),2.08-1.61(m,11H). Chiral AD-HA (40% MeOH): ee 36.3%, Rt=0.84min

[0640] Example 25: 2-Phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (compound 25)

[0641] Step 1: 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0642]

[0643] A mixture containing 7-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (300 mg, 0.99 mmol), 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (200 mg, 0.99 mmol), EDCI (228 mg, 3.41 mmol), HOBt (135 mg, 0.99 mmol), and DIEA (255 mg, 1.98 mmol) in DMF (3 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, tert-butyl 3-(4-((5,6,7,8-tetrahydro-1,8-naphthidine-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid (295 mg), as a yellow oil. Yield 63% (ESI 415(M+H)). + ).

[0644] Step 2: Azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-yl)methyl ketone

[0645]

[0646] 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester (295 mg, 0.71 mmol) was treated overnight with HCl (4 mL, 15.4 mmol) in 5 mL of 1,4-dioxane. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 40:1) to give the desired product, a yellow oil, azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl ketone (140 mg). Yield 62% (ESI 315(M+H)). + ).

[0647] Step 3: 2-Phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)ethyl acetate

[0648]

[0649] A mixture of piperidine-4-one hydrochloride (140 mg, 0.45 mmol), ethyl 2-bromo-2-phenylacetate (130 mg, 0.54 mmol), and K₂CO₃ (150 mg, 1.1 mmol) in MeCN (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, ethyl 2-phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetate (130 mg), as a colorless oil. Yield 71% (ESI 477 (M+H)). + ).

[0650] Step 4: 2-Phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (compound 25)

[0651]

[0652] Ethyl 2-phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)ethyl acetate (130 mg, 0.27 mmol)) was treated with LiOH-H2O (57 mg, 1.4 mmol) in EtOH (4 mL) and H2O (1 mL) for 2 h at 50 °C. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give racemic compound 25 (42 mg) as a white solid. Yield 34% (ESI 449(M+H)). + ).

[0653] Compound B, 25 LC / MS: Rt = 1.08 min, ESI 449(M+H)+. 1H NMR(500MHz,CD3OD)δ7.51(s,2H),7.44(s,3H),7.17(d,J=7.2Hz,1H),6.36(d,J=7.2Hz,1H),4.69 (s,1H),4.47(d,J=13.7Hz,1H),4.32(s,1H),4.16(s,1H),4.04(d,J=26.8Hz,1H),3.88(s,2H),3.5 6(d,J=13.6Hz,1H),3.43-3.37(m,2H),3.00(t,J=12.5Hz,1H),2.72(t,J=6.2Hz,2H),2.66(t,J=12 .3Hz, 1H), 2.47 (d, J = 7.1Hz, 2H), 1.98-1.85 (m, 3H), 1.69 (d, J = 13.1Hz, 2H), 1.14 (d, J = 9.0Hz, 2H).

[0654] Example 26: Preparation of 2-(4-((3-(6-(methylamino)pyridin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 26)

[0655] Step 1: Piperidine-4-carboxylic acid benzyl ester

[0656]

[0657] 1-tert-butyl piperidine-1,4-dicarboxylic acid 4-benzyl ester (5 g, 15.6 mmol) was treated overnight with 4N HCl / dioxane (20 mL). The solvent was removed under vacuum to give the desired product, benzyl piperidine-4-carboxylic acid ester (4 g), as a white solid. Yield 100% (100% purity, UV = 214 nm, ESI 220 (M+H)). + ).

[0658] Step 2: 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid benzyl ester

[0659]

[0660] A mixture containing benzyl piperidine-4-carboxylate (4 g, 15 mmol), tert-butyl 2-bromoacetate (4.3 g, 22.5 mmol), and K₂CO₃ (6.1 g, 45 mmol) in DMF (20 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc 2:1) to give the desired product, 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (3.5 g), as a colorless oil. Yield 67% (95% purity, UV = 214 nm, ESI 334 (M+H)). +).

[0661] Step 3: 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid

[0662]

[0663] Under balloon hydrogen atmosphere at room temperature, a mixture containing benzyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid (3.2 g, 9.6 mmol) and Pd / C (400 mg) in EtOAc (50 mL) was stirred for 18 hours. The mixture was filtered and concentrated under vacuum to give 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylic acid (2.1 g) as a white solid. Yield 79% (100% purity, UV = 214 nm, ESI 244 (M+H)). + ).

[0664] Step 4: tert-butyl 3-(6-(methylamino)pyridin-2-yl)prop-2-ynylcarbamate

[0665]

[0666] Under a nitrogen atmosphere, at 100 °C, a mixture containing 6-bromo-N-methylpiperidin-2-amine (600 mg, 3.2 mmol), Pd(PPh3)Cl2 (141 mg, 0.3 mmol), CuI (121 mg, 0.64 mmol), triethylamine (970 mg, 9.6 mmol), and tert-butyl propionyl-2-ynylcarbamate (990 mg, 6.4 mmol) in DMF (30 mL) was stirred for 8 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (MeOH:DCM 1:15) to give the desired product, tert-butyl 3-(6-(methylamino)pyridin-2-yl)propionyl-2-ynylcarbamate (500 mg), as a colorless oil. Yield 60% (98% purity, UV = 214 nm, ESI 262 (M+H)). + ).

[0667] Step 5: tert-butyl 3-(6-(methylamino)pyridin-2-yl)propylcarbamate

[0668]

[0669] Under balloon hydrogen atmosphere at room temperature, a mixture of tert-butyl 3-(6-(methylamino)pyridin-2-yl)prop-2-ynylcarbamate (500 mg, 1.91 mmol) and Pd / C (50 mg) in EtOAc (15 mL) was stirred for 18 hours. The mixture was filtered and concentrated under vacuum to give tert-butyl 3-(6-(methylamino)pyridin-2-yl)prop-2-ylcarbamate (460 mg) as a yellow oil. Yield 91% (100% purity, UV = 214 nm, ESI 266 (M+H)). + ).

[0670] Step 6: 6-(3-aminopropyl)-N-methylpyridine-2-amine

[0671]

[0672] 3-(6-(methylamino)pyridin-2-yl)propylcarbamate tert-butyl ester (460 mg, 1.73 mmol) was treated with 4N HCl / dioxane (10 mL) for 14 h at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 7:1) to give the desired product, 6-(3-aminopropyl)-N-methylpyridin-2-amine (280 mg), as a yellow oil. Yield 90% (98% purity, UV = 214 nm, ESI 166 (M+H)). + ).

[0673] Step 7: 2-(4-(3-(6-(methylamino)pyridin-2-yl)propylcarbamoyl)piperidin-1-yl)tert-butyl acetate

[0674]

[0675] A mixture containing 6-(3-aminopropyl)-N-methylpyridin-2-amine (120 mg, 0.73 mmol), 1-(2-tert-butoxy-2-oxoethyl)piperidin-4-carboxylic acid (176.7 mg, 0.73 mmol), EDCI (210 mg, 1.1 mmol), HOBt (78.8 mg, 0.58 mmol), and DIEA (283 mg, 2.19 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc 1:10) to give the desired product, 2-(4-(3-(6-(methylamino)pyridin-2-yl)propylcarbamoyl)piperidin-1-yl)tert-butyl acetate (110 mg), as a yellow oil. Yield 39% (98% purity, UV = 214 nm, ESI 391 (M+H)). + ).

[0676] Step 8: 2-(4-(3-(6-(methylamino)pyridin-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compound 26)

[0677]

[0678] At room temperature, 110 mg (0.28 mmol) of 2-(4-(3-(6-(methylamino)pyridin-2-yl)propylcarbamoyl)piperidin-1-yl)tert-butyl acetate was treated with 3 mL of TFA in 5 mL of DCM for 4 hours. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 70% MeCN) to give compound 26 as a white solid (35.5 mg, 37.9% yield). LC / MS A: 100% purity, UV = 214 nm, Rt = 1.30 min, ESI 335 (M+H). + . 1 H NMR (500MHz, MeOD) δ7.40(dd,J=8.2,7.5Hz,1H),6.46(d,J=7.2Hz,1H),6.34(d,J=8.4Hz,1H),3.65(d,J=12.3Hz,2H),3.59(s,2H),3.24(t ,J=7.0Hz,2H),3.03(td,J=11.9,4.2Hz,2H),2.87(s,3H),2.62(t,J=8.0Hz,2H),2.51-2.46(m,1H),2.09-1.98(m,4H),1.92-1.84(m,2H).

[0679] Example 27: 2-(4-(methyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 27)

[0680] Step 1: 3-(1,8-Naphthid-2-yl)propyl(methyl)carbamate tert-butyl ester

[0681]

[0682] At 0 °C, NaH (60% contained in mineral oil, 0.7 g, 17.5 mmol) was fractionally added to a mixture of tert-butyl 3-(1,8-naphthid-2-yl)propylcarbamate (1 g, 3.5 mmol) contained in anhydrous THF (30 mL). The mixture was stirred at 0 °C for 30 min, and then methyl iodide (600 mg, 4.2 mmol) was added. The mixture was stirred at room temperature for 18 h, then stopped with water, concentrated, and purified by preparative-HPLC A to give the desired product, tert-butyl 3-(1,8-naphthid-2-yl)propyl(methyl)carbamate (180 mg), in oil form. Yield 17% (98% purity, UV = 214 nm, ESI 302.2 (M+H)). + ).

[0683] Step 2: N-methyl-3-(1,8-naphthid-2-yl)propyl-1-amine

[0684]

[0685] 3-(1,8-naphthid-2-yl)propyl(methyl)carbamate tert-butyl ester (180 mg, 0.60 mmol) was treated with TFA (5 mL) for 3 hours at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, N-methyl-3-(1,8-naphthid-2-yl)propyl-1-amine (110 mg), as a yellow oil. Yield 92% (93% purity, UV = 214 nm, ESI 202.2 (M+H)). + ).

[0686] Step 3: 2-(4-((3-(1,8-naphthid-2-yl)propyl)(methyl)carbamoyl)piperidin-1-yl)tert-butyl acetate

[0687]

[0688] A mixture containing N-methyl-3-(1,8-naphthid-2-yl)propyl-1-amine (110 mg, 0.55 mmol), 1-(2-tert-butoxy-2-oxoethyl)piperidin-4-carboxylic acid (134 mg, 0.55 mmol), HATU (420 mg, 1.1 mmol), and DIPEA (280 mg, 2.2 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (MeOH:EtOAc 1:10) to give the desired product, 2-(4-((3-(1,8-naphthid-2-yl)propyl)(methyl)carbamoyl)piperidin-1-yl)tert-butyl acetate (120 mg), as a yellow oil. Yield 52% (98% purity, UV = 214 nm, ESI 427.0 (M+H)). + ).

[0689] Step 4: 2-(4-(methyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)tert-butyl acetate)

[0690]

[0691] Under H2 (1 atm, 1 L), at room temperature, a mixture of 2-(4-((3-(1,8-naphthid-2-yl)propyl)(methyl)carbamoyl)piperidin-1-yl)tert-butyl acetate (120 mg, 0.28 mmol) and Pd / C (25 mg) in EtOH (15 mL) was stirred for 18 hours. The mixture was filtered and concentrated under vacuum to give 2-(4-(methyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)tert-butyl acetate (100 mg) as an oil. Yield 83% (100% purity, UV = 214 nm, ESI 431.1 (M+H)). + ).

[0692] Step 5: 2-(4-(methyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 27)

[0693]

[0694] 2-(4-(methyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)tert-butyl acetate (100 mg, 0.28 mmol) was treated with TFA (3 mL) in DCM (5 mL) for 4 hours at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 27 as a white solid (9 mg, 10% yield). LC / MS A: 99% purity, UV = 214 nm, Rt = 1.41 min, ESI 375.1 (M+H) + . 1 H NMR (500MHz, MeOD) δ8.33(s,1H),7.38(d,J=7.1Hz,1H),6.49(d,J=7.4Hz,1H),3.61(d,J=11.2Hz,2H),3.55(s,2H),3. 38(dd,J=13.8,6.8Hz,4H),3.11-2.80(m,6H),2.70(dd,J=14.2,8.1Hz,2H),2.55(t,J=7.6Hz,2H),2.02-1.76(m,8H).

[0695] Example 28: 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)propionic acid (compound 28)

[0696] Step 1: 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0697]

[0698] A mixture containing 7-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (100 mg crude), 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (79 mg, 0.394 mmol), HATU (149 mg, 0.394 mmol), and DIEA (127 mg, 0.986 mmol) in DMF (5 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, tert-butyl 3-(4-((5,6,7,8-tetrahydro-1,8-naphthidine-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylic acid (90 mg), as a yellow oil. Yield 61% (93% purity, UV = 214 nm, ESI 415.2 (M+H)). + ).

[0699] Step 2: Azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-yl)methyl ketone

[0700]

[0701] At room temperature, tert-butyl 3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-carboxylate (90 mg, 0.217 mmol) was treated with TFA in DCM (3 mL) for 2 hours. The solvent was removed under vacuum to give crude azacyclobutane-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl ketone (70 mg) as a yellow oil. Yield 68.7% (100% purity, UV = 214 nm, ESI 315.2 (M+H)). + The crude product is then directly applied to the next step.

[0702] Step 3: Methyl 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)propionate

[0703]

[0704] A mixture containing aziridine-3-yl(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl ketone (70 mg crude), methyl 2-bromopropionate (55 mg, 0.333 mmol), and K₂CO₃ (92 mg, 0.667 mmol) in anhydrous DMF (2 mL) was stirred at room temperature for 5 hours. The reaction was filtered and concentrated under vacuum. The residue was purified by preparative-HPLC A (33 to 65% MeCN) to give methyl 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)aziridine-1-yl)propionate (49 mg, 29% yield) as a white solid. (91% purity, UV = 254 nm, ESI 401.2 (M+H)) + ).

[0705] Step 4: 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)propionic acid (compound 28)

[0706]

[0707] Methyl 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)propionate (49 mg, 0.12 mmol) was treated with LiOH (10 mg, 0.25 mmol) in EtOH (3 mL) and H₂O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (33 to 65% MeCN) to give compound 28 (27 mg, 57% yield) as a white solid. LC / MS A: 100% purity, UV = 214 nm, Rt = 1.45 min, ESI 387.3 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.15(d,J=7.3Hz,1H),6.36(d,J=7.3Hz,1H),4.48(d,J=13.2Hz ,1H),4.33-4.04(m,4H),3.87(t,J=8.4Hz,1H),3.63(dd,J=20.6,11.3Hz,2H),3.43 -3.36(m,2H),3.02(t,J=12.8Hz,1H),2.75-2.63(m,3H),2.47(d,J=7.1Hz,2H),1.9 7-1.87(m,3H),1.69(d,J=7.8Hz,2H),1.39(d,J=8.1Hz,3H),1.16(d,J=9.6Hz,2H).

[0708] Example 29: Preparation of 2-phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 129-E1 and 129-E2)

[0709] Step 1: (R)-3-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0710]

[0711] A mixture containing tert-butyl (R)-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 for 6 hours at 100 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to give the desired product (R)-3-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)pyrrolidine-1-carboxylate (380 mg) as a colorless oil. Yield 21% (ESI 330.2 (M+H)). + ).

[0712] Step 2: (R)-3-(5-oxohexyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0713]

[0714] (R)-3-(4-(2-methyl-1,3-dioxolane-2-yl)butoxy)pyrrolidine-1-carboxylate tert-butyl ester (1.3 g, 3.95 mmol) was treated with a solution of HCl / dioxane (4.0 M, 10 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was diluted with acetone (10 mL) and H₂O (1 mL). Potassium carbonate was added to adjust the pH to 8 or 9, followed by the addition of Boc₂O (1.24 g, 5.69 mmol). The reaction was stirred at room temperature for 3 h, then filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 15:1) to give the desired product (R)-3-(5-oxohexyloxy)pyrrolidine-1-carboxylate tert-butyl ester (820 mg) as a colorless oil. Yield 73% (ESI 186 (M-100)). + 230 (M-56) + ).

[0715] Step 3: (R)-3-(4-(1,8-naphthid-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0716]

[0717] A mixture containing (R)-3-(5-oxohexyloxy)pyrrolidine-1-carboxylate tert-butyl ester (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 for 4 hours at 85 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 15:1) to give the desired product (R)-3-(4-(1,8-naphthid-2-yl)butoxy)pyrrolidine-1-carboxylate tert-butyl ester (750 mg) as a colorless oil. Yield 70% (ESI 372.2 (M+H)). + ).

[0718] Step 4: (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0719]

[0720] Under hydrogen atmosphere and at 60 °C, a mixture of (R)-3-(4-(1,8-naphthyl-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (750 mg, 2.02 mmol) and Pd / C (10%, 500 mg) in EtOAc (10 mL) was stirred for 6 hours. The reaction was filtered and concentrated under vacuum. At room temperature, the residue was treated with a solution of HCl / dioxane (4.0 M, 4 mL) for 2 hours, and the solvent was removed under vacuum to give the desired product (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine (600 mg) as a white solid. Yield 96% (ESI 276.2(M+H)+).

[0721] Step 5: Methyl 2-phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetate

[0722]

[0723] A mixture containing (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine (200 mg, 0.576 mmol), methyl 2-bromo-2-phenylacetate (140 mg, 0.576 mmol), and K₂CO₃ (240 mg, 1.73 mmol) in MeCN (3 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was directly subjected to the next step. (ESI 424.0 (M+H)) + ).

[0724] Step 6: 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compounds 129-E1 and 129-E2)

[0725]

[0726] Methyl 2-phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butoxy)pyrrolidine-1-yl)acetate (180 mg, 0.426 mmol) was treated with LiOH-H2O (126 mg, 3.0 mmol) in EtOH (4 mL) and H2O (1 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 129 (105 mg, 60% yield) as a white solid. The racemic product was separated by preparative chiral SFCA to give the enantiomers compound 129-E1 (38.7 mg) and compound 129-E2 (37.5 mg) as white solids.

[0727] Compound 129-E1 LC / MS ESI 410 (M+H) +1 H NMR(400MHz,MeOD)δ7.55-7.53(m,2H),7.43-7.41(m,3H),7.17(d,J=7.2Hz,1H), 6.39(d,J=7.6Hz,1H),4.49(s,1H),4.18(s,1H),3.48-3.43(m,3H),3.39-3.36(t, J=11.5Hz,2H),3.13(d,J=10.8Hz,1H),3.01(m,1H),2.72-2.69(t,J=12.4Hz,2H) ,2.56-2.52(t,J=15.4Hz,2H),2.11(s,2H),1.89-1.86(m,2H),1.74-1.59(m,5H). Chiral SFC A (40% MeOH): ee 89.9%, Rt = 2.14 min.

[0728] Compound 129-E2 LC / MS ESI 410 (M+H) +1H NMR (400MHz, MeOD) δ7.56-7.53(m,2H),7.42-7.41(m,3H),7.16(d,J=7.2Hz,1H),6.39(d,J=7.2Hz,1H),4.48(s,1H),4.17(m,1H),3.47-3.3 5(m,6H),3.17-3.12(m,2H),2.70(t,J=12.4Hz,2H),2.57-2.53(t,J=10.8Hz,2H),2.21-2.17(m,2H),1.90-1.84(m,2H),1.73-1.58(m,4H). Chiral SFC A (40% MeOH): ee 94.4%, Rt = 3.46 min.

[0729] Example 30: Preparation of 2-phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazol-1-yl)pyrrolidine-1-yl)acetic acid (compounds 130-E1 and 130-E2)

[0730] Step 1: (R)-3-(4-carboxy-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0731]

[0732] A mixture containing 1H-pyrazole-4-carboxaldehyde (400 mg, 4.17 mmol), (S)-3-(methanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.21 g, 4.58 mmol), and Cs₂CO₃ (4.08 g, 12.51 mmol) in DMF (30 mL) was stirred for 18 hours at 100 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product (R)-3-(4-carboxyl-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g) as a colorless oil. Yield 91% (ESI 266.0(M+H)+).

[0733] Step 2: (R)-3-(4-(3-oxobutyl-1-enyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0734]

[0735] A mixture of (R)-3-(4-carboxymethyl-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 3.77 mmol) and 1-(triphenylphosphine)prop-2-one (1.2 g, 5.66 mmol) in toluene (40 mL) was stirred for 18 hours at 110 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product (R)-3-(4-(3-oxobutyl-1-enyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (920 mg) as a colorless oil. Yield 80% (ESI 306.0(M+H)+).

[0736] Step 3: (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0737]

[0738] Under H2 conditions at 40 °C, a mixture of (R)-3-(4-(3-oxobutyl-1-enyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (920 mg, 3.02 mmol) and 10% Pd / C (184 mg) in MeOH (20 mL) was stirred for 18 hours. The mixture was filtered, and the solvent was removed under vacuum to give the desired product (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg) as a colorless oil. Yield 97% (ESI 308.0(M+H)+).

[0739] Step 4: (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0740]

[0741] A mixture of (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, 2.93 mmol)), 2-aminonicotinaldehyde (465 mg, 3.81 mmol), and pyrrolidine (270 mg, 3.81 mmol) in EtOH (30 mL) was stirred for 16 hours at 80 °C. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (650 mg) as a yellow oil. Yield 56% (ESI 394.0(M+H)+).

[0742] Step 5: (R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0743]

[0744] At 40 °C, a mixture of (R)-3-(4-(3-oxobutyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (650 mg, 1.65 mmol) and 10% Pd / C (130 mg) in MeOH (20 mL) was stirred for 15 hours. The mixture was filtered and the solvent was removed under vacuum to give the desired product (R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg) as a yellow oil. Yield 93% (ESI 398.0(M+H)+).

[0745] Step 6: (R)-7-(2-(1-(pyrrolidone-3-yl)-1H-pyrazole-4-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0746]

[0747] (R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 1.54 mmol) was treated with HCl (4 M in 1,4-dioxane, 3.9 mL, 15.4 mmol) for 2 hours at 25 °C. The solvent was removed under vacuum to give the desired product (R)-7-(2-(1-(pyrrolidine-3-yl)-1H-pyrazole-4-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (450 mg) as a yellow oil. Yield 98% (ESI 298.0(M+H)+).

[0748] Step 7: Methyl 2-phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazol-1-yl)pyrrolidine-1-yl)acetate

[0749]

[0750] At 50 °C, a mixture containing (R)-7-(2-(1-(pyrrolidin-3-yl)-1H-pyrazole-4-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (450 mg, 1.51 mmol), methyl 2-bromo-2-phenylacetate (415 mg, 1.81 mmol), and K2CO3 (625 mg, 4.53 mmol) in MeCN (20 mL) was stirred for 16 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 20:1) to give the desired product, methyl 2-phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidine-2-yl)ethyl)-1H-pyrazole-1-yl)pyrrolidin-1-yl)acetate (120 mg), as a yellow oil. Yield 19% (ESI 446.0(M+H)+).

[0751] Step 8: 2-Phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazol-1-yl)pyrrolidine-1-yl)acetic acid (compounds 130-E1 and 130-E2)

[0752]

[0753] Methyl 2-phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1H-pyrazol-1-yl)pyrrolidine-1-yl)acetate (120 mg, 0.27 mmol) was treated with LiOH-H2O (45.4 mg, 1.08 mmol) in MeOH (4 mL) and H2O (1 mL) for 2 h at 65 °C. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 130 (60 mg, 52% yield) as a white solid. The racemic product was separated by preparative chiral SFC B to give the enantiomers compound 130-E1 (46 mg) and compound 130-E2 (27 mg) as white solids.

[0754] Compound 130-E1 LC / MS ESI 432 (M+H)+ 1H NMR (400MHz, MeOD) δ7.59-7.56(m,3H),7.39-7.21(m,5H),6.39(d,J=7.3Hz,1H),4.97(s,1H),4.44(s,1H),3.44-3.36(m, 4H),3.32-3.15(m,2H),2.81-2.79(m,4H),2.71(t,J=6.0Hz,2H),2.50-2.45(m,1H),2.25-2.20(m,1H),1.88-1.85(m,2H). Chiral SFC B (40% MeOH): ee 100%, Rt = 1.34 min.

[0755] Compound 130-E2 LC / MS ESI 432 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.59-7.56(m,3H),7.39-7.21(m,5H),6.39(d,J=7.3Hz,1H),4.87(s,1H),4.07(s ,1H),3.44-3.26(m,4H),2.92-2.51(m,8H),2.50-2.40(m,1H),2.20-2.10(m,1H),1.88-1.85(m,2H). Chiral SFC B (40% MeOH): ee 99.5%, Rt = 2.89 min.

[0756] Example 31: Preparation of 2-phenyl-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 131-E1 and 131-E2)

[0757] Step 1: (R)-3-(iodomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0758]

[0759] Iodine (4.95 g, 19.5 mmol) was slowly added to a solution of triphenylphosphine (5.11 g, 19.5 mmol) and 1H-imidazolium (1.33 g, 19.5 mmol) in DCM (50 mL) at 0 °C. The reaction was stirred at 0 °C for 30 min, and then a solution of (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added. The reaction was stirred overnight at room temperature, then diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to give the desired product (R)-3-(iodomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 g) as a colorless oil. Yield: 80%. (ESI 256(M+H-56)+).

[0760] Step 2: (R)-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium

[0761]

[0762] A solution containing (R)-3-(iodomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 g, 12 mmol) and triphenylphosphine (4.1 g, 15.5 mmol) in DMF (50 mL) was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 10:1) to give a crude product. Diethyl ether (30 mL) was added to the crude product, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and dried under vacuum to give the desired product (R)-((1-(tert-butyloxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium (5.6 g) as a white solid. Yield 84%. (ESI N / A)

[0763] Step 3: Ethyl 4-(2-methyl-1,3-dioxolane-2-yl)butyrate

[0764]

[0765] A solution containing 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 refluxed for 6 hours using a Dean-Stark trap. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to give the desired product, ethyl 4-(2-methyl-1,3-dioxolane-2-yl)butyrate (1.4 g, 50% yield), as a colorless oil. (ESI 203(M+H)+).

[0766] Step 4: 4-(2-Methyl-1,3-dioxolane-2-yl)butyraldehyde

[0767]

[0768] DIBAL-H (1 M, 3.7 mL, 3.7 mmol) was slowly added to a solution of ethyl 4-(2-methyl-1,3-dioxolane-2-yl)butyrate (500 mg, 2.48 mmol) in DCM (10 mL) at -78 °C under Ar conditions. The reaction was stirred at -78 °C for 30 min, then stopped with 20 mL of water, heated to room temperature, and extracted with DCM (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, 4-(2-methyl-1,3-dioxolane-2-yl)butyraldehyde (220 mg), as a colorless oil. Yield: 56%. (ESI 159(M+H)+).

[0769] Step 5: (S)-3-(5-(2-methyl-1,3-dioxolane-2-yl)pent-1-enyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0770]

[0771] At 0 °C under nitrogen atmosphere, LiHMDS (1 M, 5.4 mL, 5.4 mmol) was added to a solution of (R)-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)methyl)triphenylphosphonium (2.0 g, 3.6 mmol) in DCM (30 mL). The mixture was stirred at 0 °C for 30 min, and then 4-(2-methyl-1,3-dioxolane-2-yl)butanal (565 mg, 3.6 mmol) was added. The reaction was stirred at room temperature for 4 h, and then stopped with MeOH (20 mL). The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 3:1) to give the desired product (S)-3-(5-(2-methyl-1,3-dioxolane-2-yl)pent-1-enyl)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg) as a yellow oil. Yield: 43%. (ESI 226(M+H-100)+).

[0772] Step 6: (R)-7-(pyrrolidone-3-yl)hepta-2-one

[0773]

[0774] At 40 °C and under hydrogen atmosphere, a mixture of (S)-3-(5-(2-methyl-1,3-dioxolane-2-yl)pent-1-enyl)pyrrolidine-1-carboxylic acid tert-butyl ester (440 mg, 1.35 mmol) and Pd / C (10%, 40 mg) in EtOAc (20 mL) was stirred overnight. The reaction was filtered and concentrated under vacuum. The residue was treated with 5 mL of 1,4-dioxane solution (4 M) of HCl. The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give the desired product (R)-7-(pyrrolidine-3-yl)hepta-2-one as a yellow oil (220 mg). Yield 89%. (ESI 184(M+H)+).

[0775] Step 7: Methyl 2-((R)-3-(6-oxoheptyl)pyrrolidine-1-yl)-2-phenylacetate

[0776]

[0777] A mixture of (R)-7-(pyrrolidone-3-yl)hepta-2-one (210 mg, 1.15 mmol), methyl 2-bromo-2-phenylacetate (315 mg, 1.4 mmol), and K₂CO₃ (476 mg, 3.45 mmol) in 10 mL of MeCN was stirred overnight at 40 °C. The reaction was filtered and concentrated under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the desired product, methyl 2-((R)-3-(6-oxoheptyl)pyrrolidone-1-yl)-2-phenylacetate (260 mg), as a yellow oil. Yield: 68%. (ESI 331(M+H)+).

[0778] Step 8: Methyl 2-((R)-3-(5-(1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)-2-phenylacetate

[0779]

[0780] 2-Aminonicotinaldehyde (144 mg, 1.18 mmol) and pyrrolidine (28 mg, 0.39 mmol) were added to a solution of methyl 2-((R)-3-(6-oxoheptyl)pyrrolidine-1-yl)-2-phenylacetate (260 mg, 0.78 mmol) in EtOH (10 mL). The reaction was heated to reflux overnight, then concentrated under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the desired product, methyl 2-((R)-3-(5-(1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)-2-phenylacetate (260 mg), as a yellow oil. Yield 78%. (ESI 418(M+H)+).

[0781] Step 9: Methyl 2-phenyl-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)pyrrolidine-1-yl)acetate

[0782]

[0783] At 40 °C and under hydrogen atmosphere, a mixture of methyl 2-((R)-3-(5-(1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)-2-phenylacetate (260 mg, 0.62 mmol) and Pd / C (10%, 30 mg) in EtOAc (10 mL) was stirred overnight. The reaction was filtered and concentrated under vacuum to give the desired product, methyl 2-phenyl-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)acetate (220 mg), as a yellow oil. Yield 84%. (ESI 422(M+H)+).

[0784] Step 10: 2-Phenyl-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (compounds 131-E1 and 131-E2)

[0785]

[0786] Methyl 2-phenyl-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)acetate (200 mg, 0.49 mmol) was treated with LiOH-H2O (83 mg, 1.97 mmol) in MeOH (10 mL) and H2O (2 mL) for 2 h at room temperature. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC to give compound 131 (120 mg, 62% yield) as a white solid. The racemic product was separated by preparative chiral SFC A to give the enantiomers compound 131-E1 (35 mg) and compound 131-E2 (39 mg) as white solids.

[0787] Compound 131-E1 LC / MS ESI 408 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.58-7.55(m,2H),7.44-7.41(m,3H),7.12(d,J=7.2Hz,1H),6.35(d,J=7.2Hz,1H),4.49(s,1H),3.71-3.62(m,1H), 3.41-3.36(m,3H),3.02-2.95(m,1H),2.72-2.66(m,3H),2.50(t,J=7.2Hz,2H),2.41-2.11(m,2H),1.92-1.84(m,2H),1.69-1.25(m,9H). Chiral SFC A (40% MeOH): ee100%, Rt=2.04min.

[0788] Compound 131-E2 LC / MS ESI 408 (M+H)+ 1H NMR (400MHz, MeOD) δ7.47-7.44(m,2H),7.34-7.31(m,3H),7.00(d,J=7.2Hz,1H),6.22(d,J=7.2Hz,1H),4.39(s,1H),3.39-3.26( m,3H),2.98-2.78(m,3H),2.58(t,J=6.4Hz,2H),2.38(t,J=7.6Hz,2H),2.28-2.01(m,2H),1.78-1.74(m,2H),1.60-1.15(m,9H). Chiral SFC A (40% MeOH): ee 100%, Rt=3.86 min.

[0789] Example 32: Preparation of 2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)-2-phenylacetic acid (compounds 132-E1 and 132-E2)

[0790] Step 1: 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0791]

[0792] I₂ (202 mg, 1.09 mmol) was added to a mixture of (4-bromobutoxy)methyl)benzene (9.45 g, 38.87 mmol) and Mg (1.89 g, 77.74 mmol) contained in Et₂O (20 mL). 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) contained in 30 mL of Et₂O. The reaction was stirred overnight at room temperature, then stopped with an aqueous solution of NH₄Cl (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 5:1 to 2:1) to give the desired product, tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate (1.7 g), as a yellow oil. Yield 38% (ESI 294(M+H-56)). + ).

[0793] Step 2: tert-butyl 3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate

[0794]

[0795] A mixture of tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate (1.7 g, 4.86 mmol) and BAST (10.76 g, 48.6 mmol) in DCM (30 mL) was stirred for 24 hours at 40 °C. The reaction mixture was diluted with MeOH (2 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 20:1 to 10:1) to give the desired product, tert-butyl 3-(4-(benzyloxy)butyl)-3-fluoropyrrolidine-1-carboxylate (1.1 g), as a pale yellow oil. Yield: 64% (ESI 296).

[0796] (M+H-56) + ).

[0797] Step 3: tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate

[0798]

[0799] Under hydrogen atmosphere and at 45°C, 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 EtOAc (100 mL) was stirred overnight. The mixture was filtered and concentrated under vacuum to give the desired product, tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate (780 mg), as a pale yellow oil. Yield 95% (ESI 206(M+H-56)). + ).

[0800] Step 4: tert-butyl 3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate

[0801]

[0802] I₂ (835 mg, 3.29 mmol) was added to a solution of triphenylphosphine (1.58 g, 6.04 mmol) and imidazole (411 mg, 6.04 mmol) in DCM (40 mL) at 5 °C. The reaction mixture was stirred at 5 °C for 15 min, and then a solution of tert-butyl 3-fluoro-3-(4-hydroxybutyl)pyrrolidine-1-carboxylate (780 mg, 2.99 mmol) in DCM (15 mL) was added. The reaction mixture was stirred at 5 °C for 1 h, then concentrated under vacuum at 15 °C, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 20:1 to 10:1) to give the desired product, tert-butyl 3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate (700 mg), as a pale yellow oil. Yield 63% (ESI 316(M+H-56)).+ ).

[0803] Step 5: 3-(5-(1,8-naphthid-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

[0804]

[0805] At 0 °C, LiHMDS (2.82 mL, 1 M, 2.82 mmol) was added to a solution containing tert-butyl 3-fluoro-3-(4-iodobutyl)pyrrolidine-1-carboxylate (700 mg, 1.88 mmol) and 2-methyl-1,8-naphthidine (407 mg, 2.82 mmol) in THF (12 mL). The reaction mixture was stirred at 0 °C for 3 hours, then stopped with saturated ammonium chloride solution (6 mL), diluted with water (15 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-TLC to give the desired product, tert-butyl 3-(5-(1,8-naphthid-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate (350 mg), as a pale yellow solid. Yield 48% (ESI 388(M+H)). + ).

[0806] Step 6: 7-(5-(3-fluoropyrrolidone-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0807]

[0808] Under hydrogen atmosphere and at 45 °C, a mixture of tert-butyl 3-(5-(1,8-naphthid-2-yl)pentyl)-3-fluoropyrrolidine-1-carboxylate (200 mg, 0.516 mmol) and Pd / C (5%, 200 mg) in EtOAc (20 mL) was stirred overnight. The reaction mixture was filtered and concentrated under vacuum. At room temperature, 1,4-dioxane (2 mL) and HCl / dioxane (2 mL, 4 M) were added to the residue. The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under vacuum to give the desired product 7-(5-(3-fluoropyrrolidine-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (140 mg) as a pale yellow solid. Yield 93% (ESI 292(M+H)). + ).

[0809] Step 7: 2-(3-fluoro-3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)pyrrolidine-1-yl)-2-phenylacetic acid (compounds 132-E1 and 132-E2)

[0810]

[0811] A mixture of 7-(5-(3-fluoropyrrolidone-3-yl)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (140 mg, 0.48 mmol), 2-oxoacetic acid (76.5 mg, 0.62 mmol), and phenyl dihydroxyboronic acid (75.6 mg, 0.62 mmol) in MeCN (1.5 mL) was heated for 2 hours at 50 °C. The solvent was removed under vacuum, and the residue was purified by preparative HPLC-A to give compound 132 (90 mg, 44% yield) as a white solid. The racemic product was separated by preparative chiral SFCA to give compounds 132-E1 (41 mg) and 132-E2 (36 mg) as white solids.

[0812] Compound 132-E1 LC / MS ESI 426 (M+H)+ 1 H NMR (500MHz, MeOD) δ7.47-7.45(m,2H),7.31-7.29(m,3H),7.08(d,J=7.5Hz,1H),6.27(d,J=7.5Hz,1H),4.31(d,1H),3.43-3.27(m,4H),3. 08-2.90(m,2H),2.60(t,J=6.0Hz,2H),2.42(t,J=8.5Hz,2H),2.11-1.93(m,2H),1.80-1.63(m,4H),1.57-1.49(m,2H),1.39-1.19(m,4H). Chiral SFC A (40% MeOH): ee100%, Rt=2.45min.

[0813] Compound 132-E2 LC / MS ESI 426 (M+H)+ 1 H NMR(500MHz,MeOD)δ7.59-7.57(m,2H),7.42-7.38(m,3H),7.22(d,J=8.0H z,1H),6.40(d,J=7.5Hz,1H),4.33(d,1H),3.46-3.30(m,4H),3.16-2.93( m,2H),2.72(t,J=6.0Hz,2H),2.55(t,J=7.5Hz,2H),2.25-2.05(m,2H),1. 91-1.87(m,2H),1.85-1.73(m,2H),1.68-1.62(m,2H),1.48-1.31(m,4H). Chiral SFC A (40% MeOH): ee 98%, Rt = 3.92, 4.42 min.

[0814] Example 33: Preparation of 2-(4-isopropoxypyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 133)

[0815] Step 1: 3-Bromo-4-isopropoxypyridine

[0816]

[0817] At 0 °C, NaH (60%, 1.25 g, 31.2 mmol) was added to a solution containing i-PrOH (1.87 g, 31.2 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 1 hour, and 3-bromo-4-chloropyridine (2 g, 10.4 mmol) was added. The reaction was stirred overnight at 80 °C, then cooled to room temperature, diluted with H₂O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 5:1) to give the desired product, 3-bromo-4-isopropoxypyridine (1.7 g), as a colorless oil. Yield 76% (ESI 216.0 (M+H)). + ).

[0818] Step 2: 4-Isopropoxypyridine-3-yldihydroxyboronic acid

[0819]

[0820] Under Ar conditions at -78°C, n-BuLi (2.5 M in hexane, 2.8 mL) was added to a solution of 3-bromo-4-isopropoxypyridine (1 g, 4.63 mmol) in anhydrous THF (20 mL). The reaction was stirred at -78°C for 1 hour, followed by the addition of trimethyl borate (722 mg, 6.95 mmol). The reaction was stirred overnight at room temperature, then stopped with MeOH (5 mL), concentrated under vacuum, and the residue was used directly in the next step.

[0821] Step 3: 2-(4-isopropoxypyridin-3-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 133)

[0822]

[0823] The residue was diluted with MeCN (10 mL), and (R)-7-(4-(pyrrolidine-3-yloxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine (150 mg, 0.54 mmol) and glyoxylic acid (50% in water, 161 mg, 1.08 mmol) were added. The reaction was stirred under reflux for 15 hours. The solvent was removed under vacuum, and the residue was purified by preparative-HPLC A (30 to 65% MeCN) to give compound 133 (20 mg) as a white solid.

[0824] Compound 133 LC / MS ESI 469 (M+H) +1 H NMR(400MHz,MeOD)δ8.56(s,1H),8.40(d,J=6Hz,1H),7.19-7.14(m,2H),6.38(d,J=7.2Hz,1H),4.89-4.86(m,2H),4.2 5-4.19(m,1H),3.48-3.30(m,8H),2.71(t,J=6.4Hz,2H),2.55(t,J=7.6Hz,2H),2.25-1.88(m,4H),1.71-1.38(m,10H).

[0825] Other examples

[0826] Compounds 29 to 128 and 134 to 201 were prepared using the general procedure based on the method used to prepare compounds 1 to 28 and 129 to 133.

[0827] 2-(4-((4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)acetic acid (compound 29)

[0828]

[0829] Compound 29 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.18 min, ESI 387.2 (M+H) + . 1H NMR(500MHz,MeOD)δ7.13(d,J=7.3Hz,1H),6.34(d,J=7.3Hz,1H),3.50-3.48(m,4H) ,3.38(dd,J=14.9,9.3Hz,2H),2.93(d,J=11.5Hz,2H),2.85(t,J=11.8Hz,2H),2.71( t,J=6.2Hz,2H),2.45(d,J=7.0Hz,2H),2.28(d,J=7.0Hz,2H),2.01-1.98(m,4H),1.6 5-1.62(m,3H),1.73-1.56(m,3H),1.52-1.40(m,2H),1.33(dd,J=22.6,10.5Hz,2H).

[0830] 2-(2-oxo-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)acetate (compound 30)

[0831]

[0832] Compound 30 LC / MS D: 100% purity, UV = 214 nm, Rt = 1.427 min, ESI 415.1(M+H)+. 1 HNMR(400MHz,DMSO-d6)δ8.18(0.73H,HCOOH),7.03(d,J=7.6Hz,1H),6.41(s,1 H),6.23(d,J=7.2Hz,1H),4.36-4.33(m,1H),4.08-4.03(m,1H),3.92-3.78(m, 2H),3.39-3.15(m,5H),2.98-2.92(m,1H),2.62-2.59(m,2H),2.50-2.23(m,5H ),1.88-1.85(m,2H),1.76-1.72(m,3H),1.68-1.59(m,2H),1.13-0.96(m,2H).

[0833] 2-(2-oxo-4-((2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)carbamoyl)piperidin-1-yl)acetate (compound 31)

[0834]

[0835] Compound 31 LC / MS D: 100% purity, UV = 214 nm, Rt = 1.290 min, ESI 361.0(M+H)+. 1HNMR(400MHz,DMSO-d6)δ8.18(1H,HCOOH),7.98-7.95(m,1H),7.04(d,J=7.2Hz,1H),6.41(s,1H),6.24(d,J=7.6Hz,1H),4.12- 4.07(m,1H),3.78-3.74(m,1H),3.33-3.24(m,5H),2.62-2.53(m,6H),2.32-2.29(m,2H),1.90-1.87(m,1H),1.77-1.72(m,3H).

[0836] 2-(2-oxo-4-((2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)carbamoyl)piperazin-1-yl)acetic acid (compound 32)

[0837]

[0838] Compound 32 LC / MS D: 97% purity, UV = 214 nm, Rt = 0.838 min, ESI 362.1(M+H)+. 1 HNMR (400MHz, DMSO-d6) δ7.06(d,J=7.2Hz,1H),6.72(t,J=5.2Hz,1H),6.49(s,1H),6.26(d,J=7.2Hz,1H),4.02(s ,2H),3.93(s,2H),3.56-3.53(m,2H),3.36-3.33(m,2H),3.29-3.24(m,4H),2.62-2.57(m,4H),1.78-1.72(m,2H).

[0839] 2-(2-oxo-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid formate (compound 33)

[0840]

[0841] Compound 33 LC / MS D: 100% purity, UV = 214 nm, Rt = 1.353 min, ESI 375.1(M+H)+. 1HNMR(400MHz,DMSO-d6)δ8.14(0.27H,HCOOH),7.97-7.94(m,1H),7.37(s,1H),7.26(d,J=6.8Hz,1H),6.40(d,J=7.2Hz,1H),3.97 -3.86(m,2H),3.39-3.29(m,4H),3.10-3.04(m,2H),2.66-2.63(m,3H),2.50-2.48(m,2H),2.38-2.34(m,2H),1.90-1.68(m,6H).

[0842] 2-(2-oxo-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperazin-1-yl)acetic acid (compound 34)

[0843]

[0844] Compound B, 34 LC / MS: 96% purity, UV = 214 nm, Rt = 1.285 min, ESI 376.3(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.48(d,J=7.6Hz,1H),6.53(d,J=7.6Hz,1H),4.12(s,2H),3.94(s,2H),3.76-3.74(m,2H),3.52-3.4 9(m,2H),3.46-3.43(m,2H),3.30-3.28(m,2H),2.79-2.75(m,2H),2.70-2.66(m,2H),1.93-1.90(m,2H),1.79-1.75(m,2H).

[0845] 2-(2-oxo-4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)piperidin-1-yl)acetic acid (compound 35)

[0846]

[0847] Compound 35 LC / MS C: 98% purity, UV = 214 nm, Rt = 1.378 min, ESI 389.1(M+H)+. 1HNMR(400MHz,DMSO-d6)δ8.18(0.37H,HCOOH),7.89-7.86(m,1H),7.07(d,J=7.2Hz,1H), 6.87(s,1H),6.27(d,J=7.2Hz,1H),4.01-3.97(m,1H),3.85-3.80(m,1H),3.32-3.29(m, 2H),3.27-3.20(m,2H),3.08-3.03(m,2H),2.64-2.59(m,3H),2.46-2.38(m,2H),2.38-2 .31(m,2H),1.91-1.87(m,1H),1.80-1.73(m,3H),1.58-1.53(m,2H),1.43-1.37(m,2H).

[0848] 2-(2-oxo-4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)piperazin-1-yl)acetic acid (compound 36)

[0849]

[0850] Compound 36 LC / MS D: 100% purity, UV = 214 nm, Rt = 0.999 min, ESI 390.3(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.59(d,J=7.2Hz,1H),6.63(d,J=7.6Hz,1H),4.17(s,2H),4.08(s,2H),3.71-3.68(m,2H),3.52-3.48(m ,4H),3.24-3.20(m,2H),2.84-2.80(m,2H),2.75-2.71(m,2H),1.97-1.94(m,2H),1.70(d,J=7.6Hz,2H),1.58(d,J=7.6Hz,2H).

[0851] 2-(4-((2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)carbamoyl)piperidin-1-yl)acetic acid (compound 37)

[0852]

[0853] Compound 37 LC / MS A: 96.8% purity, UV = 214 nm, Rt = 1.31 min, ESI 347.2(M+H)+. 1HNMR(400MHz,CD3OD)δ7.17(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H),3.62-3.57(m,4H),3.4 8-3.36(m,4H),3.03-2.96(m,2H),2.73-2.69(m,4H),2.50-2.44(m,1H),2.02-1.86(m,6H).

[0854] 2-(4-((2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)carbamoyl)piperazin-1-yl)acetic acid (compound 38)

[0855]

[0856] Compound 38 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.28 min, ESI 348.3(M+H)+. 1 H NMR(500MHz,MeOD)δ7.25(d,J=7.3Hz,1H),6.44(d,J=7.3Hz,1H),3.59-3.57(m, 4H),3.49-3.38(m,6H),3.04-3.03(m,4H),2.77-2.74(m,4H),1.93-1.88(m,2H).

[0857] 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)piperidin-1-yl)acetic acid (compound 39)

[0858]

[0859] Compound 39 LC / MS A: 97.4% purity, UV = 214 nm, Rt = 1.71 min, ESI 375.3(M+H)+. 1 HNMR (400MHz, CD3OD) δ7.03(d,J=7.6Hz,1H),6.26(d,J=7.6Hz,1H),3.52-3.45(m,4H),3.27(t,J=5.2Hz,2H),3.09( t,J=6.4Hz,2H),2.92-2.85(m,2H),2.59(t,J=6.4Hz,2H),2.44-2.35(m,3H),1.92-1.74(m,6H),1.56-1.39(m,4H).

[0860] 2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)piperazin-1-yl)acetic acid (compound 40)

[0861]

[0862] Compound B: 40 LC / MS: 100% purity, UV = 214 nm, Rt = 0.82 min, ESI 376.0 (M+H)+. 1 HNMR (400MHz, MeOD) δ7.32(d,J=7.3Hz,1H),6.45(d,J=7.3Hz,1H),3.54(t,J=4.Hz,4H),3.42(t,J=5.6Hz,2H),3.37(s,2H),3. 21(t,J=6.6Hz,2H),2.98(t,J=5.2Hz,2H),2.75(t,J=6.2Hz,2H),2.61(t,J=7.6Hz,2H),1.98-1.83(m,2H),1.75-1.48(m,4H).

[0863] (R)-2-(3-(hydroxymethyl)-2-oxo-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperazin-1-yl)acetic acid (compound 41)

[0864]

[0865] Compound 41 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.01 min, ESI 406.2(M+H)+. 1 HNMR(400MHz,CD3OD)δ7.35(d,J=7.2Hz,1H),6.42(d,J=7.2Hz,1H),4.50(brs,1H),4.40(m,1H),4.00-3.95(m,2H) ,3.83-3.79(m,1H),3.66-3.51(m,2H),3.36-3.30(m,4H),3.15-3.07(m,2H),2.68-2.49(m,4H),1.85-1.63(m,4H).

[0866] 2-(2,2-Dimethyl-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperazin-1-yl)acetic acid (compound 42)

[0867]

[0868] Compound 42 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.12 min, ESI 390.2(M+H)+. 1HNMR (400MHz, CD3OD) δ7.24(d,J=7.6Hz,1H),6.44(d,J=7.6Hz,1H),3.67-3.65(m,2H),3.50(s,2H),3.46(s,2H ),3.43-3.40(m,2H),3.24-3.19(m,4H),2.75-2.72(m,2H),2.62-2.57(m,2H),1.92-1.83(m,4H),1.30(s,6H).

[0869] 2-(3-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)acetic acid (compound 43)

[0870]

[0871] Compound 43 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.12 min, ESI 387(M+H)+. 1 H NMR(500MHz,MeOD)δ7.19(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),3.98(s,2H),3.88(d,J=12.2Hz,2H),3.52(s,2H),3.43 -3.34(m,4H),3.22(t,J=6.9Hz,2H),2.73(t,J=6.3Hz,2H),2.57(t,J=7.6Hz,2H),2.24-2.12(m,2H),1.98-1.79(m,6H).

[0872] 2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)propionic acid (enantiomers 44-E1 and 44-E2)

[0873]

[0874] Compound 44-E1 LC / MS A: 95% purity, UV = 214 nm, Rt = 1.377 min, ESI 374(M+H)+. 1HNMR(500MHz,MeOD)δ7.16(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),3.97-3.86(m,1H),3.56-3.37(m,5H),3.14-3.04(m,2H),2. 71(t,J=6.2Hz,2H),2.56(t,J=7.6Hz,2H),2.23(t,J=7.5Hz,2H),2.23-2.08(m,2H),1.98-1.78(m,6H),1.51(d,J=7.0Hz,3H). Chiral SFC A (45% MeOH): ee 100%, Rt=4.06 min.

[0875] Compound 44-E2 LC / MS A: 95% purity, UV = 214 nm, Rt = 1.386 min, ESI 374(M+H)+. 1 HNMR(500MHz,MeOD)δ7.16(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),3.97-3.86(m,1H),3.56-3.37(m,5H),3.14-3.04(m,2H),2. 71(t,J=6.2Hz,2H),2.56(t,J=7.6Hz,2H),2.23(t,J=7.5Hz,2H),2.23-2.08(m,2H),1.98-1.78(m,6H),1.51(d,J=7.0Hz,3H). Chiral SFC A (45% MeOH): ee 100%, Rt = 8.73 min.

[0876] 2-Phenyl-2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutan-1-yl)acetic acid (enantiomers 45-E1 and 45-E2)

[0877]

[0878] Compound 45-E1 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.44 min, ESI 409.4(M+H)+. 1HNMR (400MHz, MeOD) δ7.41-7.24(m,5H),7.07(d,J=7.3Hz,1H),6.28(d,J=7.2Hz,1H),4.48(s,1H),4.46–4.40(m,1H),4.23(t,J=8. 8Hz,1H),3.72-3.70(m,3H),3.28-3.26(m,2H),2.59(t,J=6.2Hz,2H),2.45(t,J=7.2Hz,2H),2.14-2.10(m,2H),1.90-1.65(m,4H). Chiral SFC A (45% MeOH): ee100%, Rt=1.65min

[0879] Compound 45-E2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.44 min, ESI 409.4(M+H)+. 1 HNMR (400MHz, MeOD) δ7.41–7.24(m,5H),7.07(d,J=7.3Hz,1H),6.28(d,J=7.2Hz,1H),4.48(s,1H),4.46-4.40(m,1H),4.23(t,J=8. 8Hz,1H),3.72-3.70(m,3H),3.28-3.26(m,2H),2.59(t,J=6.2Hz,2H),2.45(t,J=7.2Hz,2H),2.14-2.10(m,2H),1.90-1.65(m,4H). Chiral SFC A (45% MeOH): ee100%, Rt=2.72min

[0880] 2-Phenyl-2-(3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)azacyclobutan-1-yl)acetic acid (enantiomers 46-E1 and 46-E2)

[0881]

[0882] Compound 46-E1 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.49 min, ESI 423.4(M+H)+. 1HNMR(400MHz,CD3OD)δ7.51-7.48(m,2H),7.44-7.41(m,3H),7.18(d,J=7.6Hz,1H),6.3 8(d,J=7.2Hz,1H),4.70(s,1H),4.20-4.18(m,1H),4.08-4.03(m,1H),3.99-3.94(m,1H ),3.81-3.76(m,1H),3.50-3.46(m,1H),3.39-3.36(m,2H),3.25-3.21(m,1H),2.72-2. 69(m,2H),2.57-2.53(m,2H),1.90-1.84(m,2H),1.68-1.62(m,2H),1.57-1.52(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt=1.62 min.

[0883] Compound 46-E2 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.49 min, ESI 423.3(M+H)+. 1 HNMR(400MHz,CD3OD)δ7.51-7.48(m,2H),7.44-7.41(m,3H),7.18(d,J=7.6Hz,1H),6.3 8(d,J=7.2Hz,1H),4.70(s,1H),4.20-4.18(m,1H),4.08-4.03(m,1H),3.99-3.94(m,1H ),3.81-3.76(m,1H),3.50-3.46(m,1H),3.39-3.36(m,2H),3.25-3.21(m,1H),2.72-2. 69(m,2H),2.57-2.53(m,2H),1.90-1.84(m,2H),1.68-1.62(m,2H),1.57-1.52(m,2H). Chiral SFC A (45% MeOH): ee 99%, Rt = 3.17 min.

[0884] 2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)azacyclobutane-1-yl)propionic acid (compound 47)

[0885]

[0886] Compound 47 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.37 min, ESI 347.4(M+H)+. 1H NMR(400MHz,MeOD)δ7.06(d,J=7.1Hz,1H),6.28(d,J=7.2Hz,1H),4.50-4.33(m,1H),4.22(s,1H),4.04(s,1H),3.89 -3.39(m,3H),3.36-3.25(m,2H),2.67-2.38(m,4H),2.13(t,J=7.3Hz,2H),1.91-1.70(m,4H),1.24(d,J=6.8Hz,3H).

[0887] 2-Phenyl-2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanone)piperazin-1-yl)acetic acid (enantiomers 48-E1 and 48-E2)

[0888]

[0889] Compound 48-E1 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.46 min, ESI 437.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.54(d,J=7.0Hz,2H),7.39-7.29(m,4H),6.48(d,J=7.3Hz,1H),3.88(s,1H) ,3.76-3.46(m,4H),3.43-3.37(m,2H),2.77-2.36(m,10H),1.96-1.79(m,2H),1.70-1.59(m,4H). Chiral SFC A (40% MeOH): ee 100%, Rt = 3.55 min.

[0890] Compound 48-E2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.46 min, ESI 437.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.54(d,J=7.0Hz,2H),7.39-7.29(m,4H),6.48(d,J=7.3Hz,1H),3.88(s,1H) ,3.76-3.46(m,4H),3.43-3.37(m,2H),2.77-2.36(m,10H),1.96-1.79(m,2H),1.70-1.59(m,4H). Chiral SFC A (40% MeOH): ee 95%, Rt=4.31 min.

[0891] 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)-2-phenylacetic acid (enantiomers 49-E1 and 49-E2)

[0892]

[0893] Compound 49-E1 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.53 min, ESI 437.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.46(d,J=7.3Hz,1H),7.42-7.28(m,5H),6.51(d,J=7.3Hz,1H),6.30(s,1H),3.85-3 .68(m,1H),3.59-3.37(m,3H),3.08-2.94(m,2H),2.91-2.50(m,8H),2.02-1.83(m,2H),1.81-1.50(m,6H). Chiral SFC A (35% MeOH): ee 100%, Rt=3.5 min.

[0894] Compound 49-E2 LC / MS A: 96.8% purity, UV = 214 nm, Rt = 1.53 min, ESI 437.4(M+H)+. 1 H NMR(400MHz,MeOD)δ7.46(d,J=7.3Hz,1H),7.42-7.28(m,5H),6.51(d,J=7.3Hz,1H),6.30(s,1H),3.85-3. 68(m,1H),3.59-3.37(m,3H),3.08-2.94(m,2H),2.91-2.50(m,8H),2.02-1.83(m,2H),1.81-1.50(m,6H). Chiral SFC A (35% MeOH): ee 97%, Rt = 4.48 min.

[0895] 2-(4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)propionic acid (enantiomers 50-E1 and 50-E2)

[0896]

[0897] Compound 50-E1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.203 min, ESI 361.0(M+H)+. 1H NMR (500MHz, CD3OD) δ7.13(d,J=9.0Hz,1H),6.35(d,J=9.5Hz,1H),3.39-3.36(m,2H),3.27-3.25(m, 1H),3.03-2.68(m,9H),2.56-2.51(m,4H),1.89-1.86(m,2H),1.69-1.56(m,4H),1.39-1.34(m,6H). Chiral SFC B (40% MeOH): ee 100%, Rt=1.51 min.

[0898] Compound 50-E2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.203 min, ESI 361.0(M+H)+. 1 H NMR(500MHz,CD3OD)δ7.11(d,J=9.0Hz,3H),6.36(d,J=9.5Hz,2H),3.39-3.36(m,2H),2.88(q,J=6.8Hz, 1H), 2.71-2.49 (m, 11H), 2.34 (t, J = 8.0Hz, 2H), 1.89-1.86 (m, 2H), 1.69-1.56 (m, 4H), 1.39-1.34 (m, 6H). Chiral SFC B (40% MeOH): ee 100%, Rt = 3.47 min.

[0899] 2-(2-oxo-4-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)piperazin-1-yl)propionic acid (enantiomers 51-E1 and 51-E2)

[0900]

[0901] Compound 51-E1 LC / MS A: 97% purity, UV = 214 nm, Rt = 1.45 min, ESI 375.4(M+H)+. 1HNMR(400MHz,MeOD)δ7.42(d,J=7.3Hz,1H),6.48(d,J=7.3Hz,1H),5.01-4.9(m,1H),3.71-3.56(m,1H),3.53-3.34(m,4H),3.23(d,J= 17.1Hz,1H),3.10-3.05(m,9.4Hz,2H),2.90-2.71(m,4H),2.67-2.53(m,2H),1.99-1.86(m,2H),1.78-1.49(m,6H),1.45-1.41(m,3H). Chiral SFC E (45% MeOH): ee 100%, Rt = 3.36 min.

[0902] Compound 51-E2 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.44 min, ESI 375.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.42(d,J=7.3Hz,1H),6.48(d,J=7.3Hz,1H),5.01-4.9(m,1H),3.71-3.56(m,1H),3.53-3.34(m,4H),3.23(d,J= 17.1Hz,1H),3.10-3.05(m,9.4Hz,2H),2.90-2.71(m,4H),2.67-2.53(m,2H),1.99-1.86(m,2H),1.78-1.49(m,6H),1.45-1.41(m,3H). Chiral SFC E (45% MeOH): ee 97%, Rt = 5.29 min.

[0903] 2-Phenyl-2-(3-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)amino)azacyclobutan-1-yl)acetic acid (compound 52)

[0904]

[0905] Compound 52 LC / MS A: 98.2% purity, UV = 214 nm, Rt = 1.55 min, ESI 409.2(M+H)+. 1HNMR(400MHz,MeOD)δ7.49-7.47(m,2H),7.44-7.36(m,3H),7.14(d,J=7.3Hz,1 H),6.37(d,J=7.3Hz,1H),4.49(s,1H),4.21-4.16(m,1H),3.77-3.58(m,4H),3. 42-3.36(m,2H),2.70(t,J=6.3Hz,2H),2.60(t,J=7.2Hz,2H),2.2(t,J=7.6Hz,2 H),1.90-1.85(m,2H),1.69-1.62(m,2H),1.61-1.51(m,2H),1.49-1.34(m,2H).

[0906] 2-Phenylacetyl-2-(4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (enantiomers 53-E1 and 53-E2)

[0907]

[0908] Compound 53-E1 LC / MS A: 94% purity, UV = 214 nm, Rt = 1.56 min, ESI 477.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.58-7.56(m,2H),7.46-7.44(m,3H),7.14(d,J=7.2Hz,1H),6.36-6.33(m,1H),4.57-4.40(m,2H),4.07-3.69(m,2H ),3.46-3.35(m,2H),3.16-2.79(m,5H),2.71(t,J=6.1Hz,2H),2.58(m,1H),2.45(t,J=6.6Hz,2H),2.17-1.59(m,9H),1.26-1.00(m,2H). Chiral SFC D (25% MeOH): ee 96%, Rt = 2.75 min.

[0909] Compound 53-E2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.56 min, ESI 477.4(M+H)+. 1HNMR(400MHz,MeOD)δ7.58-7.56(m,2H),7.46-7.44(m,3H),7.14(d,J=7.2Hz,1H),6.36-6.33(m,1H),4.57-4.40(m,2H),4.07-3.69(m,2H ),3.46-3.35(m,2H),3.16-2.79(m,5H),2.71(t,J=6.1Hz,2H),2.58(m,1H),2.45(t,J=6.6Hz,2H),2.17-1.59(m,9H),1.26-1.00(m,2H). Chiral SFC D (25% MeOH): ee 100%, Rt = 3.73 min.

[0910] 2-Phenylacetyl-2-(4-((4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)acetic acid (enantiomers 54-E1 and 54-E2)

[0911]

[0912] Compound 54-E1 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.59 min, ESI 449.4(M+H)+. 1 H NMR (400MHz, CD3OD) δ7.59-7.55(m,2H),7.45-7.42(m,3H),7.15(d,J=7.6Hz,1H),6.36 (d,J=7.2Hz,1H),4.35(s,1H),3.69-3.65(brs,1H),3.38-3.35(m,2H),3.09-3.06(m,2 H), 2.98-2.95(m,1H), 2.89-2.83(m,1H), 2.71-2.67(m,3H), 2.48-2.40(m,1H), 2.37-2.35(m,2H), 2.20-2.10(m,2H), 2.00-1.97(m,1H), 1.89-1.71(m,8H), 1.60-1.41(m,1H). Chiral SFC A (40% MeOH): ee 100%, Rt = 2.51 min.

[0913] Compound 54-E2 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.59 min, ESI 449.4(M+H)+. 1H NMR (400MHz, CD3OD) δ7.59-7.55(m,2H),7.44-7.41(m,3H),7.14(d,J=7.6Hz,1H),6.37 (d,J=7.6Hz,1H),4.35(s,1H),3.70-3.69(brs,1H),3.38-3.35(m,2H),3.09-3.06(m,2 H), 2.98-2.95(m,1H), 2.89-2.83(m,1H), 2.71-2.68(m,3H), 2.47-2.40(m,1H), 2.37-2.35(m,2H), 2.19-2.19(m,2H), 2.02-1.97(m,1H), 1.90-1.71(m,8H), 1.59-1.41(m,1H). Chiral SFC A (40% MeOH): ee 97%, Rt = 3.75 min.

[0914] 2-Phenyl-2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (enantiomers 55-E1 and 55-E2)

[0915]

[0916] Compound 55-E1 LC / MS A: 97.7% purity, UV = 214 nm, Rt = 1.0 min, ESI 435.2(M+H)+. 1 H NMR(400MHz,CD3OD)δ7.42-7.40(m,2H),7.35-7.32(m,3H),7.04(d,J=6.0Hz,1H),6 .26(dd,J=7.2Hz,2.4Hz,1H),4.59(s,1H),4.52-4.50(m,1H),4.24-4.22(m,1H),4.1 1-4.07(m,1H),4.00-3.93(m,1H),3.83-3.76(m,2H),3.59-3.56(m,1H),3.28-3.26 (m,2H),3.06-3.01(m,1H),2.68-2.56(m,4H),1.77-1.75(m,4H),1.54-1.45(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt = 2.39 min.

[0917] Compound 55-E2 LC / MS A: 96.7% purity, UV = 214 nm, Rt = 1.0 min, ESI 435.2(M+H)+. 1H NMR(400MHz,CD3OD)δ7.41-7.40(m,2H),7.34-7.32(m,3H),7.04(d,J=6.0Hz,1H),6 .26(dd,J=7.2Hz,1.6Hz,1H),4.57(s,1H),4.53-4.50(m,1H),4.23-4.21(m,1H),4.1 0-4.06(m,1H),3.97-3.90(m,1H),3.83-3.75(m,2H),3.59-3.54(m,1H),3.28-3.26 (m,2H),3.06-3.01(m,1H),2.69-2.56(m,4H),1.77-1.75(m,4H),1.54-1.45(m,2H). Chiral SFC A (40% MeOH): ee 100%, Rt = 4.37 min.

[0918] 2-Phenyl-2-(3-((4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-yl)methyl)azacyclobutan-1-yl)acetic acid (enantiomers 56-E1 and 56-E2)

[0919]

[0920] Compound 56-E1 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.53 min, ESI 435.4(M+H)+. 1 HNMR(400MHz,MeOD)δ7.55-7.33(m,5H),7.12(d,J=7.3Hz,1H),6.32(d,J=7.3Hz,1H),4 .59(s,1H),4.17-4.13(m,1H),3.70(d,J=8.1Hz,2H),3.53.57-3.39(m,1H),3.44-3.34 (m,2H),3.02-2.98(m,1H),2.84(d,J=11.3Hz,2H),2.74-2.61(m,4H),2.42(d,J=6.8Hz ,2H),2.03(t,J=11.7Hz,2H),1.93-1.80(m,2H),1.67-1.61(m,3H),1.32-1.26(m,2H). Chiral SFCA (45% MeOH): ee51%, Rt=2.89min.

[0921] Compound 56-E2 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.53 min, ESI 435.4(M+H)+. 1HNMR(400MHz,MeOD)δ7.55-7.33(m,5H),7.12(d,J=7.3Hz,1H),6.32(d,J=7.3Hz,1H),4 .59(s,1H),4.17-4.13(m,1H),3.70(d,J=8.1Hz,2H),3.53.57-3.39(m,1H),3.44-3.34 (m,2H),3.02-2.98(m,1H),2.84(d,J=11.3Hz,2H),2.74-2.61(m,4H),2.42(d,J=6.8Hz ,2H),2.03(t,J=11.7Hz,2H),1.93-1.80(m,2H),1.67-1.61(m,3H),1.32-1.26(m,2H). Chiral SFCA (45% MeOH): ee100%, Rt=3.84min.

[0922] 2-Phenylacetyl-2-((S)-3-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)pyrrolidone-1-yl)acetic acid (compound 57)

[0923]

[0924] Compound 57 / MS B: 100% purity, UV = 214 nm, Rt = 1.22 min, ESI 423.3(M+H)+. 1 ¹H NMR (400MHz, CD₃OD) δ 8.49 (s, 1.6H, formate), 7.58–7.43 (m, 6H), 6.52 (d, J = 7.2Hz, 1H), 4.70 (s, 0.6H), 4.56 (s, 0.4H), 3.65–3.56 (m, 1H), 3.47–3.39 (m, 3H), 3.29–3.01 (m, 5H), 2.77 (t, J = 6Hz, 2H), 2.67 (t, J = 6Hz, 2H), 2.36–2.10 (m, 2H), 1.95–1.82 (m, 4H).

[0925] 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (enantiomers 58-E1 and 58-E2)

[0926]

[0927] Compound 58-E1 LC / MS B: 97% purity, UV = 214 nm, Rt = 1.24 min, ESI 449.3(M+H)+.1 HNMR(400MHz,MeOD)δ7.62-7.59(m,2H),7.45-7.44(m,3H),7.15(d,J=7.4H z,1H),6.37(t,J=7.0Hz,1H),4.65-4.61(m,2H),4.06(d,J=13.3Hz,1H),3.7 3-3.57(m,2H),3.38(t,J=5.6Hz,3H),3.25-3.14(m,3H),2.75-2.68(m,4H), 2.41-2.35(m,1H),2.22-2.10(m,1H),1.96-1.84(m,4H),1.64-1.58(m,2H). Chiral SFC B (35% MeOH): ee 98%, Rt = 2.15 min.

[0928] Compound 58-E2 LC / MS B: 93% purity, UV = 214 nm, Rt = 1.24 min, ESI 449.3(M+H)+. 1 HNMR(400MHz,MeOD)δ7.60-7.58(m,2H),7.45-7.43(m,3H),7.14(d,J=7.2Hz,1H), 6.37(dd,J1=7.4Hz,3.1Hz,1H),4.65-4.58(m,2H),4.08(d,J=13.0Hz,1H),3.72-3. 60 (m, 2H), 3.38 (t, J = 5.6 Hz, 3H), 3.25-3.18 (m, 2H), 3.04-2.98 (m, 1H), 2.76-2.68 (m, 4H), 2.36-2.27 (m, 1H), 2.17-2.06 (m, 1H), 1.95-1.86 (m, 4H), 1.70-1.54 (m, 2H). Chiral SFC B (35% MeOH): ee 99%, Rt = 3.15 min.

[0929] 2-(3-fluoro-3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (compound 59)

[0930]

[0931] Compound 59 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.05 min, ESI 391 (M+H) + . 1H NMR(400MHz,MeOD)δ7.22(d,J=7.3Hz,1H),6.38(d,J=7.3Hz,1H),4.49-4.35(m,1H),4.32-4.10(m,2H),4.03-3.86(m,2H),3.67(m,1H),3 .51-3.34(m,4H),3.05(t,J=15.4Hz,1H),2.74-2.68(m,3H),2.57-2.41(m,2H),1.98-1.85(m,3H),1.91-1.81(m,2H),1.33-1.06(m,2H).

[0932] 2-(3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)azacyclobutane-1-yl)acetic acid (compound 60)

[0933]

[0934] Compound B, 60 LC / MS: 100% purity, UV = 214 nm, Rt = 1.06 min. ESI 347.1 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ8.47(s,1H),7.45(d,J=7.3Hz,1H),6.53(d,J=7.3Hz,1H),4.36-4.27(m,4H),3.82(s,2H),3.64-3.54(m,1H),3. 50-3.43(m,2H),3.30(t,J=6.8Hz,2H),2.82-2.76(m,2H),2.73-2.65(m,2H),1.98-1.89(m,2H),1.78-1.66(m,2H),1.65-1.54(m,2H).

[0935] 2-(3-Fluoro-3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)azacyclobutan-1-yl)acetic acid (compound 61)

[0936]

[0937] Compound 61 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 365.2 (M+H) + . 1H NMR (500MHz, methanol-d4) δ7.20(d,J=7.3Hz,1H),6.41(d,J=7.2Hz,1H),3.92(dd,J=20.0,10.4Hz,2H),3.76(dd,J=20.6,10.3Hz,2 H),3.44-3.38(m,2H),3.36-3.28(m,4H),2.73(t,J=6.3Hz,2H),2.57(t,J=7.6Hz,2H),1.92-1.85(m,2H),1.71-1.55(m,4H).

[0938] 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (enantiomers 62-E1 and 62-E2)

[0939]

[0940] Compound 62-E1 LC / MS A: 100% purity, UV = 214 nm, R t =1.54min, ESI 387.3(M+H) + . 1 HNMR (500MHz, methanol-d4) δ7.16(d,J=7.3Hz,1H),6.37(d,J=7.2Hz,1H),4.53-4.45(m,1H),4.02-3.94(m,1H),3.85-3.65(m,4H),3.58-3.36(m,5H), 3.14-3.06(m,1H),2.74-2.61(m,3H),2.45(dd,J=34.6,7.4Hz,3H),2.1 8-2.04(m,1H),2.01-1.85(m,3H),1.79-1.66(m,2H),1.26-1.11(m,2H). Chiral SFC B (40% MeOH): ee 95%, Rt = 1.24 min.

[0941] Compound 62-E2 LC / MS A: 100% purity, UV = 214 nm, R t =1.54min, ESI 387.3(M+H) + . 1HNMR (500MHz, methanol-d4) δ7.16(d,J=7.3Hz,1H),6.37(d,J=7.1Hz,1H),4.54-4.45(m,1H),4.02-3.95(m,1H),3.86-3.63(m,4H),3.60-3.36(m,5H), 3.10(td,J=13.3,2.7Hz,1H),2.76-2.59(m,3H),2.51-2.34(m,3H),2.2 0-2.06(m,1H),2.02-1.83(m,3H),1.80-1.66(m,2H),1.28-1.08(m,2H). Chiral SFC B (40% MeOH): ee 96%, Rt = 2.45 min

[0942] (R)-2-(3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)pyrrolidine-1-yl)acetic acid (compound 63)

[0943]

[0944] Compound 63 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.43 min, ESI 361.4 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.24(d,J=7.3Hz,1H),6.41(d,J=7.3Hz,1H),3.62(d,J=15.8Hz,1H),3.43-3.13(m,7H),3.07-2.97(m,3H),2.74(t,J=6. 3Hz,2H),2.66-2.60(m,1H),2.56-2.47(m,1H),2.31-2.23(m,1H),2.09 -2.01(m,1H),1.94-1.87(m,2H),1.81-1.71(m,1H),1.69-1.50(m,3H).

[0945] (S)-2-(3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)pyrrolidone-1-yl)acetic acid (compound 64)

[0946]

[0947] Compound 64 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.43 min, ESI 361.4 (M+H) + . 1H NMR (500MHz, methanol-d4) δ7.26(d,J=7.2Hz,1H),6.42(d,J=7.3Hz,1H),3.69(d,J=15 .9Hz,1H),3.52-3.38(m,4H),3.38-3.28(m,2H),3.22-3.13(m,1H),3.10-3.01( m,3H),2.77-2.71(m,2H),2.68-2.61(m,1H),2.57-2.48(m,1H),2.36-2.25(m,1 H),2.12-2.03(m,1H),1.96-1.86(m,2H),1.83-1.71(m,1H),1.69-1.51(m,3H).

[0948] 2-(3-fluoro-3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (compound 65)

[0949]

[0950] Compound 65 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.45 min, ESI 405.2 (M+H) + . 1 H NMR(500MHz,DMSO-d6)δ7.23(d,J=7.3Hz,1H),7.12(s,1H),6.36(d,J=7.3Hz ,1H),4.29(d,J=12.8Hz,1H),3.98(d,J=13.4Hz,1H),3.39-3.11(m,6H),3.0 5-2.91(m,2H),2.70-2.52(m,5H),2.44(d,J=7.2Hz,2H),2.21-2.04(m,1H), 1.99-1.87(m,1H),1.81-1.72(m,2H),1.67-1.55(m,2H),1.18-0.96(m,2H).

[0951] 2-(3-Fluoro-3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)pyrrolidone-1-yl)acetic acid (compound 66)

[0952]

[0953] Compound 66 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.59 min, ESI 379.3 (M+H) + . 1H NMR (500MHz, methanol-d4) δ7.37(d,J=7.3Hz,1H),6.47(d,J=7.3Hz,1H),3.59-3.50(m,2H),3.48-3.40(m,3H),3.38-3.30(m, 1H),3.26-3.05(m,4H),2.79-2.68(m,3H),2.61-2.42(m,2H),2.32-2.19(m,1H),1.95-1.89(m,2H),1.85-1.54(m,4H).

[0954] 2-(4-Fluoro-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (compound 67)

[0955]

[0956] Compound 67 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.59 min, ESI 419.3 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ7.13(d,J=7.3Hz,1H),6.33(d,J=7.3Hz,1H),4.32-4.13(m,2H),3.42-3.25(m,6H),3.08-2.97(m,3H),2.6 8-2.60(m,3H),2.43-2.27(m,4H),2.21-2.08(m,2H),1.94-1.84(m,1H),1.81-1.72(m,2H),1.68-1.59(m,2H),1.19-0.99(m,2H).

[0957] 2-((1R,3s,5S)-3-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-yl)acetic acid (compound 68)

[0958]

[0959] Compound 68 LC / MS B: 100% purity, UV = 214 nm, Rt = 1.05 min, ESI 427.0 (M+H) + . 1¹H NMR (400MHz, methanol-d⁴) δ 5.87 (d, J = 7.3Hz, 1H), 4.93 (d, J = 7.3Hz, 1H), 2.90 (d, J = 13.3Hz, 1H), 2.55–2.39 (m, 3H), 1.98 (s, 2H), 1.73–1.62 (m, 2H), 1.51 (t, J = 12.6Hz, 1H), 1.23–1.13 (m, 2H), 1.07–0.93 (m, 3H), 0.75–0.04 (m, 14H), -0.29–-0.54 (m, 2H).

[0960] 2-(4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)ureido)piperidin-1-yl)acetic acid (compound 69)

[0961]

[0962] Compound 69 LC / MS A: 97% purity, UV = 254 nm, Rt = 1.34 min, ESI 362.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.16(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),3.78-3.68(m,1H),3.55(s,2H),3.53-3.45(m,2H ),3.44-3.37(m,4H),3.13-3.00(m,2H),2.74-2.65(m,4H),2.12-2.03(m,2H),1.93-1.85(m,2H),1.80-1.69(m,2H).

[0963] (R)-2-(3-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)pyrrolidine-1-yl)acetic acid (compound 70)

[0964]

[0965] Compound 70 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.46 min, ESI 347 (M+H) + . 1H NMR (400MHz, MeOD) δ7.19(d,J=7.3Hz,1H),6.41(d,J=7.3Hz,1H),3.66(dd,J=35.1,15.9Hz,2H),3.56-3.31(m ,5),3.32-3.08(m,4H),2.71(t,J=6.2Hz,2H),2.63-2.49(m,2H),2.33(m,1H),2.13(m,1H),1.94-1.77(m,4H). Chiral SFC B (40% MeOH): ee 100%, Rt = 2.12 min.

[0966] (S)-2-(3-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)pyrrolidine-1-yl)acetic acid (compound 71)

[0967]

[0968] Compound 71 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.45 min, ESI 347.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.19(d,J=7.3Hz,1H),6.41(d,J=7.3Hz,1H),3.68(d,J=15.9Hz,1H),3.59(d,J=15.9Hz,1H),3.51-3.43(m,1H), 3.43-3.34(m,4H),3.29-3.11(m,4H),2.76-2.69(m,2H),2.63-2.51(m,2H),2.37-2.26(m,1H),2.18-2.08(m,1H),1.95-1.80(m,4H). Chiral SFC B (40% MeOH): ee 100%, Rt = 1.77 min.

[0969] 2-(1-oxo-2-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)-2,9-diazaspiro[5.5]undecane-9-yl)acetic acid (compound 72)

[0970]

[0971] Compound 72 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.69 min, ESI 401.3 (M+H) + . 1H NMR(500MHz,MeOD)δ7.14(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),3.60(d,J=16.7Hz,4H),3.44-3.35(m,6H), 3.19(s,2H),2.71(t,J=6.2Hz,2H),2.53(t,J=7.7Hz,2H),2.29(s,2H),1.96-1.81(m,8H),1.81-1.69(m,2H).

[0972] 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentanoylamino)azacyclobutan-1-yl)acetic acid (compound 73)

[0973]

[0974] Compound 73 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.51 min, ESI 347.3 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.19(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),4.58(p,J=7.4Hz,1H),4.37-4.30(m,2H),4.05-3.97(m,2H),3 .74(s,2H),3.43-3.37(m,2H),2.72(t,J=6.3Hz,2H),2.61-2.52(m,2H),2.30-2.22(m,2H),1.94-1.84(m,2H),1.71-1.60(m,4H).

[0975] 2-(3-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)ethyl)ureido)azacyclobutan-1-yl)acetic acid (compound 74)

[0976]

[0977] Compound 74 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.34 min, ESI 334 (M+H) + . 1H NMR(500MHz,MeOD)δ7.21(d,J=7.3Hz,1H),6.43(d,J=7.3Hz,1H),4.52(brs,1H),4.36(t,J=8.6Hz ,2H),4.14-4.01(m,2H),3.80(s,2H),3.41(d,J=7.0Hz,4H),2.79-2.65(m,4H),1.96-1.82(m,2H).

[0978] 2-(3-(3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)ureo)azacyclobutan-1-yl)acetic acid (compound 75)

[0979]

[0980] Compound 75 LC / MS C: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 348.2 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.15(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),4.54-4.45(m,1H),4.23(t,J=9.1Hz,2H),3.89-3.80(m ,2H),3.64(s,2H),3.42-3.36(m,2H),3.14(t,J=6.9Hz,2H),2.71(t,J=6.2Hz,2H),2.59-2.49(m,2H),1.90-1.78(m,4H).

[0981] 2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (enantiomers 76-E1 and 76-E2)

[0982]

[0983] Compound 76-E1 LC / MS A: 96% purity, UV = 214 nm, Rt = 1.41 min, ESI 375.2 (M+H) + . 1¹H NMR (500 MHz, methanol-d⁴) δ 7.16 (d, J = 7.3 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 3.64–3.52 (m, 3H), 3.41–3.37 (m, 2H), 3.22 (t, J = 6.9 Hz, 2H), 3.15–2.99 (m, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.58–2.45 (m, 3H), 2.10–1.96 (m, 4H), 1.93–1.78 (m, 4H), 1.52 (d, J = 7.1 Hz, 3H). Chiral SFC B (30% MeOH): ee 100%, Rt = 1.98 min.

[0984] Compound 76-E2 LC / MS A: 100% purity, UV = 214 nm, Rt = 0.91 min, ESI 375.3 (M+H) + . 1 ¹H NMR (500 MHz, methanol-d⁴) δ 7.16 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 7.4 Hz, 1H), 3.66–3.50 (m, 3H), 3.42–3.37 (m, 2H), 3.22 (t, J = 7.0 Hz, 2H), 3.15–2.98 (m, 2H), 2.72 (t, J = 6.3 Hz, 2H), 2.55 (t, J = 7.7 Hz, 2H), 2.52–2.45 (m, 1H), 2.11–1.97 (m, 4H), 1.93–1.80 (m, 4H), 1.52 (d, J = 7.2 Hz, 3H). Chiral SFC B (30% MeOH): ee 99%, Rt = 3.36 min.

[0985] 2-(4-Methyl-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (compound 77)

[0986]

[0987] Compound 77 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.61 min, ESI 415.3 (M+H) + . 1H NMR (500MHz, methanol-d4) δ7.15(d,J=7.3Hz,1H),6.37(d,J=7.1Hz,1H),4.36(d,J=12.9Hz ,2H),3.58(s,2H),3.53-3.42(m,2H),3.43-3.36(m,2H),3.21-3.08(m,2H),2.98-2. 78(m,2H),2.72(t,J=6.3Hz,2H),2.47(d,J=7.2Hz,2H),2.40(d,J=15.0Hz,2H),2.03 -1.93(m,1H),1.92-1.79(m,4H),1.75-1.67(m,2H),1.38(s,3H),1.23-1.12(m,2H).

[0988] 2-(4-hydroxy-4-(4-((5,6,7,8-tetrahydro-1,8-naphthid-2-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)acetic acid (compound 78)

[0989]

[0990] Compound 78 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.46 min, ESI 417 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.15(d,J=7.3Hz,1H),6.35(d,J=7.3Hz,1H),4.83(s,1H), 4.50(brs,1H),3.53(brs,1H),3.47-3.34(m,2H),3.22(m,3H),3.01(s,1H),2. 71(t,J=6.1Hz,2H),2.60(brs,1H),2.46(d,J=7.1Hz,2H),2.33(brs,1H),1.98 (d,J=14.6Hz,2H),1.91-1.82(m,2H),1.69(d,J=11.9Hz,21H),1.21(brs,2H).

[0991] 2-(4-Methyl-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 79)

[0992]

[0993] Compound 79 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.41 min, ESI 375.4 (M+H)+ . 1 H NMR (500MHz, methanol-d4) δ7.22(d,J=7.3Hz,1H),6.43(d,J=7.3Hz,1H),3.56(s,2H),3.42-3.37(m,2H),3.32-3.17(m,6 H), 2.73 (t, J = 6.3Hz, 2H), 2.62-2.56 (m, 2H), 2.36-2.26 (m, 2H), 1.94-1.81 (m, 4H), 1.79-1.70 (m, 2H), 1.24 (s, 3H).

[0994] 2-(3,3-Difluoro-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 80)

[0995]

[0996] Compound 80 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.48 min, ESI 397.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.51(d,J=7.3Hz,1H),6.57(d,J=7.3Hz,1H),3.48(t,J=5.6Hz,2H),3.39-3.33(m,2H),3.28 -3.17(m,3H),3.08-3.01(m,1H),2.92-2.64(m,6H),2.56(t,J=11.1Hz,1H),2.17-2.05(m,1H),1.97-1.85(m,5H).

[0997] 2-(2-propionylaminophenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 81)

[0998]

[0999] Compound 81 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.46 min, ESI 508.4(M+H)+. 1HNMR(500MHz,MeOD)δ8.40(s,1H),7.69(s,1H),7.55(s,1H),7.42(s,2H),7.29(s,1H),6.54(d,J=7.2Hz,1H ), 3.66 (s, 1H), 3.49-3.40 (m, 2H), 3.26 (m, 4H), 2.96-2.25 (m, 9H), 2.15-1.69 (m, 8H), 1.29 (t, J = 7.6Hz, 3H).

[1000] 2-(4-hydroxyphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 82)

[1001]

[1002] Compound 82 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.45 min, ESI 453 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.39(d,J=8.6Hz,2H),7.15(d,J=7.3Hz,1H),6.85(d,J=8.4Hz,2H),6.38(d,J=7.3Hz,1H),4.37(s,1H),3.72(s,1H),3. 42-3.37(m,2H),3.20(t,J=6.9Hz,2H),3.10(s,1H),2.95(s,1H),2.71(t,J=6.2Hz,3H),2.57-2.51(m,2H),2.43(s,1H),2.05-1.80(m,8H).

[1003] 2-(4-methoxyphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 83)

[1004]

[1005] Compound 83 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.49 min, ESI 467.2 (M+H) + . 1¹H NMR (500MHz, methanol-d⁴) δ 7.49 (d, J = 8.7Hz, 2H), 7.16 (d, J = 7.3Hz, 1H), 6.99 (d, J = 8.7Hz, 2H), 6.38 (d, J = 7.4Hz, 1H), 4.38 (s, 1H), 3.82 (s, 3H), 3.76–3.68 (m, 1H), 3.40–3.35 ( m,2H),3.20(t,J=6.9Hz,2H),3.12-3.02(m,1H),2.95-2.84(m,1H),2.81-2.72(m,1H ), 2.70 (t, J = 6.3Hz, 2H), 2.54 (t, J = 7.6Hz, 2H), 2.47-2.39 (m, 1H), 2.08-1.77 (m, 8H).

[1006] 3-(3-(ethylcarbamoyl)phenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 84)

[1007]

[1008] Compound 84 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.45 min, ESI 522.0 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.74(t,J=1.9Hz,1H),7.71-7.66(m,1H),7.52-7.48(m,1H),7.43 -7.38(m,1H),7.23(d,J=7.4Hz,1H),6.43(d,J=7.4Hz,1H),3.67(t,J=7.1Hz,1H),3.59- 3.46(m,2H),3.45-3.37(m,4H),3.26-3.20(m,4H),3.02-2.91(m,2H),2.73(t,J=6.3Hz, 2H), 2.58 (t, J = 7.7Hz, 2H), 2.49-2.38 (m, 1H), 2.00-1.78 (m, 8H), 1.25 (t, J = 7.3Hz, 3H).

[1009] 2-(6-aminopyridin-3-yl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 85)

[1010]

[1011] Compound 85 LC / MS A: 100% purity, UV = 214 nm, Rt = 0.90 min, ESI 453 (M+H) + . 1 H NMR (500MHz, MeOD) δ8.01(d,J=1.4Hz,1H),7.66(dd,J=8.7,2.2Hz,1H),7.14(d,J=7.2Hz,1H),6.62(d,J=8.8Hz,1H),6.38(d,J=7.3Hz,1H),4.18(s,1 H),3.60(brs,1H),3.44-3.35(m,2H),3.20(t,J=6.9Hz,2H),3.07(m,1H),2 .83-2.65(m,3H),2.58-2.49(m,2H),2.41-2.31(m,1H),2.03-1.76(m,8H).

[1012] 2-(4-Carbamoylphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 86)

[1013]

[1014] Compound 86 LC / MS A: 100% purity, UV = 214 nm, Rt = 0.90 min, ESI 480 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.94(d,J=8.3Hz,2H),7.69(d,J=8.3Hz,2H),7.19(d,J=7 .3Hz,1H),6.40(d,J=7.3Hz,1H),4.43(s,1H),3.73(brs,1H),3.44-3.35(m,2 H),3.21(t,J=6.9Hz,2H),3.12-2.97(m,1H),2.87(m,1H),2.79-2.67(m,3H), 2.62-2.49(m,2H),2.43(m,1H),2.11-1.92(m,3H),1.88(m,3H),1.82(m,2H).

[1015] 2-(pyridin-2-yl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 87)

[1016]

[1017] Compound 87 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.54 min, ESI 438 (M+H) + . 1 H NMR(400MHz,MeOD)δ8.59(d,J=4.3Hz,1H),7.86(td,J=7.7,1.7Hz,1H),7.67(d ,J=7.8Hz,1H),7.41-7.37(m,1H),7.25(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H), 4.48(s,1H),3.66(d,J=10.9Hz,1H),3.45-3.38(m,2H),3.20(t,J=6.8Hz,2H),3 .07(d,J=11.4Hz,1H),2.76-2.52(m,6H),2.44-2.36(m,1H),1.97-1.79(m,8H).

[1018] 2-(pyridin-3-yl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 88)

[1019]

[1020] Compound 88 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.48 min, ESI 438 (M+H) + . 1 H NMR(500MHz,MeOD)δ8.72(s,1H),8.57(d,J=4.2Hz,1H),8.07(d,J=8.0Hz,1H),7.50 (dd,J=7.8,4.9Hz,1H),7.27(d,J=7.3Hz,1H),6.45(d,J=7.3Hz,1H),4.34(s,1H),3 .63(s,1H),3.44-3.37(m,2H),3.22(t,J=6.8Hz,2H),3.02(d,J=11.6Hz,1H),2.74( t,J=6.2Hz,3H),2.64-2.48(m,3H),2.39(dd,J=12.8,8.5Hz,1H),2.04-1.79(m,8H).

[1021] 2-(pyridin-4-yl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 89)

[1022]

[1023] Compound 89 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.38 min, ESI 438 (M+H) + . 1 H NMR (500MHz, DMSO) δ8.51(d,J=5.3Hz,2H),7.76(t,J=5.3Hz,1H),7.33(d,J=5. 0Hz,2H),7.05(d,J=7.3Hz,1H),6.35(s,1H),6.27(d,J=7.2Hz,1H),3.52(s,1H) ,3.24(s,2H),3.03(dd,J=12.9,6.9Hz,2H),2.81(d,J=10.0Hz,2H),2.61(dd,J =15.0,8.9Hz,2H),2.42(t,J=7.6Hz,2H),2.12-1.88(m,3H),1.76-1.54(m,8H).

[1024] 2-(2-Chlorophenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 90)

[1025]

[1026] Compound 90 (500 MHz, methanol-d4) δ 7.84–7.78 (m, 1H), 7.57–7.51 (m, 1H), 7.46–7.37 (m, 2H), 7.20 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.3 Hz, 1H), 4.97 (s, 1H), 3.87–3.77 (m, 1H), 3.42–3.36 (m, 2H), 3.21 (t, J = 6.9 Hz, 2H), 3.11–3.03 (m, 1H), 2.98–2.80 (m, 2H), 2.72 (t, J = 6.3 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.50–2.41 (m, 1H), 2.09–1.79 (m, 8H).

[1027] 2-(3-Chlorophenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 91)

[1028]

[1029] Compound 91 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.68 min, ESI 471.3 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.67(s,1H),7.53-7.49(m,1H),7.47-7.40(m,2H),7.22(d ,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),4.36(d,J=3.6Hz,1H),3.75-3.67(m,1H),3 .42-3.38(m,2H),3.21(t,J=6.9Hz,2H),3.09-3.00(m,1H),2.89-2.80(m,1H),2. 72(t,J=6.3Hz,3H),2.57(t,J=7.7Hz,2H),2.47-2.37(m,1H),2.07-1.80(m,8H).

[1030] 2-(4-Chlorophenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 92)

[1031]

[1032] Compound 92 LC / MS A: 99% purity, UV = 214 nm, Rt = 1.52 min, ESI 471.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.57(d,J=8.5Hz,2H),7.49-7.43(m,2H),7.19(d,J=7 .3Hz,1H),6.41(d,J=7.3Hz,1H),4.40(s,1H),3.77-3.66(m,1H),3.41-3.3 7(m,2H),3.21(t,J=6.9Hz,2H),3.11-3.01(m,1H),2.94-2.83(m,1H),2.82 -2.67(m,3H),2.56(t,J=7.6Hz,2H),2.48-2.38(m,1H),2.05-1.79(m,8H).

[1033] 2-(3-Carbamoylphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 93)

[1034]

[1035] Compound 93 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.09 min, ESI 480.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ8.07(d,J=1.9Hz,1H),7.91(d,J=8.1Hz,1H),7.76(d,J=7.8Hz,1H ),7.58-7.51(m,1H),7.18(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),4.42(s,1H),3.79-3 .67(m,1H),3.42-3.37(m,2H),3.20(t,J=6.9Hz,2H),3.09-3.01(m,1H),2.91-2.82(m, 1H), 2.71 (t, J = 6.3Hz, 3H), 2.55 (t, J = 7.7Hz, 2H), 2.46-2.36 (m, 1H), 2.08-1.80 (m, 8H).

[1036] 2-(3-Methoxyphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 94)

[1037]

[1038] Compound 94 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.50 min, ESI 467.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.35(t,J=8.0Hz,1H),7.21-7.11(m,3H),7.00(dd,J=8.3,2. 3Hz,1H),6.39(d,J=7.3Hz,1H),4.38(s,1H),3.75(s,1H),3.46-3.34(m,2H),3.20 (t,J=6.9Hz,2H),3.06(s,1H),2.93(t,J=8.6Hz,1H),2.82(s,1H),2.71(t,J=6.3H z,2H),2.60-2.51(m,2H),2.45(ddd,J=14.7,10.4,4.2Hz,1H),2.20-1.76(m,8H).

[1039] 2-(2-Methoxyphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 95)

[1040]

[1041] Compound 95 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 467.2 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.56 (dd, J=7.7, 1.5Hz, 1H), 7.50-7.43 (m, 1H), 7.13 (dd, J= 9.7,8.2Hz,2H),7.05(t,J=7.4Hz,1H),6.38(d,J=7.3Hz,1H),4.97(s,1H),3.92( s,3H),3.43-3.34(m,2H),3.21(dd,J=15.7,8.8Hz,3H),3.02(d,J=3.3Hz,1H),2 .72(dd,J=18.3,12.0Hz,2H),2.59-2.50(m,2H),2.45(s,1H),2.14-1.69(m,8H).

[1042] 2-Cyclopropyl-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 96)

[1043]

[1044] Compound 96 LC / MS A: 98% purity, UV = 214 nm, Rt = 1.42 min, ESI 401.2 (M+H) + . 1 H NMR (500MHz, methanol-d4) δ7.16(d,J=7.4Hz,1H),6.40(d,J=7.3Hz,1H),3.87(d,J=12.3Hz,1H),3.5 9(dd,J=10.2,6.0Hz,1H),3.42-3.37(m,2H),3.22(t,J=7.0Hz,2H),3.10-2.96(m,2H),2.84(d, J=9.5Hz,1H),2.71(t,J=6.3Hz,2H),2.58-2.53(m,2H),2.53-2.45(m,1H),2.10-1.97(m,4H), 1.92-1.79(m,4H),1.18-1.07(m,1H),0.88-0.76(m,1H),0.76-0.64(m,2H),0.62-0.54(m,1H).

[1045] 2-(1H-indol-3-yl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 97)

[1046]

[1047] Compound 97 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.52 min, ESI 476 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.78(d,J=7.9Hz,1H),7.54(s,1H),7.43(d,J=8.1Hz,1H),7.18( t,J=7.3Hz,1H),7.12(t,J=6.9Hz,2H),6.36(d,J=7.3Hz,1H),4.84(s,1H),3.69(s,1 H),3.36(d,J=5.6Hz,3H),3.18(t,J=6.9Hz,2H),3.05(t,J=10.8Hz,1H),2.68(t,J=6 .2Hz,3H),2.52(t,J=7.6Hz,2H),2.38(s,1H),1.86(ddt,J=21.9,14.3,11.8Hz,8H).

[1048] 2-(1-oxo-2-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2,9-diazaspiro[5.5]undecane-9-yl)acetic acid (compound 98)

[1049]

[1050] Compound 98 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.41 min, ESI 387.2(M+H)+. 1 HNMR(500MHz,MeOD)δ7.30(d,J=7.3Hz,1H),6.47(d,J=7.3Hz,1H),3.70-3.57(m,4H),3.54(s,2H),3.48-3.41(m,2H),3. 19(s,4H),2.83(t,J=6.9Hz,2H),2.76(t,J=6.2Hz,2H),2.13(br,2H),1.96-1.89(m,2H),1.84(s,2H),1.78-1.69(m,2H).

[1051] 2-(1-oxo-2-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-2,8-diazaspiro[4.5]decane-8-yl)acetic acid (compound 99)

[1052]

[1053] Compound 99 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.36 min, ESI 373.0(M+H)+. 1 HNMR(500MHz,MeOD)δ7.14(d,J=7.3Hz,1H),6.41(d,J=7.3Hz,1H),3.59(m,6H),3.45-3.34(m,4H),3.18 (s,2H),2.74(dt,J=12.4,6.5Hz,4H),2.00(d,J=6.8Hz,4H),1.91-1.81(m,2H),1.71(d,J=14.1Hz,2H).

[1054] 2-(4-((4-(pyridin-2-ylamino)butyl)carbamoyl)piperidin-1-yl)acetic acid (compound 100)

[1055]

[1056] Compound 100 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.30 min, ESI 335.2 (M+H) + . 1 HNMR(500MHz,MeOD)δ7.90(d,J=5.2Hz,1H),7.50(t,J=7.8Hz,1H),6.60(dd,J=12.3,7.5Hz,2H),4.95(s,2H ),3.74-3.58(m,4H),3.25(t,J=5.9Hz,2H),3.07(s,2H),2.57-2.46(m,1H),2.10-1.97(m,4H),1.64(s,4H).

[1057] 2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)piperidin-1-yl)acetic acid (compound 101)

[1058]

[1059] Compound B, 101 LC / MS: 100% purity, UV = 214 nm, Rt = 1.44 min, ESI 375 (M+H) + .1 H NMR(500MHz,MeOD)δ8.45(s,1H),7.47(d,J=7.4Hz,1H),6.57(d,J=7.4Hz,1H),3.71(t,J=11.2Hz,2H),3.64(s,2H),3.51-3.46(m,2H),3.23 -3.17(m,2H),3.10(s,2H),2.86-2.77(m,3H),2.52(s,1H),2.09-2.01(m,4H),1.97-1.87(m,3H),1.82-1.79(m,1H),1.32(d,J=7.0Hz,3H).

[1060] 2-(4-(phenyl(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 102)

[1061]

[1062] Compound 102 LC / MS A: 100% purity, UV = 254 nm, Rt = 1.53 min, ESI 437 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.53(dd,J=10.3,4.7Hz,2H),7.46(t,J=7.4Hz,1H),7.34(d,J=7.3Hz,2H),7.16(d,J=7.3Hz,1H),6.37(d,J=7.3Hz,1H),3.77-3.72 (m,2H),3.56(d,J=12.6Hz,2H),3.48(s,2H),3.41-3.36(m,2H),2.81-2.68( m, 4H), 2.56-2.49 (m, 3H), 2.06 (dd, J = 23.5, 11.1Hz, 2H), 1.94-1.84 (m, 6H).

[1063] 2-(3-((4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)carbamoyl)azacyclobutane-1-yl)propionic acid (compound 103)

[1064]

[1065] Compound 103 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.51 min, ESI 361.3(M+H)+. 1HNMR(500MHz,MeOD)δ7.16(d,J=7.3Hz,1H),6.38(d,J=7.3Hz,1H),4.36-4.15(m, 2H), 4.09 (t, J = 9.0Hz, 2H), 3.74 (q, J = 7.0Hz, 1H), 3.50 (dt, J = 16.2, 8.1Hz, 1H), 3. 44-3.36(m,2H),3.25(t,J=6.9Hz,2H),2.72(t,J=6.2Hz,2H),2.55(t,J=7.6Hz,2H ),1.95-1.78(m,2H),1.75-1.60(m,2H),1.56-1.39(m,2H),1.39(d,J=7.1Hz,3H).

[1066] 2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperazin-1-yl)propionic acid (compound 104)

[1067]

[1068] Compound 104 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.34 min, ESI 376 (M+H) + . 1 H NMR(500MHz,MeOD)δ8.50(s,1H),7.50(d,J=7.3Hz,1H),6.57(d,J=7.3Hz,1H),3.66(m,5H),3.52-3.44(m,2H),3.41-3.33(m,4H ),3.28(t,J=6.3Hz,2H),2.80(t,J=6.1Hz,2H),2.75-2.66(m,2H),2.00-1.90(m,2H),1.91-1.81(m,2H),1.55(d,J=7.2Hz,3H).

[1069] 2-Phenylacetyl-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperazin-1-yl)acetic acid (compound 105)

[1070]

[1071] Compound 105 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.42 min, ESI 438 (M+H) + . 1H NMR(500MHz,MeOD)δ7.55(d,J=8.2Hz,2H),7.42-7.29(m,4H),6.49(d,J=7.3Hz,1H),4.01(s,1H) ,3.55-3.44(m,3H),3.43-3.38(m,3H),3.22(m,2H),2.79(m,4H),2.63(m,4H),1.95-1.79(m,4H).

[1072] 2-(4-Fluoro-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 106)

[1073]

[1074] Compound 106 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.41 min, ESI 393.2 (M+H) + . 1 HNMR (500MHz, methanol-d4) δ7.17(d,J=7.3Hz,1H),6.41(d,J=7.4Hz,1H),3.56( q,J=7.1Hz,1H),3.52-3.44(m,2H),3.41-3.36(m,2H),3.28(t,J=7.0Hz,2 H),3.24-3.09(m,2H),2.72(t,J=6.0Hz,2H),2.57(t,J=7.7Hz,2H),2.53- 2.38(m,2H),2.15-2.03(m,2H),1.93-1.83(m,4H),1.51(d,J=7.1Hz,3H).

[1075] 2-(4-Fluoro-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)-2-phenylacetic acid (compound 107)

[1076]

[1077] Compound 107 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.50 min, ESI 455.3 (M+H) + . 1HNMR (500MHz, methanol-d4) δ 7.63–7.54 (m, 2H), 7.46–7.37 (m, 3H), 7.24 (d, J = 7.4 Hz, 1H), 6.43 (d, J = 7.3 Hz, 1H), 4.34 (s, 1H), 3.67–3.57 (m, 1H), 3.41–3.37 (m, 2H), 3.26 (t, J = 6 .9Hz,2H),3.06-2.96(m,1H),2.94-2.87(m,1H),2.85-2.75(m,1H),2.72(t,J=6.3Hz ,2H),2.58(t,J=7.7Hz,2H),2.54-2.30(m,2H),2.09-2.00(m,1H),1.95-1.81(m,5H).

[1078] 2-(4-Methyl-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 108)

[1079]

[1080] Compound 108 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.41 min, ESI 389.2 (M+H) + . 1 HNMR(500MHz,MeOD)δ7.23(d,J=7.3Hz,1H),6.44(d,J=7.3Hz,1H),3.52(d, J=7.2Hz,1H),3.44-3.38(m,2H),3.31-3.15(m,6H),2.73(t,J=6.2Hz,2H),2 .64-2.56(m,2H),2.31(d,J=12.2Hz,2H),1.88(ddd,J=22.2,13.4,6.9Hz,4 H), 1.73 (ddd, J=19.4, 13.3, 3.9Hz, 2H), 1.47 (d, J=7.2Hz, 3H), 1.24 (s, 3H).

[1081] 2-(4-Methyl-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)-2-phenylacetic acid (compound 109)

[1082]

[1083] Compound 109 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.49 min, ESI 451.2 (M+H) + .1 HNMR(500MHz,MeOD)δ7.55(dd,J=7.3,2.1Hz,2H),7.47-7.37(m,3H),7.22(d,J=7.3Hz,1H),6.43(d,J=7.3Hz,1H),4.51(s,1H),3.43-3.37(m,2H),3 .26(td,J=6.6,3.3Hz,3H),2.99(s,3H),2.73(t,J=6.2Hz,2H),2.58(dd,J =14.6,7.2Hz,2H),2.24(d,J=13.1Hz,2H),1.96-1.65(m,6H),1.22(s,3H).

[1084] 2-(4-hydroxy-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 110)

[1085]

[1086] Compound 110 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.38 min, ESI 391 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.15(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),3.62(q,J=7.1Hz,1H),3.54-3.46(m,2H),3.43-3.37(m,2H),3.33 -3.23(m,4H),2.72(t,J=6.3Hz,2H),2.57(t,J=7.6Hz,2H),2.40(td,J=14.6,4.2Hz,2H),1.92-1.80(m,6H),1.54(d,J=7.1Hz,3H).

[1087] 2-(4-hydroxy-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)-2-phenylacetic acid (compound 111)

[1088]

[1089] (Compound 111) LC / MS A: 98% purity, UV = 214 nm, Rt = 1.46 min, ESI 453 (M+H) + . 1H NMR (500MHz, MeOD) δ7.61 (dd, J=6.6, 2.9Hz, 2H), 7.48-7.42 (m, 3H), 7.15 (d, J=7.3Hz, 1H),6.39(d,J=7.3Hz,1H),4.53(s,1H),3.71(s,1H),3.42-3.36(m,2H),3.24(t,J=6.9 Hz,3H),3.01(d,J=54.4Hz,2H),2.71(t,J=6.3Hz,2H),2.55(t,J=7.5Hz,2H),2.45(t,J =12.3Hz, 1H), 2.34 (dd, J = 19.3, 8.9Hz, 1H), 1.90-1.78 (m, 5H), 1.69 (d, J = 12.8Hz, 1H).

[1090] 2-(4-Fluoro-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 112)

[1091]

[1092] Compound 112 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.40 min, ESI 379.1 (M+H) + . 1 HNMR (500MHz, methanol-d4) δ7.19(d,J=7.3Hz,1H),6.42(d,J=7.4Hz,1H),3.48(s,2H),3.46-3.38(m,4H),3.28(t,J=6.9Hz,2H) ,3.05-2.95(m,2H),2.72(t,J=6.2Hz,2H),2.57(t,J=7.6Hz,2H),2.52-2.36(m,2H),2.06-1.97(m,2H),1.92-1.83(m,4H).

[1093] 2-(4-hydroxy-4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (compound 113)

[1094]

[1095] Compound 113 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.38 min, ESI 377 (M+H) + . 1H NMR(500MHz,MeOD)δ7.15(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),3.64(s,2H),3.56(d,J=12.4Hz,2H),3.42-3.37(m,2H) ,3.27(dd,J=16.8,9.9Hz,4H),2.72(t,J=6.3Hz,2H),2.59-2.53(m,2H),2.39(td,J=14.5,4.3Hz,2H),1.92-1.78(m,6H).

[1096] 2-(2-Chlorophenyl)-2-((1R,5S,6r)-6-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-yl)acetic acid (compound 114)

[1097]

[1098] Compound 114 LC / MS A: 100% purity, UV = 214 nm, Rt = 1.51 min, ESI 469 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.76-7.70(m,1H),7.42(d,J=7.5Hz,1H),7.37(d,J=7.2Hz,1H),7.34-7. 25(m,2H),6.51(d,J=7.3Hz,1H),4.72(s,1H),3.43(dd,J=12.2,7.0Hz,3H),3.22(t,J=6.7Hz, 2H),2.95(d,J=7.0Hz,1H),2.87(d,J=9.8Hz,1H),2.76(t,J=6.1Hz,3H),2.63(t,J=7.5Hz,2H ), 2.09 (s, 1H), 2.03-1.97 (m, 1H), 1.92 (dt, J = 12.0, 5.8Hz, 3H), 1.85 (dd, J = 14.4, 7.2Hz, 2H).

[1099] 2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 115)

[1100]

[1101] Compound 115 LC / MS F: 97% purity, UV 254 nm, Rt = 1.896, ESI 375.2 (M+H). 1H NMR (400MHz, DMSO-d6) δ7.8-7.75(m,1H),7.03(d,J=7.2Hz,1H),6.34(bs,1H),6.26(d,1H),3.27-3.21(m,3 H),3.11-2.99(m,4H),2.62-2.53(m,3H),2.41(m,2H),2.16(m,3H),1.78-1.59(m,8H),1.21(d,J=7.2Hz,3H)

[1102] 3-Methoxy-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 116)

[1103]

[1104] Compound 116 LC / MS F: 96% purity, UV 254nm, Rt = 1.842, ESI 437.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.72(t,1H),7.02(d,1H),6.28(bs,1H),6.24(d,J=7.24,1H),3.68-3.64(m,1H),3.61-3.57(m,1H), 3.34(t,1H)3.26-3.21(q,5H),3.05-2.98(m,4H),2.62-2.55(m,3H),2.43-2.37(m,2H),2.17-2.09(m,2H),1.79-1.59(m,8H)

[1105] 3-Phenyl-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)propionic acid (compound 117)

[1106]

[1107] Compound 117 LC / MS F: 96% purity, UV 254 nm, Rt = 3.123 min, ESI 451.2 (M+H). 1 H NMR 1H NMR (400MHz, DMSO-d6) δ7.66(t,J=5.6Hz,1H),7.31-7.12(m,4H),6.95(d,J=7.2Hz,1H),6.21-6.14(m,2H),3.72(dd,J=10.5,5.3Hz,2H ),3.20-3.12(m,2H),3.08-2.90(m,5H),2.86(m,1H),2.53(t,J=6.3Hz,2H),2.37(t,J=6.5Hz,2H),2.14-1.87(m,3H),1.74-1.35(m,8H)

[1108] 2-(4-(N-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)aminosulfonyl)piperidin-1-yl)acetic acid (compound 118)

[1109]

[1110] Compound 118 LC / MS F: 96% purity, UV 254nm ESI 397.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.04(t,J=5.7Hz,1H),6.96(d,J=7.2Hz,1H),6.22-6.15(m,2H),3.21-3.12(m,2H),3.09(s, 2H),2.99-2.78(m,5H),2.53(t,J=6.3Hz,2H),2.42-2.33(m,2H),2.29-2.18(m,2H),1.85(m,2H),1.71-1.52(m,6H)

[1111] 2-((1R,5S,6S)-6-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-yl)acetic acid (compound 119)

[1112]

[1113] Compound 119 LC / MS F: 95% purity, UV 254 nm, Rt = 2.78 min, ESI 359.2 (M+H). 1H NMR (400MHz, DMSO-d6) δ8.67(t,J=5.5Hz,1H),7.05-6.98(d,J=7.2Hz,1H),6.67(bs,1H),6.23(d,J=7.2Hz,1H),3.38(d,J=10.7Hz,2 H),3.28(s,2H)3.22-3.14(m,2H),3.09-2.92(m,4H),2.54(t,J=6.3Hz,2H),2.43-2.28(m,2H),1.93-1.85(m,2H),1.74-1.54(m,5H).

[1114] 2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)amino)piperidin-1-yl)acetic acid (compound 120)

[1115]

[1116] Compound 120 LC / MS F: 95% purity, UV 254nm ESI 333.2 (M+H). 1 H NMR(400MHz, DMSO-d6)δ7.04(d,J=7.3Hz,1H),6.31-6.22(m,2H),3.26-3.22(m,2H),3.15(s,2H),3.09-3.02(m,2H), 2.74-2.65(m,2H),2.61(t,J=6.3Hz,2H),2.50-2.42(m,3H),1.93-1.84(m,2H),1.83-1.7(m,4H),1.56-1.42(m,2H).

[1117] 2-((1R,5S,6r)-6-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-yl)acetic acid (compound 121)

[1118]

[1119] Compound 121 LC / MS F: 95% purity, UV 254nm, Rt=2.586, ESI 359.2(M+H). 1H NMR(400MHz,D2O)δ7.46(d,J=7.4Hz,1H),6.52(d,J=7.3Hz,1H),3.72(m,4H),3.52(bs,2H),3.43-3.35(m,2H),3.18(t,J= 6.6Hz, 2H), 2.71 (t, J = 6.3Hz, 2H), 2.63 (t, J = 7.4Hz, 2H), 2.19 (t, J = 3.1Hz, 2H), 1.91-1.81 (m, 4H), 1.78 (t, J = 3.4Hz, 1H).

[1120] 2-Phenylacetyl-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)amino)piperidin-1-yl)acetic acid (compound 122)

[1121]

[1122] Compound 122 LC / MS F: 98% purity, UV 254nm, Rt = 1.315min, ESI 409.3 (M+H). 1 H NMR(400MHz,DMSO-d6)δ7.45-7.28(m,5H),7.06(d,J=7.3Hz,1H),6.33-6 .26(m,2H),4.03(s,1H),3.3-3.22(m,2H),3.07-3.01(m,1H),2.96-2.81( m,3H),2.78-2.73(m,1H),2.62(t,J=6.2Hz,2H),2.48(t,J=6.2Hz,2H),2 .27-2.2(m,1H),2.09-1.86(m,5H),1.82-1.71(m,2H),1.68-1.54(m,2H).

[1123] 2-(4-((4-methyl-3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)phenyl)carbamoyl)piperidin-1-yl)acetic acid (compound 123)

[1124]

[1125] Compound 123 LC / MS F: 97% purity, UV 254nm, Rt = 3.218min, ESI 409.2 (M+H). 1H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 7.57 (d, J = 2.3Hz, 1H), 7.45 (dd, J = 8.2, 2. 3Hz,1H),7.23-7.16(m,1H),7.12(d,J=8.3Hz,1H),6.45(d,J=7.3Hz,1H),6.39( s,1H),3.33-3.26(m,2H),3.22(s,2H),3.19-3.13(m,2H),2.69(t,J=6.2Hz,2H) ,2.55-2.51(m,J=3.6Hz,2H),2.43-2.35(m,1H),2.24(s,3H),1.86-1.74(m,6H)

[1126] 2-(4-((4-methyl-3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)phenyl)carbamoyl)piperidin-1-yl)propionic acid (compound 124)

[1127]

[1128] Compound 124 LC / MS F: 99% purity, UV 254 nm, Rt = 3.232 min, ESI 423.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.57 (d, J = 2.4Hz, 1H), 7.44 (dd, J = 8.2, 2. 4Hz,1H),7.20(d,J=7.4Hz,1H),7.12(d,J=8.2Hz,1H),6.45(d,J=7.3Hz,1H),6. 38(s,1H),3.30-3.20(m,3H),3.06(m,2H),2.69(t,J=6.2Hz,2H),2.59-2.49(m ,2H),2.43-2.31(m,2H),2.24(s,3H),1.86-1.65(m,6H),1.21(d,J=7.0Hz,3H).

[1129] 2-(4-((4-methyl-3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)phenyl)carbamoyl)piperidin-1-yl)-2-phenylacetic acid (compound 125)

[1130]

[1131] Compound 125 LC / MS F: 95% purity, UV 254 nm, Rt = 3.399 min, ESI 485.2 (M+H). 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.56 (d, J = 2.3Hz, 1H), 7.48-7.25 (m, 6H), 7.19 (d, J = 7.4Hz, 1H), 7.11 (d, J = 8.3Hz, 1H), 6.45 (d, J = 7.2Hz, 1H), 6. 38(bs,1H),3.31-3.26(s,4H),3.22-3.18(m,1H),2.79-3.72(m,1H),2.69 (t,J=6.3Hz,2H),2.43-2.32(m,1H),2.25-2.13(m,4H),1.84-1.70(m,6H).

[1132] 2-(4-(N-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)aminosulfonyl)piperidin-1-yl)propionic acid (compound 126)

[1133]

[1134] Compound 126 LC / MS F: 99% purity, UV 254 nm, Rt = 2.929 min, ESI 411.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ7.56-7.49(d,7.3Hz,1H),7.36(t,J=5.8Hz,1H),6.57(d,J=7.3Hz,1H),3.71-3.61(m,1H),3.42-3.36(m,2H) ,3.31-3.15(m,3H),3.01-2.95(m,2H),2.9-2.8(m,2H),2.75-2.64(m,4H),2.12-2.03(m,2H),1.94-1.75(m,6H),1.34(d,J=7.2,3H).

[1135] 2-(4-((4-methyl-3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)benzyl)carbamoyl)piperidin-1-yl)acetic acid (compound 127)

[1136]

[1137] Compound 127 LC / MS F: 97% purity, UV 254 nm, Rt = 3.216 min, ESI 423.2 (M+H). 1H NMR (400MHz, DMSO-d6) δ8.30(t,J=5.9Hz,1H),7.23-7.12(m,3H),7.08(dd,J=7.8,1.9Hz,1H),6.45(d,J=7.3Hz,1H),6.38(s,1H),4.23(d, J=5.9Hz,2H),3.27(m,2H),3.17(s,2H),3.14-3.06(m,2H),2.69(t,J=6.3Hz,2H),2.50-2.42(m,2H),2.2-2.17(m,4H),1.84-1.67(m,6H).

[1138] 2-(4-((4-methyl-3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)benzyl)carbamoyl)piperidin-1-yl)propionic acid (compound 128)

[1139]

[1140] Compound 128 LC / MS F: 99% purity, UV 254 nm, Rt = 3.226 min, ESI 437.2 (M+H). 1 H NMR (400MHz, DMSO-d6) δ8.29(t,J=5.9Hz,1H),7.23-7.12(m,3H),7.08(dd,J=7.8,1.9Hz,1H),6.48-6.38(m,2H),4.23(d,J=5.9Hz,2H),3.33 -3.21(m,3H),3.05(t,J=13.3Hz,2H),2.69(t,J=6.3Hz,2H),2.58-2.51(m,2H),2.28-2.21(m,4H),1.83-1.65(m,6H),1.20(d,J=7.1Hz,3H).

[1141] According to the general procedure, compounds 134 to 201 were prepared using methods similar to those used to prepare compounds 1 to 28 and 129 to 133.

[1142] 2-Phenyl-2-(3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butoxy)azacyclobutan-1-yl)acetic acid (enantiomers 134-E1 and 134-E2)

[1143]

[1144] Compound 134-E1 LC / MS ESI 396 (M+H) +1H NMR (400MHz, MeOD) δ7.56-7.35(m,5H),7.15(d,J=7.3Hz,1H),6.37(d,J=7.3Hz,1H),4.65(s,1H),4.30-4.28(m,2H),3.93-3.91(m,2H),3. 75-3.71(m,1H),3.47-3.36(m,4H),2.70(t,J=6.3Hz,2H),2.54(t,J=7.5Hz,2H),1.96-1.81(m,2H),1.76-1.64(m,2H),1.59-1.55(m,2H). Chiral SFC B (30% MeOH): ee100%, Rt=1.06min.

[1145] Compound 134-E2 LC / MS ESI 396 (M+H) +1 H NMR (400MHz, MeOD) δ7.56-7.35(m,5H),7.15(d,J=7.3Hz,1H),6.37(d,J=7.3Hz,1H),4.65(s,1H),4.30-4.28(m,2H),3.93-3.91(m,2H),3. 75-3.71(m,1H),3.47-3.36(m,4H),2.70(t,J=6.3Hz,2H),2.54(t,J=7.5Hz,2H),1.96-1.81(m,2H),1.76-1.64(m,2H),1.59-1.55(m,2H). Chiral SFC B (30% MeOH): ee99.5%, Rt=2.58min.

[1146] 2-Phenylacetyl-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)azacyclobutan-1-yl)acetic acid (enantiomers 135-E1 and 135-E2)

[1147]

[1148] Compound 135-E1 LC / MS ESI 394.2 (M+H) + . 1H NMR (400MHz, MeOD) δ7.51-7.41(m,5H),7.11(d,J=7.2Hz,1H),6.34(d,J=7.2Hz,1H),4.67(s,1H),4.22(s,1H),3.7 7-3.33(m,5H),2.79-2.68(m,3H),2.49(t,J=7.6Hz,2H),1.92-1.84(m,2H),1.66-1.58(m,4H),1.34-1.22(m,4H). Chiral SFC A (40% MeOH): ee 98%, Rt = 1.96 min.

[1149] Compound 135-E2 LC / MS ESI 394.2 (M+H) + . 1 H NMR(400MHz,MeODδ7.40-7.31(m,5H),7.003(d,J=7.2Hz,1H),6.231(d,J=7.2Hz,1H),4.55(s,1H),4.10(s,1H),3.63- 3.20(m,5H),2.68-2.56(m,3H),2.38(t,J=7.6Hz,2H),1.80-1.73(m,2H),1.55-1.47(m,4H),1.22-1.11(m,4H). A (40% MeOH): ee 98%, Rt = 3.63 min.

[1150] 2-Phenyl-2-((R)-3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 136-E1 and 136-E2)

[1151]

[1152] Compound 136-E1 LC / MS ESI 463.2 (M+H) + . 1H NMR(500MHz,MeOD)δ7.59-7.56(m,2H),7.44-7.43(m,3H),7.12(d,J=7.3Hz, 1H),6.35(m,J=5.5Hz,1H),4.46(m,2H),3.94(d,J=13.5Hz,1H),3.67(m,2H), 3.39-3.35(m,3H),3.09-3.02(m,3H),2.69(m,3H),2.46(m,2H),2.43(m,1H) ,2.11-2.09(m,1H),1.96-1.83(m,3H),1.84-1.65(m,2H),1.19-1.09(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 2.16 min.

[1153] Compound 136-E2 LC / MS ESI 463.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.59-7.56(m,2H),7.44-7.43(m,3H),7.12(d,J=7.3Hz, 1H),6.35(m,J=5.5Hz,1H),4.46(m,2H),3.94(d,J=13.5Hz,1H),3.67(m,2H), 3.39-3.35(m,3H),3.09-3.02(m,3H),2.69(m,3H),2.46(m,2H),2.43(m,1H) ,2.11-2.09(m,1H),1.96-1.83(m,3H),1.84-1.65(m,2H),1.19-1.09(m,2H). Chiral SFC A (45% MeOH): ee 97%, Rt = 3.68 min.

[1154] 2-Phenyl-2-((S)-3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 137-E1 and 137-E2)

[1155]

[1156] Compound 137-E1 LC / MS ESI 463.2 (M+H) + . 1H NMR(500MHz,MeOD)δ7.59-7.52(m,2H),7.45-7.37(m,3H),7.12(d,J=7.3Hz,1H),6.35(t,J =5.5Hz,1H),4.46(d,J=13.8Hz,2H),3.91(d,J=13.5Hz,1H),3.54(s,3H),3.39-3.35(m,2H) ,3.09-3.02(m,3H),2.69(t,J=6.2Hz,2H),2.64-2.60(m,1H),2.43(t,J=7.1Hz,2H),2.30(d,J=6.7Hz,1H),2.11-2.09(m,1H),1.96-1.83(m,3H),1.73-1.65(m,2H),1.20-1.04(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt=2.41min.

[1157] Compound 137-E2 LC / MS ESI 463.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.59-7.52(m,2H),7.46-7.38(m,3H),7.13(d,J=7.1Hz,1H),6.33(d,J=7.3Hz,1H) ,4.59(s,1H),4.46(d,J=12.3Hz,1H),3.92(d,J=13.4Hz,1H),3.63(s,2H),3.39-3.35(m,3H),3.16(br, 1H),3.10-3.00(m,2H),2.69(t,J=6.3Hz,2H),2.61(t,J=13.3Hz,1H),2.44(d,J=7.1Hz,2H),2.28(d,J =18.9Hz,1H),2.11-2.00(m,1H),1.92(s,1H),1.89-1.84(m,2H),1.73-1.65(m,2H),1.20-1.04(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 3.43 min.

[1158] 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butylamino)pyrrolidone-1-yl)acetic acid (diastereomeric compounds 138-E1 and 138-E2)

[1159]

[1160] Compound 138-E1 LC / MS ESI 409.2 (M+H) + , 1 H NMR(500MHz,MeOD)δ7.50(d,J=6.9Hz,2H),7.34-7.29(m,3H),7.18(d,J=7.3Hz,1H),6.41( d,J=7.3Hz,1H),3.86(s,1H),3.56(s,1H),3.42-3.38(m,2H),3.32-3.26(m,1H),2.97-2.90 (m,1H),2.85-2.80(m,1H),2.75-2.69(m,3H),2.59(t,J=7.1Hz,2H),2.37-2.30(m,2H),2.2 5-2.20(m,1H),2.09-2.07(m,2H),2.01-1.94(m,1H),1.92-1.86(m,2H),1.77-1.66(m,4H). Chiral SFC F (45% MeOH): ee 100%, Rt=3.6 min.

[1161] Compound 138-E2 LC / MS ESI 409.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.50(d,J=6.9Hz,2H),7.34-7.30(m,3H),7.18(d,J=7.3Hz,1H),6.43( d,J=7.3Hz,1H),3.86(s,1H),3.56(s,1H),3.45-3.38(m,2H),3.36-3.26(m,1H),2.98-2.90 (m,1H),2.83-2.80(m,1H),2.75-2.69(m,3H),2.59(t,J=7.1Hz,2H),2.35-2.30(m,2H),2.2 4-2.20(m,1H),2.08-2.07(m,2H),2.02-1.94(m,1H),1.93-1.86(m,2H),1.79-1.66(m,4H). Chiral SFC F (45% MeOH): ee 100%, Rt = 5.6 min.

[1162] 2-(2-methoxyphenyl)-2-(4-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)piperidin-1-yl)acetic acid (enantiomers 139-E1 and 139-E2)

[1163]

[1164] Compound 139-E1 LC / MS ESI 467.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.56(d,J=7.7Hz,1H),7.47-7.42(m,1H),7.15-7.11(m,2H),7.04 (t,J=7.5Hz,1H),6.37(d,J=7.3Hz,1H),4.97(s,1H),3.92(s,3H),3.89(s,1H),3.72( br,1H),3.39(t,J=6Hz,2H),3.17(s,1H),3.09(t,J=11.2Hz,2H),2.71(t,J=6.2Hz,2H ), 2.53 (t, J = 7.5Hz, 2H), 2.20 (t, J = 7.5Hz, 2H), 2.06-2.02 (m, 2H), 1.95-1.84 (m, 6H). Chiral SFC A (45% MeOH): ee 100%, Rt=2.35 min.

[1165] Compound 139-E2 LC / MS ESI 467.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.56(dd,J=7.6,1H),7.47-7.41(m,1H),7.15-7.11(m,2H),7.04( t,J=7.5Hz,1H),6.37(d,J=7.3Hz,1H),4.97(s,1H),3.92(s,3H),3.88(s,1H),3.71(br ,1H),3.39(t,J=6Hz,2H),3.16(s,1H),3.08(t,J=11.3Hz,2H),2.71(t,J=6.3Hz,2H),2 .53(t,J=7.6Hz,2H),2.20(t,J=7.5Hz,2H),2.05(t,J=16.2Hz,2H),1.95-1.76(m,6H). Chiral SFC A (45% MeOH): ee 100%, Rt = 3.03 min.

[1166] 2-Phenyl-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyrylamino)pyrrolidone-1-yl)acetic acid (diastereomeric compounds 140-E1 and 140-E2)

[1167]

[1168] Compound 140-E1 LC / MS ESI 423.2 (M+H)+ . 1 H NMR (500MHz, MeOD) δ7.55(m,2H),7.43-7.39(m,3H),7.24(d,J=9.0Hz,1H),6.42(d,J=7.3Hz,1H),4.47(s,1H),4.33(s,1H),3. 60-3.44(m,4H),2.99(s,2H),2.74-2.71(t,J=15.5Hz,2H),2.59-2.55(t,J=19.3Hz,2H),2.30-2.20(m,3H),2.04-1.85(m,5H). Chiral SFC A (45% MeOH): ee 100%, Rt=2.15 min.

[1169] Compound 140-E2 LC / MS ESI 423.2 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.55(m,2H),7.43-7.39(m,3H),7.24(d,J=9.0Hz,1H),6.42(d,J=7.3Hz,1H),4.47(s,1H),4.33(s,1H),3. 60-3.44(m,4H),2.99(s,2H),2.74-2.71(t,J=15.5Hz,2H),2.59-2.55(t,J=19.3Hz,2H),2.30-2.20(m,3H),2.04-1.85(m,5H). Chiral SFC A (45% MeOH): ee 100%, Rt=4.59 min.

[1170] 2-Phenyl-2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)oxazol-2-yl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 141-E1 and 141-E2)

[1171]

[1172] Compound 141-E1 LC / MS ESI 433 (M+H)+ 1H NMR (400MHz, MeOD) δ7.60-7.57(m,2H),7.49(s,1H),7.40-7.37(m,3H),7.11(d,J=7.6Hz,1H),6.34(d,J=7.2Hz,1H),4.34(s,1H),3.69-3.67 (m,1H),3.50-3.23(m,5H),3.03-3.00(m,1H),2.82-2.80(m,4H),2.71 -2.68(m,2H),2.39-2.37(m,1H),2.28-2.25(m,1H),1.89-1.86(m,2H).

[1173] Compound 141-E2 LC / MS ESI 433 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.60-7.57(m,2H),7.51-7.50(m,1H),7.43-7.38(m,3H),7.16(d,J=7.2Hz,1H),6.37(d,J=7.2Hz,1H),4.45(s,1H),3.78-3. 75(m,2H),3.39-3.23(m,7H),3.03-3.00(m,1H),2.85-2.83(m,4H),2.7 1-2.68(m,2H),2.39-2.37(m,1H),2.28-2.25(m,1H),1.89-1.83(m,2H).

[1174] 2-(4-Chlorophenyl)-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-piperidin-1'-yl)acetic acid (compound 142)

[1175]

[1176] Compound 142 LC / MS ESI 483 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.50(d,J=8.8,2H),7.32(d,J=8.4,2H),7.14(d,J=7.2Hz,1H),6.35(d,J=7.2Hz,1H),3.8 0(s,1H),3.49-3.31(m,5H),2.95-2.69(m,6H),2.47(d,J=9.2Hz,2H),2.37-1.67(m,11H),1.51-1.38(m,2H).

[1177] 2-(3-Chlorophenyl)-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-piperidin-1'-yl)acetic acid (compound 143)

[1178]

[1179] Compound 143 LC / MS ESI 483.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.61(s,1H),7.44-7.42(m,1H),7.32-7.29(m,2H),7.16(d,J=7.0Hz,1H),6.38(d,J=7.3Hz,1H),3.86(s,1H),3.46-3.37(m,6 H),3.01(m,1H),2.85(m,2H),2.79(t,J=6.2Hz,2H),2.51(t,J=7.5Hz,2H ),2.25(s,2H),2.04(m.1H),1.97-1.84(m,8H),1.77(m,1H),1.65(m,2H).

[1180] 2-(2-Chlorophenyl)-2-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)-1,4'-piperidin-1'-yl)acetic acid (enantiomers 144-E1 and 144-E2)

[1181]

[1182] Compound 144-E1 LC / MS ESI 483 (M+H) + . 1H NMR(500MHz,MeOD)δ7.82(dd,J=7.7,1.8Hz,1H),7.41(dd,J=7.8,1.3Hz,1H),7.32-7.15(m,2H) ,7.16(d,J=7.3Hz,1H),6.37(d,J=7.3Hz,1H),4.52(s,1H),3.48(d,J=10.5Hz,1H),3.43-3.35( m,4H),2.99(s,1H),2.88-2.74(m,3H),2.72(t,J=6.2Hz,2H),2.49(d,J=6.9Hz,2H),2.37(s,1H ), 2.22 (s, 1H), 2.04 (d, J = 12.0Hz, 1H), 1.93-1.85 (m, 7H), 1.77-1.67 (m, 1H), 1.51-1.38 (m, 2H). Chiral SFC I (50% EtOH): ee 100%, Rt=8.05 min.

[1183] Compound 144-E2 LC / MS ESI 483 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.82(dd,J=7.6,1.8Hz,1H),7.41(dd,J=7.8,1.2Hz,1H),7.32-7.15(m,2H) ,7.16(d,J=7.3Hz,1H),6.37(d,J=7.3Hz,1H),4.52(s,1H),3.47(d,J=9.3Hz,1H),3.42-3.35(m ,4H),2.99(s,1H),2.87-2.74(m,3H),2.72(t,J=6.2Hz,2H),2.49(d,J=6.9Hz,2H),2.37(s,1H) ,2.22(s,1H),2.04(d,J=12.7Hz,1H),1.94-1.82(m,7H),1.76-1.68(m,1H),1.49-1.42(m,2H). Chiral SFC I (50% EtOH): ee 100%, Rt=11.00 min.

[1184] 2-Phenylacetyl-2-((3R,3'R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)-1,3'-bipyrrolidone-1'-yl)acetic acid (compound 145)

[1185]

[1186] Compound 145 LC / MS ESI 435.2 (M+H)+ . 1 H NMR(500MHz,MeOD)δ7.45-7.40(m,2H),7.25-7.18(m,3H),7.03-7.01(m,1H),6.27(t,J=7.5Hz,1H ),3.78-3.74(m,1H),3.30-3.25(m,2H),3.15-2.90(m,2H),2.85-1.85(m,16H),1.80-1.44(m,6H).

[1187] 2-(3-chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 146-E1 and 146-E2)

[1188]

[1189] Compound 146-E1 LC / MS ESI 375.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.61(s,1H),7.48-7.39(m,3H),7.20(d,J=9.0Hz,1H),6.41(d,J=9.0Hz,1H),4.42(s,1H),4.16(s,1H),3.47-3. 37(m,5H),3.13(m,1H),2.98(m,1H),2.73(t,J=8.0Hz,2H),2.58(t,J=9.5Hz,2H),2.09(s,2H),1.90-1.88(m,2H),1.74-1.59(m,5H). Chiral SFC A (35% MeOH): ee100%, Rt=2.81 min.

[1190] Compound 146-E2 LC / MS ESI 375.2 (M+H) + . 1H NMR(500MHz,MeOD)δ7.62(s,1H),7.48-7.39(m,3H),7.20(d,J=9.0Hz,1H),6.41(d,J=9.0Hz,1H),4.33(s,1H),4.15(s,1H),3.47-3 .37(m,4H),3.27(m,2H),3.05(m,2H),2.73(t,J=8.0Hz,2H),2.58(m,2H),2.09(s,1H),1.90-1.88(m,2H),1.74(m,2H),1.61(m,2H). Chiral SFC A (35% MeOH): ee 100%, Rt=5.23 min.

[1191] 2-(4-chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 147-E1 and 147-E2)

[1192]

[1193] Compound 147-E1 LC / MS ESI 444 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.51(d,J=8.8,2H),7.42(d,J=8.8,2H),7.19(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),4.49-4.47(m, 1H), 4.17 (s, 1H), 3.49-3.31 (m, 5H), 3.25-2.91 (m, 3H), 2.98 (t, J = 5.6Hz, 2H), 2.56 (t, J = 8.0Hz, 2H), 2.11-1.61 (m, 8H). Chiral SFC A (40% MeOH): ee 100%, Rt=2.21 min.

[1194] Compound 147-E2 LC / MS ESI 444 (M+H) + . 1H NMR (400MHz, MeOD) δ7.51(d,J=8.8,2H),7.42(d,J=8.8,2H),7.19(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),4.41-4.37( m,1H),4.18(s,1H),3.49-3.31(m,4H),3.25-2.95(m,4H),2.71(t,J=6.4Hz,2H),2.65-2.56(m,2H),2.15-1.55(m,8H). Chiral SFC A (40% MeOH): ee 100%, Rt = 4.29 min.

[1195] 2-(2-chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 148-E1 and 148-E2)

[1196]

[1197] Compound 148-E1 LC / MS ESI 444 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.81-7.39(m,4H),7.19(d,J=7.2Hz,1H),6.40(d,J=7.6Hz,1H),5.03(s, 1H),4.16(s,1H),3.49-3.31(m,5H),3.22-3.05(m,3H),2.73-2.55(m,4H),2.25-1.55(m,8H). Chiral SFC F (45% MeOH): ee100%, Rt=5.41 min.

[1198] Compound 148-E2 LC / MS ESI 444 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.81-7.39(m,4H),7.19(d,J=7.2Hz,1H),6.40(d,J=7.6Hz,1H),5.16(s, 1H),4.18(s,1H),3.49-3.31(m,5H),3.22-3.05(m,3H),2.73-2.55(m,4H),2.25-1.55(m,8H). Chiral SFC F (45% MeOH): ee100%, Rt=7.48min.

[1199] 2-(3-Chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 149-E1 and 149-E2)

[1200]

[1201] Compound 149-E1 LC / MS ESI 483.2 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.56(s,1H),7.52-7.41(m,3H),7.17-7.14(m,1H),6.38(d,J=7.2Hz,1H),4.63(d,J=11.6Hz,1H),4.53(s ,1H),4.08(d,J=12.8Hz,1H),3.71-3.58(m,2H),3.40-2.98(m,6H),2.80-2.68(m,4H),2.38-1.85(m,6H),1.73-1.55(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 1.89 min.

[1202] Compound 149-E2 LC / MS ESI 483.2 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.56 (s, 1H), 7.52-7.41 (m, 3H), 7.05 (d, J = 7.6Hz, 1H), 6.26 (t, J = 7.2Hz, 1H), 4.53 (d, J = 12.4Hz, 1H), 4.36 (s,1H),3.95(d,J=14.0Hz,1H),3.51-3.38(m,5H),3.18-2.84(m,3H),2.68-2.55(m,4H),2.31-1.75(m,6H),1.60-1.45(m,2H). Chiral SFC A (45% MeOH): ee 100%, Rt=3.40 min.

[1203] 2-(2-Chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (compound 150)

[1204]

[1205] Compound 150 LC / MS ESI 483.2 (M+H) + .1 H NMR (400MHz, MeOD) δ7.81-7.75(m,1H),7.58-7.38(m,3H),7.16(d,J=7.2Hz,1H),6.40-6.35(m,1H),5.24-5.10(m,1H ),4.65-4.61(m,1H),4.10-4.06(m,1H),3.71-2.98(m,8H),2.80-2.68(m,4H),2.38-1.81(m,6H),1.75-1.55(m,2H).

[1206] 2-(4-chlorophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 151-E1 and 151-E2)

[1207]

[1208] Compound 151-E1 LC / MS ESI 483.2 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.58(d,J=7.4Hz,2H),7.45(d,J=7.4Hz,2H),7.19-7.14(m,1H),6.39-6.36(m,1H),4.65-4.60(m,2H ), 4.08 (d, J = 12.4Hz, 1H), 3.75-3.58 (m, 2H), 3.40-2.91 (m, 6H), 2.79-2.65 (m, 4H), 2.38-1.82 (m, 6H), 1.72-1.55 (m, 2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 1.96 min.

[1209] Compound 151-E2 LC / MS ESI 483.2 (M+H) + . 1H NMR (400MHz, MeOD) δ7.48-7.45(m,2H),7.33(d,J=8.4Hz,2H),7.04(d,J=7.2Hz,1H),6.26(t,J=7.2Hz,1H),4.50(d,J=13.2Hz,1H), 4.39(s,1H),3.95(d,J=13.2Hz,1H),3.55-3.31(m,5H),3.18-2.85(m,3H),2.70-2.55(m,4H),2.31-1.72(m,6H),1.60-1.41(m,2H). Chiral SFC A (45% MeOH): ee100%, Rt=3.71 min.

[1210] 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)piperidin-1-carbonyl)pyrrolidine-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 152-E1 and 152-E2)

[1211]

[1212] Compound 152-E1 LC / MS ESI 517 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.80-7.74(m,4H),7.18(t,J=6.4Hz,1H),6.39(d,J=7.2Hz,1H),4.71-4.63(m,2H),4.08(d ,J=13.2Hz,1H),3.76-3.58(m,2H),3.42-2.91(m,6H),2.79-2.65(m,4H),2.38-1.82(m,6H),1.72-1.55(m,2H). Chiral SFC A (35% MeOH): ee 100%, Rt = 2.47 min.

[1213] Compound 152-E2 LC / MS ESI 517 (M+H) + . 1H NMR(400MHz,MeOD)δ7.68-7.56(m,4H),7.03(d,J=6.8Hz,1H),6.28-6.23(m,1H),4.52(d,J=12.8Hz,1H),4.23 -4.19(m,1H),3.99-3.96(m,1H),3.45-2.65(m,8H),2.62-2.55(m,4H),2.21-1.72(m,6H),1.59-1.42(m,2H). Chiral SFC A (35% MeOH): ee 100%, Rt=3.81 min.

[1214] 2-(4-Ethylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 153-E1 and 153-E2)

[1215]

[1216] Compound 153-E1 LC / MS ESI 438 (M+H) +1 H NMR(400MHz,MeOD)δ7.43(d,J=8.4,2H),7.26(d,J=8.0,2H),7.15(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H), 4.46(s,1H),4.18(s,1H),3.55-2.95(m,8H),2.73-2.53(m,6H),2.18-1.56(m,8H),1.23(t,J=7.6Hz,3H). Chiral SFC A (35% MeOH): ee 100%, Rt = 2.86 min.

[1217] Compound 153-E2 LC / MS ESI 438 (M+H) +1 H NMR(400MHz,MeOD)δ7.43(d,J=8.4,2H),7.26(d,J=8.0,2H),7.15(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H), 4.34(s,1H),4.05(s,1H),3.41-2.95(m,8H),2.61-2.38(m,6H),2.10-1.46(m,8H),1.13(t,J=7.6Hz,3H). Chiral SFC A (35% MeOH): ee 100%, Rt = 4.99 min.

[1218] 2-(3-Ethylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 154-E1 and 154-E2)

[1219]

[1220] Compound 154-E1 LC / MS ESI 438 (M+H) +1 H NMR (400MHz, MeOD) δ7.40-7.25(m,4H),7.14(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H),4.45( s,1H),4.18(s,1H),3.53-2.95(m,8H),2.72-2.52(m,6H),2.15-1.56(m,8H),1.35(t,3H). Chiral SFC A (40% MeOH): ee 100%, Rt=1.88 min.

[1221] Compound 154-E2 LC / MS ESI 438 (M+H) +1 H NMR (400MHz, MeOD) δ7.30-7.14(m,4H),7.04(d,J=7.2Hz,1H),6.28(d,J=7.2Hz,1H),4.34( s,1H),4.06(s,1H),3.43-2.99(m,8H),2.62-2.42(m,6H),2.15-1.46(m,8H),1.25(t,3H). Chiral SFC A (40% MeOH): ee 100%, Rt = 3.59 min.

[1222] 2-(2-Ethylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 155-E1 and 155-E2)

[1223]

[1224] Compound 155-E1 LC / MS ESI 438 (M+H) +1H NMR(400MHz,MeOD)δ7.62(d,J=7.6,1H),7.32-7.14(m,4H),6.38(d,J=7.2Hz,1H),4.83(s ,1H),4.15(s,1H),3.53-3.15(m,8H),2.91-2.53(m,6H),2.18-1.56(m,8H),1.35(t,3H). Chiral SFC F (30% MeOH): ee 100%, Rt=3.28 min.

[1225] Compound 155-E2 LC / MS ESI 438 (M+H)+ 1 H NMR(400MHz,MeOD)δ7.62(d,J=7.6,1H),7.32-7.14(m,4H),6.38(d,J=7.2Hz,1H),4.73(s ,1H),4.15(s,1H),3.53-3.15(m,8H),2.91-2.53(m,6H),2.18-1.56(m,8H),1.35(t,3H). Chiral SFC F (30% MeOH): ee 100%, Rt=6.54min.

[1226] 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 156-E1 and 156-E2)

[1227]

[1228] Compound 156-E1 LC / MS ESI 478 (M+H) +1 H NMR(400MHz,MeOD)δ7.75-7.70(m,4H),7.20(d,J=7.2Hz,1H),6.41(d,J=7.2Hz,1H) ,4.42(s,1H),4.15(s,1H),3.51-2.95(m,8H),2.74-2.53(m,4H),2.18-1.56(m,8H). Chiral SFC A (35% MeOH): ee 100%, Rt = 1.73 min.

[1229] Compound 156-E2 LC / MS ESI 478 (M+H) +1H NMR(400MHz,MeOD)δ7.75-7.70(m,4H),7.22(d,J=7.6Hz,1H),6.42(d,J=7.2Hz,1H) ,4.53(s,1H),4.16(s,1H),3.51-2.95(m,8H),2.74-2.53(m,4H),2.18-1.56(m,8H). Chiral SFC A (35% MeOH): ee 100%, Rt = 2.72 min.

[1230] 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-(3-(trifluoromethyl)phenyl)acetic acid (diastereomers 157-E1 and 157-E2)

[1231]

[1232] Compound 157-E1 LC / MS ESI 478 (M+H) +1 H NMR(400MHz,MeOD)δ7.91(s,1H),7.80(d,J=7.6Hz,1H),7.61-7.50(m,2H),7.15(d,J=7.6Hz,1H), 6.37(d,J=7.6Hz,1H),4.10-4.04(m,2H),3.49-2.85(m,5H),2.75-2.51(m,7H),2.18-1.56(m,8H). Chiral SFC A (25% MeOH): ee 100%, Rt=3.28 min.

[1233] Compound 157-E2 LC / MS ESI 478 (M+H) +1 H NMR(400MHz,MeOD)δ7.93(s,1H),7.80(d,J=7.6Hz,1H),7.61-7.50(m,2H),7.21(d,J=7.2Hz,1H),6.4 1(d,J=7.6Hz,1H),4.38(s,1H),4.15(s,1H),3.50-2.95(m,8H),2.73-2.51(m,4H),2.18-1.56(m,8H). Chiral SFC A (25% MeOH): ee 100%, Rt = 4.83 min.

[1234] 2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-(2-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 158-E1 and 158-E2)

[1235]

[1236] Compound 158-E1 LC / MS ESI 478 (M+H) +1 H NMR (400MHz, MeOD) δ8.01(d,J=8.0Hz,1H),7.76(d,J=7.6Hz,1H),7.67(t,J=7.2Hz,1H),7.54(t,J=7.6Hz,1H),7.19(d, J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),4.62(s,1H),4.13(s,1H),3.49-2.85(m,8H),2.73-2.55(m,4H),2.16-1.56(m,8H).

[1237] Compound 158-E2 LC / MS ESI 478 (M+H) +1 H NMR (400MHz, MeOD) δ8.01(d,J=8.0Hz,1H),7.76(d,J=7.6Hz,1H),7.67(t,J=7.2Hz,1H),7.54(t,J=7.6Hz,1H),7.19(d, J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),4.73(s,1H),4.13(s,1H),3.49-2.85(m,8H),2.73-2.55(m,4H),2.16-1.56(m,8H).

[1238] 2-((3R)-3-(4-(7-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-phenylacetic acid (diastereomeric compounds 159-E1 and 159-E2)

[1239]

[1240] Compound 159-E1 LC / MS ESI 424 (M+H) +1H NMR (400MHz, MeOD) δ7.76-7.53(m,2H),7.42-7.40(m,3H),7.19(d,J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),4.48(s,1H), 4.18-4.16(m,1H),3.55-3.24(m,5H),3.16-2.98(m,2H),2.75-2.53(m,4H),2.16-1.45(m,8H),1.22(d,J=7.2Hz,3H). Chiral SFC A (30% MeOH): ee 100%, Rt=2.50 min.

[1241] Compound 159-E2 LC / MS ESI 424 (M+H) +1 H NMR(400MHz,MeOD)δ7.76-7.53(m,2H),7.42-7.40(m,3H),7.19(d,J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),4.39(s,1H), 4.18-4.16(m,1H),3.65-3.20(m,5H),3.18-3.02(m,2H),2.75-2.53(m,4H),2.21-1.45(m,8H),1.22(d,J=7.2Hz,3H). Chiral SFC A (30% MeOH): ee 100%, Rt = 4.40 min.

[1242] 2-((3R)-3-(4-(6-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-phenylacetic acid (diastereomeric compounds 160-E1 and 160-E2)

[1243]

[1244] Compound 160-E1 LC / MS ESI 424 (M+H) +1 H NMR(400MHz,MeOD)δ7.55-7.53(m,2H),7.42-7.40(m,3H),7.16(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H),4.46(s,1H), 4.18-4.16(m,1H),3.58-3.24(m,5H),3.16-2.91(m,3H),2.78-2.35(m,4H),2.16-1.45(m,7H),1.04(d,J=6.4Hz,3H). Chiral SFC A (40% MeOH): ee 100%, Rt=1.83 min.

[1245] Compound 160-E2 LC / MS ESI 424 (M+H) +1 H NMR (400MHz, MeOD) δ7.55-7.53(m,2H),7.42-7.40(m,3H),7.16(d,J=7.2Hz,1H),6.38(d,J=7.2Hz,1H),4.44(s,1H),4.18-4.1 6(m,1H),3.48-3.24(m,5H),3.16-2.91(m,3H),2.78-2.35(m,4H),2.16-1.90(m,4H),1.75-1.50(m,3H),1.04(d,J=6.4Hz,3H). Chiral SFC A (40% MeOH): ee 100%, Rt = 2.84 min.

[1246] 2-((3R)-3-(4-(5-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-phenylacetic acid (diastereomeric compounds 161-E1 and 161-E2)

[1247]

[1248] Compound 161-E1 LC / MS ESI 424 (M+H)+ 1 H NMR(400MHz,MeOD)δ8.54(s,1H),7.58-7.57(m,3H),7.45-7.43(m,3H),6.57(d,J=7.6Hz,1H),4.62(s,1H),4.21-4.19(m,1H),3.51-3.40(m, 6H),3.27-3.21(m,2H),2.95-2.91(m,1H),2.72-2.68(m,2H),2.16-2. 14(m,2H),1.96-1.94(m,1H),1.71-1.63(m,5H),1.30(d,J=6.8Hz,1H).

[1249] Compound 161-E2 LC / MS ESI 424 (M+H)+ 1H NMR(400MHz,MeOD)δ8.53(s,1H),7.57-7.55(m,3H),7.46-7.44(m,3H),6.56(d,J=7.2Hz,1H),4.67(s,1H),4.21–4.19(m,1H),3.51–3.40(m, 5H),3.11-3.09(m,1H),2.93-2.91(m,1H),2.72-2.65(m,2H),2.16-2. 14(m,1H),1.96-1.94(m,1H),1.71-1.63(m,5H),1.30(d,J=6.8Hz,1H).

[1250] 2-Phenyl-2-((R)-3-((1r,4R)-4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)cyclohexyloxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 162-E1 and 162-E2)

[1251]

[1252] Compound 162-E1 LC / MS ESI 436.2 (M+H)+. 1 H NMR (500MHz, CD3OD) δ7.59-7.58(m,2H),7.45-7.44(m,3H),7.14(d,J=7.5Hz,1H),6.37(d,J=7.5Hz,1H),4.46-4.42(m,2H),3.40-3.33(m,4H),3.1 9-3.17(m,2H),2.72-2.69(m,2H),2.42-2.38(m,1H),2.26-2.22(m,1H),2 .14-2.12(m,3H),1.94-1.86(m,4H),1.54-1.52(m,2H)1.43-1.30(m,3H). Chiral SFC B (40% MeOH): ee 100%, Rt = 1.83 min.

[1253] Compound 162-E2 LC / MS ESI 436.2 (M+H)+. 1H NMR (500MHz, CD3OD) δ7.59-7.57(m,2H),7.47-7.44(m,3H),7.14(d,J=8.0Hz,1H),6.38(d,J=8.0Hz,1H),4.47-4.44(m,2H),3.61-3.59(m,1H),3.3 6-3.33(m,3H),3.06-2.99(m,2H),2.72-2.69(m,2H),2.43-2.38(m,1H),2 .18-2.07(m,4H),1.94-1.86(m,4H),1.46-1.38(m,2H)1.31-1.16(m,3H). Chiral SFC B (40% MeOH): ee 95.0%, Rt = 3.14

[1254] min.

[1255] 2-(4-Cyclopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 163-E1 and 163-E2)

[1256]

[1257] Compound 163-E1 LC / MS ESI 466.3 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.47-7.45(m,2H),7.16 -7.07(m,3H),6.383(d,J=7.6Hz,1H),4.456(s,1H),4.19(s,1H),3.82-3.78(m,1H),3.46-3.31(m,6H),3.21-3.15(m,2H),2.70 -2.68(m,2H),2.55-2.53(m,2H),2.22-2.16(m,2H),1.95-1.91(m,2H),1.88-1.55(m,4H),0.81-0.79(m,2H),0.69-0.68(m,2H).

[1258] Compound 163-E2 LC / MS ESI 466.3 (M+H) + . 1H NMR(400MHz,MeOD)δ7.462-7.44(m,2H),7.16 -7.08(m,3H),6.387(d,J=7.2Hz,1H),4.462(s,1H),4.19(s,1H),3.82-3.78(m,1H),3.46-3.31(m,6H),3.21-3.15(m,2H),2.72 -2.69(m,2H),2.56-2.53(m,2H),2.2-2.00(m,2H),1.89-1.86(m,2H),1.78-1.60(m,4H),0.81-0.79(m,2H),0.69-0.68(m,2H).

[1259] 2-((R)-3-(4-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-phenylacetic acid (diastereomeric compounds 164-E1 and 164-E2)

[1260]

[1261] Compound 164-E1 LC / MS ESI 424.3 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.54-7.41(m,5H),6.37(s,1H),4.45(s,1H),4.17(s,1H),3.45-2.91(m,8H),2.68-2.52(m 4H),2.17(s,3H),2.15-1.55(m,8H). Chiral SFC B (30% MeOH): ee100%, Rt=1.48min.

[1262] Compound 164-E2 LC / MS ESI 424.3 (M+H) + . 1 ¹H NMR (400MHz, MeOD) δ 7.55–7.41 (m, 5H), 6.37 (s, 1H), 4.41 (s, 1H), 4.16 (s, 1H), 3.45–3.05 (m, 8H), 2.68–2.52 (m, 4H), 2.17 (s, 3H), 2.15–1.55 (m, 8H). Chiral SFC B (30% MeOH): ee 100%, Rt = 2.66 min.

[1263] 2-((R)-3-(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)-2-phenylacetic acid (diastereomeric compounds 165-E1 and 165-E2)

[1264]

[1265] Compound 165-E1 LC / MS ESI 424.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.54(s,2H),7.41(m,3H),7.08(s,1H),4.44(s,1H),4. 16(s,1H),3.45(m,3H),3.21(m,2H),3.18(m,2H),2.98(m,1H),2.77-2.58(m 4H),2.09(s,5H),1.88(m,2H),1.67(m,4H). Chiral SFC A (40% MeOH): ee 100%, Rt = 2.36 min.

[1266] Compound 165-E2 LC / MS ESI 424.1 (M+H) + . 1 H NMR(500MHz,MeODδ7.54(s,2H),7.41(m,3H),7.06(s,1H),4.40(s,1H),4.19(s,1H),3. 45(m,6H),3.18(m,2H),2.77-2.58(m4H),2.09(m,5H),1.88(m,2H),1.67(m,4H). A (40% MeOH): ee 99%, Rt = 3.55 min.

[1267] 2-(2-Isopropoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 166-P1 and 166-P2)

[1268]

[1269] Compound 166-P1 LC / MS ESI 468.3 (M+H) + . 1H NMR (400MHz, MeOD) δ7.55 (d, J=6.4Hz, 1H), 7.38-7.35 (m, 1H), 7.15 -6.95(m,3H),6.37(d,J=7.6Hz,1H),4.99(s,1H),4.89-4.72(m,1H),4.19(s,1H),3.64-3.36(m,6H),3.24-3.20(m,2 H),2.72-2.68(m,2H),2.55-2.51(m,2H),2.14-2.11(m,2H),1.89-1.86(m,2H),1.71-1.56(m,4H),1.38-1.35(m,6H).

[1270] Compound 166-P2 LC / MS ESI 468.3 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.51 (d, J=6.8Hz, 1H), 7.38-7.35 (m, 1H), 7.15 -6.95(m,3H),6.37(d,J=6.8Hz,1H),5.06(s,1H),4.74--4.71(m,1H),4.18(s,1H),3.64-3.36(m,6H),3.24-3.05(m,2 H),2.72-2.68(m,2H),2.55-2.51(m,2H),2.20-2.00(m,2H),1.89-1.86(m,2H),1.71-1.56(m,4H),1.38-1.35(m,6H).

[1271] 2-(2,3-Dihydrobenzofuran-7-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 167-P1 and 167-P2)

[1272]

[1273] Compound 167-P1 LC / MS ESI 452 (M+H) +1H NMR (400MHz, MeOD) δ7.26(d,J=7.6Hz,2H),7.15(d,J=7.2Hz,1H),6.88(t,J=7.6Hz,1H),6.38(d,J=7.2Hz,1H ), 4.83 (s, 1H), 4.56 (t, J = 7.6Hz, 2H), 4.15 (s, 1H), 3.55-3.15 (m, 10H), 2.71-2.52 (m, 4H), 2.20-1.56 (m, 8H). Chiral SFC C (25% MeOH): ee 100%, Rt = 0.97 min.

[1274] Compound 167-P2 LC / MS ESI 452 (M+H) +1 H NMR(400MHz,MeOD)δ7.30-7.25(m,2H),7.15(d,J=7.2Hz,1H),6.88(t,J=7.6Hz,1H),6.38(d,J=7.2Hz,1H), 4.78(s,1H),4.60(t,J=8.4Hz,2H),4.15(s,1H),3.55-3.15(m,10H),2.71-2.52(m,4H),2.20-1.56(m,8H). Chiral SFC C (25% MeOH): ee 100%, Rt = 1.73 min.

[1275] 2-(2-Methoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 168)

[1276]

[1277] Compound 168 LC / MS ESI 440 (M+H)+ 1 H NMR(400MHz,MeOD)δ8.38(s,1H),7.41-7.33(m,3H),7.02-6.92(m,2H),6.48 -6.44(m,1H),4.94-4.79(m,1H),4.20-4.15(m,1H),3.77-2.95(m,11H),2.58 -2.50(m,4H),2.15-1.49(m,8H).

[1278] 2-(2-ethoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 169)

[1279]

[1280] Compound 169 LC / MS ESI 454 (M+H)+ 1 H NMR(400MHz,MeOD)δ7.52(t,J=4.8Hz,1H),7.41(t,J=4.8Hz,1H),7.15-6.98(m,3H ),6.39-6.35(m,1H),5.09-5.02(m,1H),4.17-4.10(m,3H),3.55-3.11(m,8H),2.72 -2.50(m,4H),2.15-1.38(m,11H).

[1281] 2-(2,3-Dihydrobenzofuran-4-yl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 170-E1 and 170-E2)

[1282]

[1283] Compound 170-E1 LC / MS ESI 452.2 (M+H)+. 1 H NMR(500MHz,CD3OD)δ7.18-7.15(m,2H),7.08-7.04(m,1H),6.77(d,J=8.0Hz,1 H),6.41-6.38(m,1H),4.59-4.52(m,3H),4.21-4.19(m,1H),3.54-3.38(m,6H), 3.29-3.20(m,3H),3.11-3.07(m,1H),2.72(t,J=6.0Hz,2H),2.56(t,J=7.0Hz,2 H),2.17-2.07(m,2H),1.92-1.88(m,2H),1.76-1.71(m,2H),1.70-1.59(m,2H). Chiral SFC A (40% MeOH): ee 41.7%, Rt = 2.55 min.

[1284] Compound 170-E2 LC / MS ESI 452.2 (M+H)+. 1H NMR(500MHz,CD3OD)δ7.18-7.15(m,2H),7.08-7.04(m,1H),6.77(d,J=8.0 Hz,1H),6.41-6.39(m,1H),4.59-4.52(m,3H),4.20-4.18(m,1H),3.54-3. 36(m,6H),3.30-3.09(m,4H),2.72(t,J=6.5Hz,2H),2.60-2.53(m,2H),2. 20-2.18(m,2H),1.91-1.87(m,2H),1.76-1.65(m,2H),1.63-1.59(m,2H). Chiral SFC A (40% MeOH): ee 57.7%, Rt = 4.22 min.

[1285] 2-(2-methoxyphenyl)-2-((R)-3-(5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 171-E1 and 171-E2)

[1286]

[1287] Compound 171-E1 LC / MS ESI 438.3 (M+H) + . 1 H NMR (400MHz, MeOD) δ7.50-7.43(m,3H),7.12-7.03(m,2H),6.52(d,J=7.6Hz,1H),5.01(s,1H),3.91(s,3H),3.47-3.43(m,3H),3.3 3-3.00(m,3H),2.80-2.77(m,2H),2.65-2.62(m,2H),2.40-2.10(m,2H),1.95-1.85(m,2H),1.75-1.68(m,3H),1.52-1.24(m,6H).

[1288] Compound 171-E2 LC / MS ESI 438.3 (M+H) + . 1H NMR (400MHz, MeOD) δ7.55-7.43(m,3H),7.12-7.03(m,2H),6.52(d,J=7.2Hz,1H),5.04(s,1H),3.91(s,3H),3.47-3.43(m ,4H),3.21-3.11(m,1H),2.80-2.63(m,5H),2.45-2.12(m,2H),1.94-1.91(m,2H),1.68-1.65(m,3H),1.52-1.24(m,6H).

[1289] 2-(4-ethoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 172-E1 and 172-E2)

[1290]

[1291] Compound 172-E1 LC / MS ESI 454 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.46(d,J=8.4Hz,2H),7.17(d,J=7.2Hz,1H),6.93(d,J=8.4Hz,2H),6.37(d,J=7.2Hz,1H),4.42(s, 1H), 4.16 (s, 1H), 4.04 (q, J = 6.8Hz, 2H), 3.50-3.11 (m, 8H), 2.72-2.52 (m, 4H), 2.20-1.55 (m, 8H), 1.38 (t, J = 6.8Hz, 3H). Chiral SFC B (30% MeOH): ee 100%, Rt = 1.59 min.

[1292] Compound 172-E2 LC / MS ESI 454 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.46(d,J=8.4Hz,2H),7.17(d,J=7.2Hz,1H),6.93(d,J=8.4Hz,2H),6.37(d,J=7.2Hz,1H),4.39(s,1H),4.17(s, 1H), 4.04 (q, J = 6.8Hz, 2H), 3.50-2.95 (m, 8H), 2.70 (t, J = 6.0Hz, 2H), 2.54 (t, J = 7.2Hz, 2H), 2.10-1.45 (m, 8H), 1.38 (t, J = 6.8Hz, 3H). Chiral SFC B (30% MeOH): ee 100%, Rt=4.18 min.

[1293] 2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 173-E1 and 173-E2)

[1294]

[1295] Compound 173-E1 LC / MS ESI 508 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.67(d,J=7.9Hz,1H),7.32(d,J=10.7Hz,2H),7.17(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),5 .05(s,1H),4.19(s,1H),3.95(s,3H),3.70-3.32(m,6H),3.12-3.08(m,2H),2.64-2.54(m,4H),2.13-1.49(m,8H). Chiral SFC A (35% MeOH): ee100%, Rt=2.34min.

[1296] Compound 173-E2 LC / MS ESI 508 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.67(d,J=7.9Hz,1H),7.32(d,J=10.7Hz,2H),7.17(d,J=7.3Hz,1H),6.40(d,J=7.3Hz,1H),5 .08(s,1H),4.21(s,1H),3.95(s,3H),3.70-3.32(m,6H),3.12-3.08(m,2H),2.64-2.54(m,4H),2.13-1.49(m,8H). Chiral SFC A (35% MeOH): ee100%, Rt=3.25min.

[1297] 2-(4-tert-butoxyphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (compound 174)

[1298]

[1299] Compound 174 LC / MS ESI 482 (M+H)+ 1H NMR (400MHz, MeOD) δ7.45(d,J=8.4Hz,2H),7.15(d,J=7.6Hz,1H),7.03(d,J=8.4 Hz,2H),6.39(d,J=7.6Hz,1H),4.47(s,1H),4.19(s,1H),3.55-3.32(m,6H),3.20 -3.05(m,2H),2.75-2.54(m,4H),2.20-1.58(m,8H),1.36(s,9H).

[1300] 2-(4-cyanophenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 175-E1 and 175-E2)

[1301]

[1302] Compound 175-E1 LC / MS ESI 435 (M+H)+ 1 H NMR(400MHz,MeOD)δ7.77-7.71(m,4H),7.26(d,J=7.6Hz,1H),6.44(d,J=7.6Hz, 1H),4.31(s,1H),4.16-4.11(m,1H),3.51-3.29(m,5H),3.20-2.97(m,3H),2.75 -2.59(m,4H),2.22-1.65(m,8H). Chiral SFC B (30% MeOH): ee 100%, Rt=1.26 min.

[1303] Compound 175-E2 LC / MS ESI 435 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.77-7.71(m,4H),7.26(d,J=7.6Hz,1H),6.44(d,J=7.6Hz,1H),4.48(s,1H),4.16-4.11(m,1H),3.51-3.15(m,7H),2.85 -2.57(m,5H),2.15-1.55(m,8H). Chiral SFC B (30% MeOH): ee 100%, Rt=3.06 min.

[1304] 2-((R)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)propoxy)pyrrolidine-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diastereomers 176-E1 and 176-E2)

[1305]

[1306] Compound 176-E1 LC / MS ESI 464 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.76(d,J=8.4Hz,2H),7.69(d,J=8.0Hz,2H),7.17(d,J=7.2Hz,1H),6.39(d,J=7.2Hz, 1H),4.30(s,1H),4.12(s,1H),3.44-3.37(m,4H),3.20-2.89(m,4H),2.72-2.59(m,4H),2.20-1.85(m,6H). Chiral SFC B (35% MeOH): ee 100%, Rt=0.79min

[1307] Compound 176-E2 LC / MS ESI 464 (M+H)+ 1 H NMR (400MHz, MeOD) δ7.76(d,J=8.4Hz,2H),7.69(d,J=8.0Hz,2H),7.17(d,J=7.2Hz,1H),6.39(d,J=7.2Hz, 1H),4.20(s,1H),4.11(s,1H),3.44-3.28(m,5H),3.09-2.95(m,1H),2.78-2.55(m,6H),2.10-1.85(m,6H). Chiral SFC B (35% MeOH): ee 90%, Rt=2.65min

[1308] 2-(3,5-Dimethylphenyl)-2-((R)-3-(4-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 177-E1 and 177-E2)

[1309]

[1310] Compound 177-E1 LC / MS ESI 438(M+H)+. 1 H NMR(400MHz,MeOD)δ8.51(s,1H),7.49(d,J=7.6Hz,1H),7.18(s,2H),7.08(s, 1H),6.55(d,J=7.2Hz,1H),4.55(s,1H),4.19(s,1H),3.52-3.24(m,9H),2.80 -2.69(m,4H),2.31-2.15(m,8H),1.93-1.65(m,6H).

[1311] Compound 177-E2 LC / MS ESI 438(M+H)+. 1 H NMR(400MHz,MeOD)δ8.51(s,1H),7.49(d,J=7.6Hz,1H),7.18(s,2H),7.08(s, 1H),6.55(d,J=7.2Hz,1H),4.59(s,1H),4.20(s,1H),3.50-3.10(m,9H),2.80 -2.68(m,4H),2.31-2.15(m,8H),1.93-1.65(m,6H).

[1312] 2-Phenyl-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (enantiomers 178-E1 and 178-E2)

[1313]

[1314] Compound 178-E1 LC / MS ESI 449.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.51(d,J=7.6Hz,2H),7.41(d,J=6.5Hz,3H),7.15(d,J=7 .1Hz,1H),6.35(d,J=7.3Hz,1H),4.47(d,J=13.4Hz,2H),4.19(s,1H),3.86(M ,4H),3.64-3.54(m,1H),3.43-3.37(m,2H),2.98(t,J=13.2Hz,1H),2.68(M,3 H), 2.52-2.38 (m, 2H), 1.96-1.82 (m, 3H), 1.68 (d, J = 13.0Hz, 2H), 1.12 (M, 2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 2.12 min.

[1315] Compound 178-E2 LC / MS ESI 449.1 (M+H) + . 1H NMR(500MHz,MeOD)δ7.51(d,J=7.6Hz,2H),7.41(d,J=6.5Hz,3H),7.15(d,J=7 .1Hz,1H),6.51(d,J=7.3Hz,1H),4.47(d,J=13.4Hz,2H),4.19(s,1H),3.86(M ,4H),3.64-3.54(m,1H),3.42-3.37(m,2H),2.98(t,J=13.2Hz,1H),2.68(M,3 H), 2.62-2.38 (m, 2H), 1.96-1.82 (m, 3H), 1.68 (d, J = 13.0Hz, 2H), 1.12 (M, 2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 3.57 min.

[1316] 2-(4-(methyl(4-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)butyl)amino)piperidin-1-yl)acetic acid (compound 179)

[1317]

[1318] Compound 179 LC / MS ESI 361 (M+H)+. 1 H NMR(500MHz,MeOD)δ7.15(d,J=7.3Hz,1H),6.39(d,J=7.3Hz,1H),3.41-3.37(m,2H),3.24(s,2H),2 .78-2.63(m,6H),2.58-2.48(m,4H),2.39(s,3H),1.90(dd,J=11.1,6.5Hz,4H),1.83-1.55(m,7H).

[1319] 2-(2,4-Dimethoxyphenyl)-2-(4-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propylcarbamoyl)piperidin-1-yl)acetic acid (compound 180)

[1320]

[1321] Compound 180 LC / MS ESI 497 (M+H) + . 1H NMR(500MHz,MeOD)δ7.49(d,J=8.4Hz,1H),7.13(d,J=7.3Hz,1H),6.65-6.51(m,2 H),6.38(t,J=6.3Hz,1H),4.71(s,1H),3.87(s,3H),3.82(d,J=6.3Hz,3H),3.40- 3.36(m,2H),3.19(t,J=7.0Hz,2H),3.13(s,1H),2.71(dd,J=18.0,11.8Hz,3H),2 .57-2.49(m,2H),2.35(s,1H),2.00(dd,J=22.2,11.0Hz,1H),1.98-1.73(m,8H).

[1322] 2-(2-Isopropoxyphenyl)-2-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)carbamoyl)piperidin-1-yl)acetic acid (enantiomers 181-E1 and 181-E2)

[1323]

[1324] Compound 181-E1 LC / MS ESI 495 (M+H)+. 1 H NMR(500MHz,MeOD)δ7.56(dd,J=7.7,1.4Hz,1H),7.45-7.36(m,1H),7.12(dd,J=18.8,7.8Hz,2H),7. 00(t,J=7.5Hz,1H),6.38(d,J=7.3Hz,1H),4.96(s,1H),4.75(dt,J=12.1,6.0Hz,1H),3.71(s,1H),3 .45-3.35(m,2H),3.33-3.25(m,2H),3.19(t,J=6.9Hz,2H),2.96(s,2H),2.70(t,J=6.2Hz,2H),2.57 -2.49(m,2H),2.44(d,J=4.6Hz,1H),1.95(d,J=4.7Hz,4H),1.91-1.70(m,4H),1.42(d,J=6.0Hz,6H). Chiral SFC F (45% MeOH): ee 97%, Rt = 5.83 min.

[1325] Compound 181-E2 LC / MS ESI 495 (M+H)+. 1H NMR(500MHz,MeOD)δ7.56(dd,J=7.7,1.5Hz,1H),7.41(dd,J=12.4,5.1Hz,1H),7.12(dd,J=16.5, 7.8Hz,2H),7.01(t,J=7.5Hz,1H),6.38(d,J=7.3Hz,1H),4.98(s,1H),4.76(dt,J=12.1,6.0Hz,1 H),3.41-3.35(m,2H),3.20(t,J=7.0Hz,2H),2.99(t,J=10.5Hz,1H),2.72(dd,J=18.3,12.0Hz,2 H), 2.57-2.50 (m, 2H), 2.45 (s, 1H), 2.12-1.92 (m, 4H), 1.91-1.73 (m, 4H), 1.42 (d, J = 6.0Hz, 6H). Chiral SFC F (45% MeOH): ee94%, Rt=13.18 min.

[1326] 2-(2-Isopropoxyphenyl)-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutan-1-yl)acetic acid (enantiomers 182-E1 and 182-E2)

[1327]

[1328] Compound 182-E1 LC / MS ESI 507.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.42-7.38(m,2H),7.14-7.09(m,2H),6.99(t,J=7.5Hz,2H),6.35-6.33 (m,1H),5.13(d,J=9Hz,1H),4.78-4.52(m,1H),4.75-4.40(m,2H),4.21–4.14(m,2H),3.89– 3.86(m,2H),3.57(d,J=15Hz,1H),3.39(t,J=5.5Hz,2H),3.03-2.98(m,1H),2.78-2.60(m,3 H),2.46-2.45(m,2H),2.00-1.83(m,3H),1.71-1.68(m,2H),1.48-1.37(m,6H),1.14(s,2H). Chiral HPLC L (70% EtOH): ee 100%, Rt=17.25 min.

[1329] Compound 182-E2 LC / MS ESI 507.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.43-7.38(m,2H),7.15-7.10(m,2H),6.99(t,J=7.5Hz,2H),6.35-6.33 (m,1H),5.14(d,J=9Hz,1H),4.79-4.52(m,1H),4.76-4.40(m,2H),4.21-4.13(m,2H),3.91- 3.88(m,2H),3.57(d,J=15Hz,1H),3.39(t,J=5.5Hz,2H),3.03-2.98(m,1H),2.79-2.60(m,3 H),2.46-2.45(m,2H),2.00-1.83(m,3H),1.71-1.68(m,2H),1.48-1.37(m,6H),1.14(s,2H). Chiral HPLC L (70% EtOH): ee 100%, Rt=22.66 min.

[1330] 2-(2-chlorophenyl)-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (enantiomers 183-E1 and 183-E2)

[1331]

[1332] Compound 183-E1 LC / MS ESI 483.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.63-7.57(m,1H),7.55-7.50(m,1H),7.42-7.35(m,2H),7.24(t,J= 7.7Hz,1H),6.39(d,J=7.3Hz,1H),5.13(d,J=27.2Hz,1H),4.47(d,J=12.6Hz,1H),4.25( s, 1H), 4.08-3.73 (m, 4H), 3.60 (s, 1H), 3.45-3.37 (m, 2H), 3.04-2.95 (m, 1H), 2.73 (t, J = 6.2 Hz, 2H), 2.68-2.42 (m, 3H), 2.00-1.85 (m, 3H), 1.79-1.62 (m, 2H), 1.23-1.05 (m, 2H). Chiral HPLC K (50% EtOH): ee 100%, Rt = 12.44 min.

[1333] Compound 183-E2 LC / MS ESI 483.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.64-7.58(m,1H),7.55-7.50(m,1H),7.42-7.35(m,2H),7.25(t,J= 7.7Hz,1H),6.39(d,J=7.3Hz,1H),5.13(d,J=27.2Hz,1H),4.48(d,J=12.6Hz,1H),4.27( s, 1H), 4.09-3.75 (m, 4H), 3.62 (s, 1H), 3.45-3.37 (m, 2H), 3.04-2.95 (m, 1H), 2.73 (t, J = 6.2 Hz, 2H), 2.68-2.42 (m, 3H), 2.00-1.85 (m, 3H), 1.79-1.62 (m, 2H), 1.23-1.05 (m, 2H). Chiral HPLC K (50% EtOH): ee 100%, Rt = 22.79 min.

[1334] 2-(2-Cyclopropoxyphenyl)-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (enantiomers 184-E1 and 184-E2)

[1335]

[1336] Compound 184-E1 LC / MS ESI 505 (M+H)+. 1 H NMR(500MHz,MeOD)δ7.41(d,J=13.0Hz,3H),7.14(d,J=7.3Hz,1H),7.05(s,1H),6.35 (d,J=7.2Hz,1H),5.00(s,1H),4.50-3.84(m,7H),3.55(s,1H),3.39(dd,J=11.4,5.7H z,2H),3.00(t,J=13.2Hz,1H),2.70(dd,J=18.7,12.5Hz,3H),2.46(d,J=7.0Hz,2H), 1.99-1.85(m,3H),1.69(d,J=12.6Hz,2H),1.15(d,J=11.2Hz,2H),1.04-0.75(m,4H). Chiral H (45% MeOH): ee 100%, Rt = 17.33 min.

[1337] Compound 184-E2 LC / MS ESI 505 (M+H)+.1 H NMR (500MHz, MeOD) δ7.41(t,J=6.1Hz,3H),7.14(d,J=7.3Hz,1H),7.05(d,J=5.6Hz,1 H),6.35(d,J=7.2Hz,1H),4.98(s,1H),4.49-3.82(m,7H),3.57(s,1H),3.39(dd,J=1 1.2,5.5Hz,2H),3.00(s,1H),2.70(dd,J=19.2,13.0Hz,3H),2.46(d,J=7.1Hz,2H),2 .02-1.84(m,3H),1.69(d,J=12.6Hz,2H),1.14(d,J=12.4Hz,2H),0.99-0.74(m,4H). Chiral H (45% MeOH): ee 99%, Rt = 22.42 min.

[1338] 2-(2-Isopropoxyphenyl)-2-((R)-3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 185-E1 and 185-E2)

[1339]

[1340] Compound 185-E1 LC / MS ESI 521.2 (M+H) + . 11H NMR (500 MHz, MeOD) δ 7.53 (d, J = 7.6 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.04 - 6.95 (m, 1H), 6.35 (dd, J = 7.3, 3.1 Hz, 1H), 5.03 (s, 1H), 4.81 - 4.72 (m, 1H), 4.60 (s, 1H), 4.48 (d, J = 13.3 Hz, 1H), 3.95 - 3.85 (t, J = 23.5 Hz, 2H), 3.61 (s, 1H), 3.43 - 3.37 (m, 2H), 3.28 - 3.17 (m, 2H), 3.07 (t, J = 13.2 Hz, 1H), 2.72 (t, J = 6.2 Hz, 2H), 2.68 - 2.56 (m, 1H), 2.50 - 2.31 (m, 3H), 2.15 - 2.02 (m, 1H), 2.00 - 1.85 (m, 3H), 1.78 - 1.64 (m, 2H), 1.48 - 1.38 (m, 6H), 1.25 - 1.07 (m, 2H). Chiral HPLC K (70% EtOH): ee 100%, Rt = 13.9 min.

[1341] Compound 185 - E2 LC / MS ESI 521.2 (M + H) + . 1 1H NMR (500 MHz, MeOD) δ 7.51 (d, J = 7.0 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.35 (dd, J = 7.3, 3.8 Hz, 1H), 5.09 (s, 1H), 4.81 - 4.71 (m, 1H), 4.50 (d, J = 13.2 Hz, 1H), 3.94 (d, J = 13.3 Hz, 1H), 3.66 (s, 1H), 3.53 - 3.37 (m, 4H), 3.19 (s, 1H), 3.08 (t, J = 12.9 Hz, 1H), 2.72 (t, J = 6.2 Hz, 2H), 2.69 - 2.59 (m, 1H), 2.51 - 2.31 (m, 3H), 2.16 - 2.03 (m, 1H), 2.01 - 1.84 (m, 3H), 1.79 - 1.65 (m, 2H), 1.48 - 1.35 (m, 6H), 1.26 - 1.08 (m, 2H). Chiral HPLC K (70% EtOH): ee 100%, Rt = 25.5 min.

[1342] 2-(2-chlorophenyl)-2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)acetic acid (diastereomeric compounds 186-E1 and 186-E2)

[1343]

[1344] Compound 186-E1 LC / MS ESI 497.1 (M+H) + . 1 H NMR (500MHz, MeOD) δ7.65(s,1H),7.42(s,1H),7.30(d,J=3.9Hz,2H),7.04(d,J=7.3Hz,1H),6.24( dd,J=7.2,2.8Hz,1H),5.02(s,1H),4.35(d,J=11.8Hz,1H),3.83(d,J=12.9Hz,1H),3.48(s,3H),3 0.32-3.26(m,2H), 3.15-2.88(m,3H), 2.60(t,J=6.1Hz,2H), 2.57-2.46(m,1H), 2.34(d,J=3.5Hz,2H), 2.29-2.17(m,1H), 2.05-1.92(m,1H), 1.88-1.74(m,3H), 1.65-1.51(m,2H), 1.12-0.96(m,2H). Chiral SFC B (40% MeOH): ee 100%, Rt=1.13min.

[1345] Compound 186-E2 LC / MS ESI 497.1 (M+H) + . 1H NMR(500MHz,MeOD)δ7.78(d,J=3.7Hz,1H),7.52(d,J=3.9Hz,1H),7.43-7.38(m,2H),7.15(d,J=7.3Hz ,1H),6.36(d,J=7.2Hz,1H),5.18(s,1H),4.49(d,J=12.8Hz,1H),3.98(d,J=12.8Hz,1H),3.64(s,3H) ,3.44-3.37(m,2H),3.14-2.98(m,3H),2.72(t,J=6.2Hz,2H),2.64(t,J=12.7Hz,1H),2.47(d,J=7.1Hz,2H),2.35-2.21(m,1H),2.17-2.04(m,1H),1.99-1.86(m,3H),1.78-1.65(m,2H),1.26-1.09(m,2H). Chiral SFC B (40% MeOH): ee 86%, Rt=2.44min.

[1346] 2-(2-Isopropoxyphenyl)-2-((R)-3-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)pyrrolidine-1-carbonyl)pyrrolidine-1-yl)acetic acid (diastereomeric compounds 187-E1 and 187-E2)

[1347]

[1348] Compound 187-E1 LC / MS ESI 521.2(M+H)+. 11H NMR (500 MHz, MeOD) δ 7.54 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.15 (dd, J = 7.3, 4.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.40 (dd, J = 7.3, 2.6 Hz, 1H), 5.03 (s, 1H), 4.81 - 4.72 (m, 1H), 3.88 - 3.59 (m, 3H), 3.55 - 3.37 (m, 4H), 3.30 - 3.22 (m, 2H), 3.15 - 2.95 (m, 1H), 2.71 (t, J = 6.2 Hz, 2H), 2.62 - 2.53 (m, 2H), 2.40 (td, J = 15.8, 8.1 Hz, 1H), 2.30 - 2.06 (m, 3H), 1.92 - 1.85 (m, 2H), 1.75 (dd, J = 14.9, 7.4 Hz, 2H), 1.69 - 1.51 (m, 1H), 1.44 (dd, J = 10.7, 6.0 Hz, 6H). Chiral SFC F (40% EtOH): ee 95%, Rt = 7.8 min.

[1349] Compound 187 - E2 LC / MS ESI 521.2 (M + H)+. 1 1H NMR (500 MHz, MeOD) δ 7.43 (d, J = 7.5 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.09 - 7.05 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.32 (dd, J = 7.3, 1.5 Hz, 1H), 4.99 (s, 1H), 4.68 (dt, J = 12.1, 6.0 Hz, 1H), 3.67 - 3.51 (m, 3H), 3.46 - 3.29 (m, 5H), 3.21 - 2.86 (m, 2H), 2.64 (t, J = 6.2 Hz, 2H), 2.55 - 2.46 (m, 2H), 2.32 (s, 1H), 2.23 - 1.98 (m, 3H), 1.84 - 1.77 (m, 2H), 1.68 (dd, J = 14.9, 7.3 Hz, 2H),​​2-(2-Isopropoxyphenyl)-2-(3-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)pyrrolidine-1-carbonyl)azacyclobutane-1-yl)acetic acid (diastereomeric compounds 188-E1 and 188-E2)

[1351]

[1352] Compound 188-E1 LC / MS ESI 507.2 (M+H)+. 1 H NMR (500MHz, MeOD) δ7.33(dd,J=16.8,7.8Hz,2H),7.07(d,J=7.3Hz,1H),7.03(d,J=8.4Hz,1H),6.92(t,J=7.5H z,1H),6.32(dd,J=7.3,1.8Hz,1H),5.08(s,1H),4.69(dt,J=12.1,6.0Hz,1H),4.40-4.06(m,3H),3.86(s,1H),3 .76-3.69(m,1H),3.58-3.40(m,2H),3.31(dt,J=12.8,4.8Hz,3H),2.97-2.89(m,1H),2.64(t,J=5.7Hz,2H),2. 52-2.46(m,2H),2.18-1.99(m,2H),1.85-1.78(m,2H),1.70-1.64(m,2H),1.61-1.44(m,1H),1.40-1.34(m,6H). Chiral SFC F (40% EtOH): ee 100%, Rt=9.14min

[1353] Compound 188-E2 LC / MS ESI 507.2 (M+H)+. 1H NMR(500MHz,MeOD)δ7.33(dd,J=14.6,7.7Hz,2H),7.08(d,J=4.7Hz,1H),7.03(d,J=8.3Hz,1H),6.92 (t,J=7.5Hz,1H),6.33(d,J=6.1Hz,1H),5.09(s,1H),4.72-4.67(m,1H),4.39-4.07(m,3H),3.90-3.4 3(m,4H),3.34-3.26(m,3H),2.98-2.90(m,1H),2.64(t,J=6.1Hz,2H),2.49(d,J=5.9Hz,2H),2.11(d, J=39.5Hz,2H),1.82(s,2H),1.73-1.65(m,2H),1.53(d,J=38.0Hz,1H),1.37(dd,J=16.7,6.0Hz,6H). Chiral SFC F (40% EtOH): ee 96%, Rt=11.57min

[1354] 2-((R)-3-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 189-E1 and 189-E2)

[1355]

[1356] Compound 189-E1 LC / MS ESI 517.0 (M+H)+. 1 H NMR(500MHz,MeOD)δ7.63(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.08(d,J =7.5Hz,1H),6.32(d,J=7.3Hz,1H),3.87(s,1H),3.50(s,2H),3.34-3.26(m, 3H),3.19-3.12(m,1H),2.64(dd,J=15.8,9.5Hz,6H),2.54-2.39(m,3H),2.1 2(s,1H),1.91(s,3H),1.80(dt,J=12.1,6.1Hz,2H),1.46(m,J=92.1Hz,5H). Chiral SFC F (45% EtOH): ee 100%, Rt = 9.14 min.

[1357] Compound 189-E2 LC / MS ESI 517.0 (M+H)+. 1H NMR(500MHz,MeOD)δ7.63(d,J=8.2Hz,2H),7.56(d,J=8.2Hz,2H),7.07(d,J=7.3Hz,1H),6.31 (d,J=7.3Hz,1H),3.89(s,1H),3.41(s,2H),3.34-3.28(m,2H),3.19(s,1H),3.00(s,1H),2.6 4(dd,J=19.8,13.7Hz,6H),2.50-2.40(m,3H),2.14(dd,J=13.5,4.9Hz,1H),1.96(dd,J=23.8 ,16.9Hz,3H),1.84-1.77(m,2H),1.55(dd,J=14.9,6.8Hz,2H),1.37(dd,J=41.3,26.8Hz,3H). Chiral SFCF (45% EtOH): ee 100%, Rt = 9.14 min.

[1358] 2-(3-(3-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)propyl)-1,3'-diazacyclobutan-1'-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (enantiomers 190-E1 and 190-E2)

[1359]

[1360] Compound 190-E1 LC / MS ESI 489.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.62(s,4H),7.28(d,J=7.3Hz,1H),6.43(d,J=7.3Hz,1H),4.26(s,2H),3.83(s,1H),3.70-3.48(m,4H),3.39( dd,J=12.3,6.7Hz,3H),3.28(s,1H),3.14(s,1H),2.73(t,J=6.2Hz,3H),2.64-2.52(m,2H),1.92-1.85(m,2H),1.71-1.58(m,4H). Chiral SFC B (40% MeOH): ee 100%, Rt = 0.73 min.

[1361] Compound 190-E2 LC / MS ESI 489.1 (M+H) + . 1H NMR(500MHz,MeOD)δ7.66(s,4H),7.18(d,J=7.6Hz,1H),6.39(d,J=7.3Hz,1H),4.29(s,1H),3.67(d,J=45.8Hz,4H),3.5 3-3.37(m,4H),3.23(s,3H),2.72(t,J=6.2Hz,2H),2.63(s,1H),2.53(t,J=6.7Hz,2H),1.93-1.84(m,2H),1.61(s,4H). Chiral SFC B (40% MeOH): ee 100%, Rt=1.85 min.

[1362] 2-((R)-3-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)ethyl)azacyclobutane-1-carbonyl)pyrrolidine-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 191-E1 and 191-E2)

[1363]

[1364] Compound 191-E1 LC / MS ESI 517.2 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.76-7.71(m,4H),7.20-7.18(m,1H),6.40-6.38(m,1H),4.41(s,1H) ),4.31-4.24(m,1H),4.07-4.00(m,1H),3.93(d,J=31.7Hz,1H),3.59-3.53(m,1H),3.48 -3.34(m,3H),3.17(d,J=19.1Hz,2H),2.98(d,J=41.3Hz,2H),2.72(t,J=6.1Hz,2H),2.6 8-2.59(m,1H),2.56-2.48(m,2H),2.24(d,J=7.2Hz,1H),2.08(s,1H),1.96-1.90(m,4H). Chiral HPLC J (30% EtOH): ee100%, Rt=13.53 min.

[1365] Compound 191-E2 LC / MS ESI 517.2 (M+H) + . 1H NMR(500MHz,MeOD)δ7.79-7.72(m,4H),7.22-7.18(m,1H),6.43-6.38(m,1H),4.42(s,1H) ),4.33-4.24(m,1H),4.08-4.00(m,1H),3.94(d,J=31.7Hz,1H),3.62-3.53(m,1H),3.49 -3.34(m,3H),3.18(d,J=19.1Hz,2H),2.99(d,J=41.3Hz,2H),2.73(t,J=6.1Hz,2H),2.6 9-2.59(m,1H),2.57-2.48(m,2H),2.24(d,J=7.2Hz,1H),2.09(s,1H),1.97-1.90(m,4H). Chiral HPLC J (30% EtOH): ee100%, Rt=24.12min.

[1366] 2-((R)-3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)pyrrolidine-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (diasteroisomers 192-E1 and 192-E2)

[1367]

[1368] Compound 192-E1 LC / MS ESI 531.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.74(t,J=7.6Hz,2H),7.64-7.57(m,2H),7.12(t,J=6.8Hz,1H),6.33(dd,J=1 6.2,7.3Hz,1H),4.46(d,J=12.6Hz,1H),3.97(d,J=12.5Hz,1H),3.82(d,J=12.1Hz,1H),3.42-3.37 (m,2H),3.15(s,1H),3.04-2.93(m,1H),2.77-2.72(m,3H),2.57(dd,J=23.6,12.7Hz,1H),2.49-2 .36(m,4H),2.15-2.01(m,3H),1.89(dd,J=11.3,5.8Hz,3H),1.72-1.61(m,2H),1.20-0.99(m,2H). Chiral SFC B (35% MeOH): ee 100%, Rt=1.27 min.

[1369] Compound 192-E2 LC / MS ESI 531.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.73(s,2H),7.62-7.57(m,2H),7.14(d,J=7.7Hz,1H),6.35(t,J=6.7 Hz,1H),4.49(s,1H),4.04(d,J=13.9Hz,1H),3.79(d,J=5.7Hz,1H),3.39(dd,J=11.7,6.0H z,3H),3.19(s,1H),3.05(s,1H),2.72(t,J=6.1Hz,2H),2.63-2.52(m,2H),2.45(t,J=7.6 Hz, 4H), 2.02 (s, 2H), 1.96 (s, 1H), 1.92-1.87 (m, 2H), 1.68 (d, J = 16.6Hz, 2H), 1.12 (s, 2H). Chiral SFC B (35% MeOH): ee 100%, Rt=4.19 min.

[1370] 2-(3-(4-((5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)methyl)piperidin-1-carbonyl)azacyclobutane-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (enantiomers 193-E1 and 193-E2)

[1371]

[1372] Compound 193-E1 LC / MS ESI 517.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.72(dd,J=20.3,8.1Hz,4H),7.26(d,J=6.2Hz,1H),6.41(d,J=7.2Hz, 1H),4.64(s,1H),4.49(d,J=13.1Hz,1H),4.22(s,1H),3.91(d,J=67.7Hz,4H),3.61(d,J=1 2.8Hz,1H),3.41(s,2H),3.00(t,J=13.1Hz,1H),2.74(t,J=6.2Hz,2H),2.65(t,J=11.7Hz, 1H), 2.57-2.46 (m, 2H), 1.98-1.87 (m, 3H), 1.69 (d, J = 10.7Hz, 2H), 1.16 (d, J = 11.3Hz, 2H). Chiral SFC B (35% MeOH): ee 100%, Rt = 0.93 min.

[1373] Compound 193-E2 LC / MS ESI 517.1 (M+H) + . 1 H NMR(500MHz,MeOD)δ7.72(dd,J=19.2,8.2Hz,4H),7.26(s,1H),6.42(d,J=7.3Hz,1H ),4.62(s,1H),4.49(d,J=13.0Hz,1H),4.20(s,1H),3.83(s,4H),3.61(d,J=13.8Hz ,1H),3.42(s,2H),3.00(t,J=...

Claims

1. A compound of formula (I): ABC(I) in: A is B is either -C2-C6 alkylene-N(R)C(O)- or -C2-C6 alkylene-C(O)N(R)-; C is R is H, C1-C4 alkyl, or C6 aryl; R1 is H in all cases; R2 is H, C1-C4 alkyl, substituted or unsubstituted C6 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, -C1-C4 alkylene-C1-C4 alkoxy, or -C1-C4 alkylene-C6 aryl. The aryl group is substituted with a C1-C4 alkoxy group, OH group, halogen group, -N(H)C(O)C1-C4 alkyl group, -C(O)NH2 group, or -C(O)C1-C4 alkyl group when substituted, and the heteroaryl group is substituted with an amino group or a hydroxyl group when substituted; and R3 is H, C1-C4 alkyl, OH or halogen; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein B is selected from the group consisting of: R is either Me or phenyl; m is 0, 1, 2, or 3; and p is 0, 1, or 2.

3. The compound according to claim 1, wherein C is:

4. The compound according to claim 1, wherein C is:

5. The compound according to claim 1, wherein C is:

6. The compound according to any one of claims 1 to 5, wherein R2 is H, (C1-C4)alkyl, cyclopropyl, CH2OMe, phenyl, -CH2Ph, pyridyl or indole.

7. The compound according to any one of claims 1 to 5, wherein R2 is H, Me, unsubstituted phenyl, substituted phenyl, unsubstituted pyridyl or substituted pyridyl.

8. The compound according to claim 7, wherein R2 is a substituted phenyl group.

9. The compound of claim 8, wherein the substituted phenyl group is substituted with at least one halogen.

10. The compound according to claim 7, wherein R2 is a substituted pyridyl group.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

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