Heterocyclic compounds as inhibitors of alpha-v beta-1 integrin

Abstract

Disclosed are heterocyclic compound and their use as inhibitors of αvβ1 integrin.

Description

[0001] HETEROCYCLIC COMPOUNDS AS INHIBITORS OF ALPHA-V BETA-1 INTEGRIN

[0002] TECHNICAL FIELD

[0003] This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ1integrin.

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims priority to, and the benefit of, U.S. provisional application No. 63 / 599,246, filed on November 15, 2023, the content of which is hereby incorporated by reference in its entirety.

[0006] BACKGROUND

[0007] Fibrosis is a pathologic process, characterized by overproduction of extracellular matrix (ECM) as a response to tissue injury. Pulmonary fibrosis represents the end stage of several interstitial lung diseases, including the idiopathic interstitial pneumonias, and is characterized by the excessive deposition of extracellular matrix within the pulmonary interstitium. Among the idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis (IPF) represents the commonest and most fatal condition. Fibrosis in IPF is generally progressive, refractory to current pharmacological intervention and inexorably leads to respiratory failure.

[0008] Integrins are transmembrane receptors that bind extracellular matrix proteins or other adhesion receptors on neighboring cells. Heterodimeric pairing of integrin a and P subunits confers specificity of binding to one or more substrates. This family of adhesion molecules plays a pivotal role in broad contexts of biology, including fibrosis.

[0009] The αvβ1integrin is a therapeutic target for the treatment of tissue fibrosis. The αvβ1integrin plays a role in tissue fibrosis, and is known to recognize vitronectin, fibronectin and osteopontin, and αvβ1integrin is expressed on activated fibroblasts and mesangial cells. Fibronectin is a large multidomain glycoprotein found in connective tissue, on cell surfaces, and in plasma and other body fluids, and can inhibit meshwork formation.

[0010] Current therapeutic options for fibrotic diseases are quite limited to elimination of triggering stimuli and organ transplantation. There remains a need for a therapeutic agent to directly halt the disease progression at the cellular level, which represents a major unmet medical need. Pharmacological modulation of the αvβ1integrin by small molecules presents one route to test the role of the αvβ1integrin in tissue fibrosis. Most integrins contain either an αv chain or β1 chain, and targeting either subunit by itself provides little specificity. Accordingly, there is a need in the art for potent αvβ1integrin inhibitors. There remains a need for a small molecule integrin inhibitor of αvβ1suitable for oral administration. The oral administration route is preferred for small-molecule delivery as it allows a wide range of doses to be administered, allows convenient patient self- administration, is adaptable to varying dosage regimens and needs no special equipment. Therefore, it is also important to identify of αvβ1integrin inhibitor compounds that are not only potent at the intended biological target, but are also demonstrating other characteristics relating to the ability of the compound to be absorbed in the body (e.g., after oral delivery) in a therapeutically effective manner. SUMMARY The present disclosure provides compounds useful for inhibiting integrins. In certain embodiments, the present application discloses a compound of formula (I): A-B-C (I) wherein: A is or ; Z is CH2; each R1and R1ˈ is independently alkyl, halide, alkoxy, CF3, OH, -alkylene-OH, - alkylene-alkoxy, NO2, -N(H)-alkyl, or NH2; a is 0, 1, or 2; aˈ is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; bˈ is 0, 1, 2, or 3; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is Rais H; n is 0; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof; provided that the compound is not a compound that is. In certain embodiments, the present application also discloses a compound of formula (I): A-B-C (I) wherein: A is Z is -CH2-; a is 0; b is 0; B is –(CH2)4O-; C is n is 0; Rais H; R2is substituted or unsubstituted bicyclic heterocyclyl, bicyclic aryl, bicyclic heteroaryl, C6aryl, 6-member heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof provided that the compound is not a compound that is Further, provided are pharmaceutical compositions comprising a compound disclosed herein. The disclosure also relates to methods of treating or preventing a disease in a subject. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 depicts tables summarizing inhibition of αvβ1integrin by exemplary compounds measured in a fluorescence polarization assay of Example B. DETAILED DESCRIPTION In certain aspects, the present application discloses certain substituted azetidine compounds. In particular, such compounds disclosed herein are useful as inhibitors of αvβ1integrin. I. DEFINITIONS For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element is selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. 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”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention. The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The application also discloses compounds described herein in the form of a solvate, or hydrate thereof. Further disclosed are isotopic variants of compounds described herein. Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as2H,12C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. For example, disclosed are compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “patient” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n- propylene -(CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur moiety attached thereto. In certain embodiments, the “alkylthio” moiety is represented by one of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2)m-R1, wherein m and R1are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like.The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined below, having an oxygen moiety attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -O-(CH2)m-R10, where m and R10are described below. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the formulae: wherein R11, R12and R13each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10, or R11and R12taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R10represents an alkenyl, aryl, cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R11or R12can be a carbonyl, e.g., R11, R12, and the nitrogen together do not form an imide. In even more certain embodiments, R11and R12(and optionally R13) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R10. Thus, the term “alkylamine” as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R11and R12is an alkyl group. In certain embodiments, an amino group or an alkylamine is basic, meaning it has a conjugate acid with a pKa> 7.00, i.e., the protonated forms of these functional groups have pKas relative to water above about 7.00. The term “amide”, as used herein, refers to a group wherein each R14independently represent a hydrogen or hydrocarbyl group, or two R14are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents or just 1 substituent. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. For example, in certain embodiments, the aryl group can be an unsubstituted C5-C12aryl and in certain embodiments, the aryl group can be a substituted C5-C10aryl. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term “heterocycloalkyl” refers to a non-aromatic monocyclic heterocyclyl. The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula: wherein X’ is a bond or represents an oxygen or a sulfur, and R15represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10or a pharmaceutically acceptable salt, R16represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R10, where m and R10are as defined above. Where X’ is an oxygen and R15or R16is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and R16is a hydrogen, the formula represents a “formate.” In general, where the oxygen atom of the above formula is replaced by a sulfur, the formula represents a “thiocarbonyl” group. Where X’ is a sulfur and R15or R16is not hydrogen, the formula represents a “thioester” group. Where X’ is a sulfur and R15is a hydrogen, the formula represents a “thiocarboxylic acid” group. Where X’ is a sulfur and R16is a hydrogen, the formula represents a “thioformate” group. On the other hand, where X’ is a bond, and R15is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15is a hydrogen, the above formula represents an “aldehyde” group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “nitro” means -NO2; the term “halogen” designates - F, -Cl, -Br, or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; the term “sulfonyl” means -SO2-; the term “azido” means –N3; the term “cyano” means –CN; the term “isocyanato” means –NCO; the term “thiocyanato” means –SCN; the term “isothiocyanato” means –NCS; and the term “cyanato” means –OCN. The term “sulfamoyl” is art-recognized and includes a moiety that can be represented by the formula: in which R11and R12are as defined above. The term “sulfate” is art recognized and includes a moiety that can be represented by the formula: in which R15is as defined above. The term “sulfonamide” is art recognized and includes a moiety that can be represented by the formula: in which R11and R16are as defined above. The term “sulfonate” is art-recognized and includes a moiety that can be represented by the formula: in which R54is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. The terms “sulfoxido” or “sulfinyl”, as used herein, refers to a moiety that can be represented by the formula: in which R17is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. The term “urea” is art-recognized and may be represented by the general formula wherein each R18independently represents hydrogen or a hydrocarbyl, such as alkyl, or any occurrence of R18taken together with another and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are is selected from C1-6alkyl, C3-6cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are is selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. II. COMPOUNDS In certain embodiments, the present application discloses a compound of formula (I): A-B-C (I) wherein: A is or ; Z is CH2; each R1and R1ˈ is independently alkyl, halide, alkoxy, CF3, OH, -alkylene-OH, - alkylene-alkoxy, NO2, -N(H)-alkyl, or NH2; a is 0, 1, or 2; aˈ is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; bˈ is 0, 1, 2, or 3; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is Rais H; n is 0; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof; provided that the compound is not a compound listed in Table 8A; that is, In certain embodiments, the invention relates to compounds of Formula (I): A-B-C (I) wherein: A is ; Z is CH2; a is 0; b is 0; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is n is 0; Rais H; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound listed in Table 8A. In certain embodiments, the invention relates to compounds of Formula (IIa) wherein Z is CH2; p is 3; -L- is -O-; R3is H; each Rb1and Rb2is independently H; R2is substituted or unsubstituted aryl, heteroaryl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to still further embodiments of Formula (I), including those that are described by Formula (IIa-1), Formula (IIa-2), Formula (IIb), Formula (IIb-1), Formula (IIb-2), Formula (IIIa), Formula (IIIb), Formula (IIIa-1), Formula (IIIa-2), Formula (IIIb-1), Formula (IIIb-2), Formula (IV), Formula (IV- 1), Formula (IV-2), as described herein. In certain embodiments, these formulas exclude a compound that is In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (IIa-1) or Formula (IIa-2) wherein Z is CH2; p is 3; R2is substituted or unsubstituted aryl, heteroaryl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to compounds of Formula (IIa-2) wherein Z is CH2; p is 3; R2is substituted or unsubstituted aryl, heteroaryl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to compounds of Formula (IIb) wherein Z is CH2; p is 3; -L- is -O-; R3is H; each Rb1and Rb2is independently H; R2is substituted or unsubstituted aryl, heteroaryl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (IIb-1) or Formula (IIb-2), preferably (IIb-2): wherein Z is CH2; each of Ra1, Ra2and Ra3is H; p is 3; R2is substituted or unsubstituted C6-aryl, 6-member heteroaryl, 9- or 10-member bicyclic heterocyclyl, 9- or 10- member bicyclic aryl or 9- or 10- member bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to compounds of Formula (IIIa) or (IIIb): wherein: each R1is independently alkyl, alkoxy, or OH; R1ˈ is alkoxy; a is 0 or 1; b is 0, 1, or 2; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to a compound represented by formula (IIIa-1) or (IIIa-2), preferably formula (IIIa-2): wherein: each R1is independently alkyl, alkoxy, or OH; R1ˈ is alkoxy; a is 0 or 1; b is 0, 1, or 2; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to a compound represented by formula (IIIb-1) or (IIIb-2), preferably formula (IIIb-2):

[0011] wherein: R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In preferred embodiments, the invention relates to a compound represented by formula (IV) wherein: R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to a compound represented by formula (IV-1) or (IV-2), preferably (IV-2): wherein: R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. In all embodiments, the compound is not a compound listed in Table 8A. In certain embodiments, the invention relates to a compound of Formula (I), wherein A is , where each R1is defined above. In certain embodiments, the invention relates to a compound of formula (I), wherein A is , where each R1is defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is where each Z, a, b, R1and R1´ is defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is , where each Z, aˈ, bˈ, R1and R1´ is defined above. In some embodiments A is , wherein each a, b, R1, R1’ is defined above. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is or provided that A is not or , wherein R1xis independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R´´, or NH2; R´´ is H, alkyl, or aryl. In some embodiments, A in the compounds of formula (I) is , or wherein R1a, R1a´, R1b, R1b´, Rb1, Rb1´, Ra1, Ra2, R2c, R2d, Ra3are each independently selected from H, lower alkyl optionally substituted with hydroxyl or halogen, lower alkyl-alkoxy, heterocycloalkyl, alkoxy or hydroxyl. In some embodiments, A in the compounds of formula (I) is , wherein R1aand R1a´ are both lower alkyl or R1ais alkoxy or alkyl substituted with hydroxyl, and R1a´ is H; Z is CH2, and R1b, R1b´, Rb1, Rb1´, Ra1, Ra2, R2c, R2d, Ra3are each H. In some embodiments, A in the compounds of formula (I) is , wherein R1band R1b´ are both lower alkyl or R1bis alkoxy or alkyl substituted with hydroxyl, and R1b´ is H, Z is CH2, and R1a, R1a´, Rb1, Rb1´, Ra1, Ra2, R2c, R2d, Ra3are each H. In some embodiments, A in the compounds of formula (I) is , wherein Z is CRa1Ra2, wherein each Ra1and Ra2is independently lower alkyl, and R1a, R1a´, R1b, R1b´, R2c, and R2d, are each H. In certain embodiments, A is , , , or In certain embodiments, A is , or . In certain embodiments, each R1' is independently alkoxy or O-cycloalkyl. In certain embodiments, each R1is independently, alkyl, OH, or -alkylene-OH. In certain embodiments, the invention relates to any aforementioned compounds, wherein R1is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is -alkylene-OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is -alkylene-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is NO2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is -N(H)alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1is NH2.In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein at least one instance of R1is alkyl, halide, OMe, OH, -alkylene-OH, or NH2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein at least one instance of R1is OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein all instances of R1are H. In certain embodiments, the invention relates to any aforementioned compounds, wherein R1ˈ is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is -alkylene-OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is -alkylene-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is NO2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is -N(H)alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R1ˈ is NH2.In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein at least one instance of R1ˈ is alkyl, halide, OMe, OH, -alkylene-OH, or NH2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein at least one instance of R1ˈ is OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein all instances of R1ˈ are H. In certain embodiments, each of R1and R1ˈ is independently alkyl, halide, alkoxy, CF3, OH, -alkylene-OH, or -alkylene-alkoxy. In certain embodiments, each of R1and R1ˈ is independently lower alkyl, halide, alkoxy, CF3, OH, lower -alkylene-OH, or lower - alkylene-alkoxy. In certain embodiments, C is . In certain embodiments, C in Formula (I) is selected from: or , wherein R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. In certain embodiments, C in Formula (I) is selected from: or , wherein R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. Preferably, C in Formula (I) is , wherein R2is substituted or unsubstituted C6 aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. In certain embodiments, the invention relates to any of the aforementioned compounds, wherein R2is substituted or unsubstituted C6 aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. In some embodiments, R2is substituted or unsubstituted 9-10 member bicyclic heterocyclyl or 9-10 member bicyclic heteroaryl. In certain embodiments, R2is a substituted or unsubstituted C6 aryl or 6- member heteroaryl. In some embodiments, R2is 9-10 member bicyclic heteroaryl. In some embodiments, R2is 9-member bicyclic heteroaryl. In certain embodiments, R2is a substituted or unsubstituted C6 aryl or 6-member heteroaryl. In certain embodiments, R2in any of the above formulae is selected from: , or , wherein each R4is independently selected from alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O- cycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the alkyl is optionally substituted with CN, alkenyl, or alkoxy; and the cycloalkyl, heterocyclyl, and heterocycloalkyl are optionally substituted with one or more alkyl, cycloalkyl or alkoxy; each R5is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O- heterocycloalkyl; m is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4. In certain embodiments, R2is or each R5a, R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O-heterocycloalkyl; In certain embodiments, R2is wherein R4is alkyl optionally substituted with cyano, cycloalkyl or heterocyclyl each optionally substituted with alkyl, cycloalkyl, or alkoxy; R5b is alkyl optionally substituted with halide or alkoxy, halide, alkoxy, heterocycloalkyl or -O-heterocycloalkyl; R5c is H; R5d is H or halide; and R5e is H . In some embodiments R2is: wherein each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O-heterocycloalkyl; R4is methyl, t-butyl, cycloalkyl or heterocyclyl, wherein cycloalkyl or heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy in particular embodiments R4is methyl, t-butyl, 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl, wherein 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. In some embodiments R2is:

[0012] wherein: each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O- heterocycloalkyl; R4is methyl, t-butyl, cycloalkyl or heterocyclyl, wherein cycloalkyl or heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy in particular embodiments R4is methyl, t-butyl, 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl, wherein 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. In some embodiments R2is: wherein: R5bis selected from C1-C2 alkyl, Cl, F, CF3, C(H)F2, C(F)H2, CF2CH3, or C1-C4 alkoxy; R5d, is selected from H, Me, Cl, or F; R4is methyl, t-butyl, 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl, wherein 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. In some embodiments R2is:

[0013] wherein: each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O- heterocycloalkyl; R4a´ is selected from H or Me; R4b´ is selected from H or Me; or R4b´and R4c´taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group; R4c´ is H or Me; or R4c´ and R4b´ taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group. In certain embodiments R2is wherein: R5bis selected from H, C1-C4 alkoxy, or -O-heterocycloalkyl; R5d, is selected from H, Me, Cl, or F; R4a´ is Me; R4b´ is selected from H or Me; or R4b´and R4c´taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group; R4c´ is H or Me; or R4c´ and R4b´ taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group. In certain embodiments R2is wherein: R5d, is selected from H, Me, Cl, or F; R4a´ is Me; R4b´ is selected from H or Me; or R4b´and R4c´taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group; R4c´ is H or Me; or R4c´ and R4b´ taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group. In some embodiments, R5b is alkyl optionally substituted with halide or alkoxy, halide, alkoxy, heterocycloalkyl or -O-heterocycloalkyl; R5c is H; R5d is H or halide; and R5e is H, in particular wherein R5b is alkoxy or -O-heterocycloalkyl; R5c is H; R5d is H or halide; and R5e is H. In some embodiments, R5b is alkoxy or -O-heterocycloalkyl; R5c is H; R5d is halide; and R5e is H. In some embodiments, R5b is alkoxy; R5c is H; R5d is halide; and R5e is H. In some embodiments, R5b is alkoxy or -O-heterocycloalkyl; R5c is H; R5d is H; and R5e is H. In some embodiments, R2 is 9-10 member bicyclic heteroaryl. In some embodiments, R2is 9-member bicyclic heteroaryl. In certain embodiments, R2is selected from:

[0014] wherein: W is N or CR7; R7is H, halide, or alkyl each R15is independently alkyl or halide; each R16 is independently halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R16c is halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a, R17b, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; y is 0 or 1; xˈ is 0, 1, 2, or 3; yˈ is 0, 1, 2, or 3; and yˈˈ is 0, 1, or 2. In certain embodiments, R2is , wherein: W is N or CR7; each R15is independently alkyl or halide; each R16is independently halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; x is 0, 1, or 2; and yˈˈ is 0, 1, or 2. In certain embodiments, R2 is , wherein R16a is alkyl. In some embodiments, R2is selected from:

[0015] wherein: W is N or CR7; R7is H, halide, or lower alkyl each R15is independently lower alkyl or halide; each R16is independently H, halide, substituted or unsubstituted lower alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted lower alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; xˈ is 0, 1, 2, or 3; and yˈ is 0, 1, 2, or 3. In some embodiments, R2is selected from: wherein: W is N or CR7; R7is H, halide, or alkyl; each R15is independently alkyl or halide; each R16is independently halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R16c is halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; y is 0 or 1. In certain embodiments, R2is: wherein each W is N or CR7; R7is H or halide; R15a is H; R15c is H or alkyl; R16c is H, halide, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, or alkoxyalkyl, when substituted, alkyl is substituted with one or more halide; and R17a is substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. In some embodiments, R2is selected from: wherein: W is CR7; R7is H, halide, or alkyl wherein alkyl is optionally methyl; each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. In some embodiments, R2is selected from: wherein: W is CR7; R7is methyl or halide; each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. In some embodiments, R2is selected from: wherein: each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. In certain embodiments, R2is: wherein each W is -CH-; R15a is H; R15c is H or methyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom. In some embodiments, W is CH. In some embodiments, R16cis (C1-C4)alkyl. In some embodiments, R15cis H. In some embodiments, R15cis H or methyl. In some embodiments, R15ais H. In some embodiments, R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom. In some embodiments, R17ais (C1-C4)alkyl. In some embodiments, R17ais (C3-C6)cycloalkyl. In some embodiments, R17ais a 5-6-member heterocycloalkyl comprising a single oxygen heteroatom. In some embodiments, R15c is H, or (C1-C4)alkyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3- C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6- member heterocycloalkyl comprising an oxygen heteroatom. In some embodiments, R2is: wherein: R16is C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkylalkyl, C4-C6heterocyclyl, or C4-C6heterocycloalkyl; and R17ais selected from C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkyl-alkyl, C4-C6heterocyclyl or C4-C6heterocycloalkyl. In some embodiments, R2is

[0016] wherein: R16is C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkylalkyl, C4-C6heterocyclyl, or C4-C6heterocycloalkyl; and R17cis selected from C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkyl-alkyl, C4-C6heterocyclyl or C4-C6heterocycloalkyl. In some embodiments, R2is a 9-10 member bicyclic heterocyclyl. In certain embodiments, R2is selected from: wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; R24is H or alkyl; each R25is independently halide, or alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. In some embodiments, R2is selected from: wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; R24is H or alkyl; each R25is independently halide, or alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. In certain embodiments, R2is selected from wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, 2, or 3; R24is H or alkyl; each R25is independently halide or alkyl; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. In some embodiments R2is selected from: wherein: c is 0 and d is 2, or c is 1 and d is 1, or c is 2 and d is 0; z is 0, 1, or 2; each R25is independently halideor alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. In some embodiments R2is selected from: ; wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; each R25is independently halide, or lower alkyl optionally substituted with one or more halide; and each R26d and R26dˈ is independently H, lower alkyl, or halide. In some embodiments R2is selected from: ; wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; each R25is independently H, halide, or lower alkyl optionally substituted with one or more halide; and each R26d and R26dˈ is independently H, lower alkyl, or halide. In some embodiments R2is: wherein R25is independently H, F, Cl, or methyl optionally substituted with one or more halide. In some embodiments, R2is: wherein: R25is independently H, halide, or lower alkyl optionally substituted with one or more halide. In particular, R25is H, methyl, chloro, fluoro or methyl optionally substituted with one or more fluoro (e.g., CF3). In some embodiments R2is selected from: ; wherein: R25is H or halide; and each R26a and R26aˈ is independently H, or alkyl. In some embodiments R2is selected from: ; wherein: R25is H or F; and each R26a and R26aˈ is independently H, or methyl. In some embodiments R2is selected from: ; wherein R25is H or F. In some embodiments, R2is a substituted or unsubstituted 9-member bicyclic heteroaryl selected. In some embodiments, R2 is selected from: In some examples, R2is selected from wherein R5band R5care each independently as defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from ,

[0017] or where R3´is selected from alkyl including cycloalkyl (e.g., C1-C6linear, branched or cyclic, including methyl, and cyclopropyl) or alkoxy or O-containing heterocycloalkyl (e.g., 1-6 atom linear, branched or cyclic alkoxy or heterocycloalkyl). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from where each of R17a, and R17cis independently as defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from and , wherein each of R16a, R16c,R17a, R17c,is independently as defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is where R16cis defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from . In certain embodiments, the invention relates to any one of the aforementioned compounds, R2is selected from: , and . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from: , , , , , , , and . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is selected from: , and . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is . In certain embodiments, the invention relates to any one of the aforementioned compounds,, wherein R2is . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2is . In certain embodiments, a is 0, 1, or 2. In some embodiments, a is 0 or 1. In some embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, aˈ is 0, 1, 2, or 3. In some embodiments, aˈ is 0 or 1. In some embodiments, aˈ is 0. In certain embodiments, aˈ is 1. In certain embodiments, aˈ is 2. In certain embodiments, aˈ is 3. In certain embodiments, b is 0, 1, 2, 3, or 4. In some embodiments, b is 0 or 1. In some embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. In certain embodiments, b is 3. In certain embodiments, b is 4. In certain embodiments, bˈ is 0, 1, 2, or 3. In some embodiments, bˈ is 0 or 1. In some embodiments, bˈ is 0. In certain embodiments, bˈ is 1. In certain embodiments, bˈ is 2. In certain embodiments, bˈ is 3. In certain embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, b is 3. In certain embodiments, q is 4. In certain embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1. In some embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, xˈ is 0, 1, 2, or 3. In some embodiments, xˈ is 0 or 1. In some embodiments, xˈ is 0. In certain embodiments, xˈ is 1. In certain embodiments, xˈ is 2. In certain embodiments, xˈ is 3. In certain embodiments, y is 0 or 1. In some embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, yˈ is 0, 1, 2, or 3. In some embodiments, yˈ is 0 or 1. In some embodiments, yˈ is 0. In certain embodiments, yˈ is 1. In certain embodiments, yˈ is 2. In certain embodiments, yˈ is 3. In certain embodiments, yˈˈ is 0, 1, or 2. In some embodiments, yˈˈ is 0 or 1. In some embodiments, yˈˈ is 0. In certain embodiments, yˈˈ is 1. In certain embodiments, yˈˈ is 2. In certain embodiments, z is 0, 1, 2, or 3. In some embodiments, z is 0 or 1. In some embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the absolute configuration at any stereocenter is R. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the absolute configuration at any stereocenter is S. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the absolute configuration at any stereocenter is a mixture of R and S. Preferably, the invention relates to any one of the aforementioned compounds, wherein the absolute configuration at any stereocenter is S. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein the compound is a pharmaceutically acceptable salt. In certain embodiments, the invention relates to a compound selected from the group consisting of the compounds listed in Tables 1A-7C below. In all embodiments, the invention relates to any one of the compounds described herein, provided the compound is not a compound listed in Table 8A. Table 1A. Exemplary compounds of Formula (IIa).

[0018] Table 1B. Exemplary compounds of Formula (IIb).

[0019] Table 2A. Exemplary compounds of Formula (IIa). Table 2B. Exemplary compounds of Formula (IIb).

[0020] Table 3A. Exemplary compounds of Formula (IIa). Table 3B. Exemplary compounds of Formula (IIb).

[0021] Table 4A. Exemplary compounds of Formula (IIa). Table 4B. Exemplary compounds of Formula (IIa). Table 5A. Exemplary compounds of Formula (IIa).

[0022] Table 5B. Exemplary compounds of Formula (IIa). Table 5C. Exemplary compounds of Formula (IIa).

[0023] Table 6A. Exemplary compounds of Formula (IIa). Table 6B. Exemplary compounds of Formula (IIa). Table 7A – Exemplary Compounds of Formula (I)

[0024] Table 7B – Exemplary Compounds of Formula (I)

[0025] Table 7C – Exemplary Compounds of Formula (I)

[0026] Table 8A - Selected Compounds The invention provides the following further numbered embodiments: 1. A compound of formula (I): A-B-C (I) wherein: A is ; Z is CH2; a is 0; b is 0; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is ; n is 0; Rais H; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound listed in Table 8a. 2. The compound of embodiment 1, wherein R2is a 9-10 member bicyclic heteroaryl. 3. The compound of embodiment 2, wherein R2is selected from: wherein: W is N or C R7; R7is H, halide, or alkyl each R15is independently alkyl or halide; each R16is independently halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R16c is halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a, R17b, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; y is 0 or 1; xˈ is 0, 1, 2, or 3; yˈ is 0, 1, 2, or 3; and yˈˈ is 0, 1, or 2. 4. The compound of embodiment 3, wherein W is CH. 5. The compound of embodiment 4, wherein R2is: , wherein W is N or CR7; R7is H or halide; R15a is H; R15c is H or alkyl; R16c is H, halide, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, or alkoxyalkyl, when substituted, alkyl is substituted with one or more halide; and R17a is substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. 6. The compound of embodiment 5, wherein W is CH. 7. The compound of embodiment 6, wherein R16cis lower alkyl. 8. The compound of embodiment 7, wherein R15cis H. 9. The compound of embodiment 8, wherein R15ais H. 10. The compound of embodiment 9, wherein R17ais substituted or unsubstituted (C1- C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom. 11. The compound of embodiment 10, wherein R17ais (C1-C4)alkyl. 12. The compound of embodiment 10, wherein R17ais (C3-C6)cycloalkyl. 13. The compound of embodiment 10, wherein R17ais a 5-6-member heterocycloalkyl comprising a single oxygen heteroatom. 14. The compound of embodiment 5, wherein R15c is H, or (C1-C4)alkyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3- C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5- 6-member heterocycloalkyl comprising an oxygen heteroatom. 15. The compound of embodiment 14, wherein W is CH. 16. The compound of embodiment 15, wherein R15c is H, or methyl. 17. The compound of embodiment 1, wherein R2is a 9-10 member bicyclic heteroaryl. 18. The compound of embodiment 17, wherein R2is a 9-member bicyclic heteroaryl. 19. The compound of embodiment 18, wherein R2is: , wherein each W is -CH-; R15a is H; R15c is H or methyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3- C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5- 6-member heterocycloalkyl comprising an oxygen heteroatom. 20. The compound of embodiment 1, wherein R2is substituted or unsubstituted 6- member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. 21. The compound of embodiment 1, wherein R2is substituted or unsubstituted bicyclic heterocyclyl. 22. The compound of embodiment 1, wherein R2is selected from wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, 2, or 3; R24is H or alkyl; each R25is independently halide or alkyl; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. 23. The compound of embodiment 1, wherein R2is selected from and 24. The compound of any of embodiments 1-16, wherein C in Formula (I) is 25. A compound of formula (I): A-B-C (I) wherein: A is B is –(CH2)5-O-*; R is H, alkyl, or aryl; * denotes the point of attachment of B to C; C is R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 26. The compound of embodiment 25, wherein R2is substituted or unsubstituted C6 aryl, 6-member heteroaryl, 9- or 10- member bicyclic heterocyclyl, 9- or 10- member bicyclic aryl, or 9- or 10- member bicyclic heteroaryl. 27. The compound of embodiment 25, wherein R2is substituted or unsubstituted 9- or 10- member bicyclic heterocyclyl. 28. The compound of embodiment 25, wherein R2is substituted or unsubstituted 9- or 10- member bicyclic heteroaryl. 29. The compound of embodiment 25, wherein R2is a 9-member bicyclic heteroaryl. 30. The compound of embodiment 29, wherein R2is: wherein each W is -CH-; R15a is H; R15c is H or methyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3- C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5- 6-member heterocycloalkyl comprising an oxygen heteroatom. 31. The compound of embodiment 25, wherein R2is substituted or unsubstituted bicyclic heterocyclyl. 32. The compound of embodiment 25, wherein R2is selected from wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, 2, or 3; R24is H or alkyl; each R25is independently halide or alkyl; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. 33. The compound of embodiment 25, wherein R2is selected from and 34. The compound of any of embodiments 25-27, wherein C in Formula (I) is 35. A compound having the formula ,wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 36. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 37. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 38. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 39. A compound having the formula wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 40. A compound having the formula , , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 41. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 42. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 43. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 44. A pharmaceutical composition, comprising a compound of any one of the preceding embodiments; and a pharmaceutically acceptable excipient or carrier. 45. A method of treating of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of any preceding embodiment, thereby treating or preventing the disease. 46. The method of embodiment 45, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin- induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation- induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. 47. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition of any preceding embodiment. The invention additionally provides the following numbered embodiments: 1. A compound of formula (I): A-B-C (I) wherein: A is ; Z is CH2; each R1and R1ˈ is independently alkyl, halide, alkoxy, CF3, OH, -alkylene-OH, or -alkylene-alkoxy; a is 0, 1, or 2; aˈ is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; bˈ is 0, 1, 2, or 3; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound listed in Table 8A. 2. The compound of embodiment 1, wherein a is 0 or 1 and b is 0, 1 or 2. 3. The compound of embodiment 1 or 2, wherein aˈ is 0 or 1 and bˈ is 0, 1 or 2. 4. The compound of embodiment 1, wherein: A is ; each R1is independently alkyl, alkoxy, or OH; R1ˈ is alkoxy; a is 0 or 1; b is 0, 1, or 2; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is ; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 4, of Formula (IIIa) or (IIIb): 6. The compound of embodiment 5 represented by formula (IIIa-2) or (IIIb-2): 7. The compound of embodiment 5 or 6 wherein: each R1is independently alkyl, alkoxy, or OH; R1ˈ is C1-C2 alkoxy; a is 0 or 1; b is 0, 1, or 2; R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 8. The compound of any preceding embodiment, where each R1, if present, is independently selected from the group consisting of Me, C1-C2 alkoxy, or OH, most particularly Me, OH or OMe. 9. The compound of any preceding embodiment wherein a is 0 or 1 and b is 0 or 1, in particular a is 0 or 1 and b is 0, most particularly wherein a is 0 and b is 0.. 10. The compound of any of embodiments 1-8 wherein a is 0 and b is 0, 1 or 2, in particular a is 0 and b is 0 or 1, most particularly wherein a is 0 and b is 0. 11. The compound of any preceding embodiment represented by formula (IV) preferably of formula (IV-2),

[0027] wherein R2is substituted or unsubstituted C6aryl, 6-member heteroaryl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl; and the absolute configuration at any undefined stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 12. The compound of any preceding embodiment, wherein R2is wherein each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O-heterocycloalkyl; R4is methyl, t-butyl, cycloalkyl or heterocyclyl, wherein cycloalkyl or heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. 13. The compound of any preceding embodiment wherein R2is

[0028] wherein: each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O-heterocycloalkyl; R4is methyl, t-butyl, cycloalkyl or heterocyclyl, wherein cycloalkyl or heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. 14. The compound of any preceding embodiment wherein R2is wherein: each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O-heterocycloalkyl; R4is methyl, t-butyl, 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl, wherein 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. 15. The compound of any preceding embodiment wherein R2is ,wherein: R5bis selected from C1-C2 alkyl, Cl, F, CF3, C(H)F2, C(F)H2, CF2CH3, or C1-C4 alkoxy; R5d, is selected from H, Me, Cl, or F; R4is methyl, t-butyl, 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl, wherein 3- or 4-membered cycloalkyl or 5- or 6-membered heterocyclyl is independently optionally substituted with alkyl, cycloalkyl, or alkoxy. 16. The compound of embodiment 14 or 15 wherein R5bis selected from C1-C2, alkyl, Cl, F, CF3, C(H)F2, C(F)H2, CF2CH3, or C1-C4 alkoxy, most particularly Cl, F, CF3, OMe, or OEt. 17. The compound of any of embodiments 1-11, wherein R2is wherein: each of R5b, R5c, R5d, and R5e, is independently selected from H, halide, CF3, C(H)F2, C(F)H2, CF2CH3, alkyl, cycloalkyl, -alkylene-alkoxy, alkoxy, heterocycloalkyl, or -O- heterocycloalkyl; R4a´ is selected from H or Me; R4b´ is selected from H or Me; or R4b´and R4c´taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group; R4c´ is H or Me; or R4c´ and R4b´ taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group. 18. The compound of embodiment 17, wherein R4a´ is Me. 19. The compound of embodiment 18 wherein R2is , wherein: R5bis selected from H, C1-C4 alkoxy, or -O-heterocycloalkyl; R5d, is selected from H, Me, Cl, or F; R4a´ is Me; R4b´ is selected from H or Me; R4c´ and R4d’ taken together form a 3- to 6-membered cycloalkyl or 3- to 6- membered heterocyclyl. 20. The compound of embodiment 19, wherein R2is wherein: R5d, is selected from H, Me, Cl, or F; R4a´ is Me; R4b´ is selected from H or Me; or R4b´and R4c´taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group; R4c´ is H or Me; or R4c´ and R4b´ taken together form a substituted or unsubstituted 3-6 membered cycloalkyl or 3-6 membered heterocyclyl group. 21. The compound of embodiments 12-17, wherein R5b is alkyl optionally substituted with halide or alkoxy, halide, alkoxy, heterocycloalkyl or -O- heterocycloalkyl; R5c is H; R5d is H or halide; and R5e is H, in particular wherein R5b is alkoxy or -O-heterocycloalkyl; R5c is H; R5d is H or halide; and R5e is H. 22. The compound of embodiment 21, wherein R5b is alkoxy or -O- heterocycloalkyl; R5c is H; R5d is halide; and R5e is H. 23. The compound of embodiment 22, wherein R5b is alkoxy; R5c is H; R5d is halide; and R5e is H. 24. The compound of embodiment 21, wherein R5b is alkoxy or -O- heterocycloalkyl; R5c is H; R5d is H; and R5e is H. 25. The compound of any of embodiments 1-11, wherein R2is a 9-10 member bicyclic heteroaryl. 26. The compound of embodiment 25 wherein R2is selected from: wherein: W is N or CR7; R7is H, halide, or lower alkyl each R15 is independently lower alkyl or halide; each R16is independently H, halide, substituted or unsubstituted lower alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted lower alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; xˈ is 0, 1, 2, or 3; and yˈ is 0, 1, 2, or 3. 27. The compound of embodiment 26, wherein W is CR7. 28. The compound of embodiment 27, wherein R2is selected from: wherein: W is CR7; R7is H, halide, or alkyl each R15is independently alkyl or halide; each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2. 29. The compound of any of embodiments 26-28, wherein x is 0 or 1, in particular x is 0. 30. The compound of any of embodiments 26-29, wherein R2is selected from: wherein: W is CR7; R7is H, halide, or alkyl wherein alkyl is optionally methyl; each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. 31. The compound of embodiment 30 wherein R2is selected from: wherein: W is CR7; R7is methyl or halide; each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. 32. The compound of embodiment 30 wherein R2is selected from: wherein: each R16is independently H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. 33. The compound of any of embodiments 26-32, wherein R16is H, halide, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, particularly wherein R16is C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkylalkyl, C4-C6heterocyclyl, or C4-C6heterocycloalkyl. 34. The compound of any of embodiments 26-33, wherein R17a and R17c are each independently H, substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl, particularly wherein R17a and R17c are each independently C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkyl-alkyl, C4-C6heterocyclyl or C4-C6heterocycloalkyl. 35. The compound of embodiment 34, wherein R2is: wherein: R16is C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkylalkyl, C4-C6heterocyclyl, or C4-C6 heterocycloalkyl; and R17ais selected from C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkyl-alkyl, C4-C6heterocyclyl or C4-C6heterocycloalkyl. 36. The compound of embodiment 35, wherein R16is t-butyl, cyclopropylmethyl, or methyloxetane. 37. The compound of any of embodiments 32-34, wherein R2is wherein: R16is C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkylalkyl, C4-C6heterocyclyl, or C4-C6heterocycloalkyl; and R17cis selected from C1-C4alkyl, C3-C4cycloalkyl, C3-C4cycloalkyl-alkyl, C4-C6heterocyclyl or C4-C6heterocycloalkyl. 38. The compound of embodiment 37, wherein R17c is t-butyl, cyclopropylmethyl, or methyloxetane. 39. The compound of embodiment 1-11, wherein R2is a 9-10 member bicyclic heterocyclyl. 40. The compound of embodiment 39, wherein R2is selected from: wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; R24is H or alkyl; each R25is independently halide, or alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide;, and each R26d and R26dˈ is independently H, alkyl, or halide. 41. The compound of embodiment 40, wherein R2is selected from: wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; R24is H or alkyl; each R25is independently halide, or alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. 42. The compound of embodiment 41, wherein R2is selected from: ; wherein: c is 0 and d is 2, or c is 1 and d is 1, or c is 2 and d is 0; z is 0, 1, or 2; R24is H or alkyl; each R25is independently halide, or alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently H, alkyl, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. 43. The compound of embodiment 41, wherein R2is selected from: wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; each R25is independently halide, or lower alkyl optionally substituted with one or more halide; and each R26d and R26dˈ is independently H, lower alkyl, or halide. 44. The compound of embodiment 43, wherein R2is selected from: ; wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; each R25is independently H, halide, or lower alkyl optionally substituted with one or more halide; and each R26d and R26dˈ is independently H, lower alkyl, or halide. 45. The compound of embodiment 44, wherein R2is: 46. The compound of embodiment 40-45, wherein c is 0 and d is 2, or c is 1 and d is 1, or c is 2 and d is 0. 47. The compound of embodiment 46, wherein R2is: wherein: R25is independently H, halide, or lower alkyl optionally substituted with one or more halide. 48. The compound of embodiment 47, wherein R25is H, methyl, chloro, fluoro or CF3. 49. A compound as described in the examples herein. 50. A compound of formula (IV), wherein R2is a 9-10 member bicyclic heteroaryl; or a pharmaceutically acceptable salt thereof. 51. The compound of embodiment 50, which is a compound of formula (IV-2): (IV-2); or a pharmaceutically acceptable salt thereof. 52. The compound of any one of embodiments 50 or 51, wherein R2is: wherein W is CH; R15a is H; R15c is H; R16c is (C1-C4)alkyl; R17ais (C1-C4)alkyl. 53. The compound of embodiment 52, wherein R17ais t-butyl. 54. A compound of formula (IV) wherein R2is selected from unsubstituted or substituted heterocyclyl. 55. The compound of embodiment 54, which is a compound of formula (IV-2): (IV-2); or a pharmaceutically acceptable salt thereof. 56. The compound of any one of embodiments 54 or 55, wherein R2is selected from unsubstituted or substituted 9-10 membered heterocyclyl. 57. The compound of embodiment 56, wherein R2is selected from unsubstituted 9-10 membered heterocyclyl or 9-10 membered heterocyclyl substituted with one or more halide, or lower alkyl, wherein a lower alkyl group may be optionally substituted with one or more halide. 58. The compound of embodiment 56, wherein R2is selected from wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, or 2; R24is lower alkyl or H; each R25is independently halide, or lower alkyl optionally substituted with one or more halide; each R26a and R26aˈ is independently lower alkyl, halide or H; and each R26d and R26dˈ is independently H, lower alkyl, or halide. 59. The compound of embodiment 56, wherein R2is selected from: and wherein c is 0 and d is 2, or c is 1 and d is 1, or c is 2 and d is 0. 60. The compound of embodiment 56, wherein R2is selected from: wherein: z is 0, 1, or 2; each R25is independently halide, or lower alkyl optionally substituted with one or more halide; and each R26d and R26dˈ is independently H, lower alkyl, or halide. 61. The compound of embodiment 60, wherein z is 0 or 1. 62. The compound of embodiment 61, wherein R2is: wherein: each R25is independently lower alkyl optionally substituted with one or more halide, H, or halide. 63. A pharmaceutical composition, comprising a compound of any one of the preceding embodiments; and a pharmaceutically acceptable excipient or carrier. 64. A method of treating of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of any preceding embodiment, thereby treating or preventing the disease. 65. The method of embodiment 64, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. 66. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition of any preceding claim. 67. A compound or a pharmaceutical composition of any preceding embodiment for use in a method of treating or preventing a disease. 68. The compound or a pharmaceutical composition for use according to embodiment 67, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin- induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation- induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. 69. The compound or a pharmaceutical composition for use according to embodiment 67 wherein the disease is fibrosis. The invention additionally provides the following numbered embodiments: 1. A compound of formula (I): A-B-C (I) wherein: A is Z is CH2; a is 0; b is 0; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C is n is 0; Rais H; R2is substituted or unsubstituted bicyclic heterocyclyl, bicyclic aryl, bicyclic heteroaryl, C6aryl, or 6-member heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound listed in Table 8A. 2. The compound of embodiment 1, wherein R2is a 9-10 member bicyclic heteroaryl. 3. The compound of embodiment 2, wherein R2is selected from: wherein: W is CR7or N; R7is H, halide, or alkyl each R15 is independently alkyl or halide; each R16is independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl; when substituted, alkyl is substituted with one or more halide; or R16is halide; R17a, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; and y is 0 or 1. 4. The compound of embodiment 3, wherein W is CH. 5. The compound of embodiment 4, wherein R2is: , wherein W is CR7or N R7is H or halide; R15a is H; R15c is H or alkyl; R16c is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, when substituted, alkyl is substituted with one or more halide; or R16cis H or halide; and R17a is substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl;. 6. The compound of embodiment 5, wherein W is CH. 7. The compound of embodiment 6, wherein R16cis lower alkyl. 8. The compound of embodiment 7, wherein R15cis H. 9. The compound of embodiment 8, wherein R17ais substituted or unsubstituted (C1- C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom. 10. The compound of embodiment 9, wherein R17ais (C1-C4)alkyl. 11. The compound of any of embodiments 1-10, wherein C in Formula (I) is 12. The compound of embodiment 1, wherein R2is selected from wherein: each of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, 2, or 3; R24is H or alkyl; each R25is independently alkyl or halide; each R26a and R26aˈ is independently alkyl, H, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide. 13. A compound having the formula wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 14. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 15. A compound having the formula , , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 16. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 17. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 18. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 19. The compound according to any of embodiments 13-18, wherein the absolute configuration at any stereocenter is a mixture of R and S; or a pharmaceutically acceptable salt thereof. 20. The compound according to any of embodiments 13-18, wherein the absolute configuration at any stereocenter is S; or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition, comprising a compound of any one of the preceding embodiments; and a pharmaceutically acceptable excipient or carrier. 22. A method of treating of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of any preceding embodiment, thereby treating or preventing the disease. 23. The method of embodiment 22, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin- induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation- induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. 24. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition of any preceding embodiment. The invention additionally provides the following numbered embodiments: 1. A compound of formula (I): A-B-C (I) wherein: A is ; Z is -CH2-; a is 0; b is 0; B is –(CH2)4O-; C is ; n is 0; Rais H; R2is substituted or unsubstituted bicyclic heterocyclyl, bicyclic aryl, bicyclic heteroaryl, C6aryl, 6-member heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound that is 2. The compound of embodiment 1, wherein R2is a 9-10 member bicyclic heteroaryl. 3. The compound of embodiment 2, wherein R2is selected from: wherein: W is CR7or N; R7is H, halide, or alkyl each R15is independently alkyl or halide; each R16is independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, when substituted, alkyl is substituted with one or more halide; or R16is halide; R17a, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; y is 0 or 1. 4. The compound of embodiment 3, wherein W is CH. 5. The compound of embodiment 2, wherein R2is: , wherein each W is CR7or N; R7is H or halide; R15a is H; R15c is H or alkyl; R16c is, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl; when substituted, alkyl is substituted with one or more halide; or R16cis H or halide; and R17a is substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl. 6. The compound of embodiment 5, wherein W is CH. 7. The compound of embodiment 6, wherein R16cis lower alkyl. 8. The compound of embodiment 7, wherein R15cis H. 9. The compound of embodiment 8, wherein R17ais substituted or unsubstituted (C1- C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom. 10. The compound of embodiment 9, wherein R17ais (C1-C4)alkyl. 11. A compound of Formula (IIa) (IIa), wherein Z is CH2; p is 2; -L- is -O-; R3is H; each Rb1and Rb2is independently H; R2is substituted or unsubstituted aryl, heteroaryl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound listed in Table 8a. 12. The compound of embodiment 11, wherein R2is a 9-10 member bicyclic heteroaryl. 13. The compound of embodiment 12, wherein R2is a 9-member bicyclic heteroaryl. 14. The compound of embodiment 13, wherein R2is: , wherein each W is -CH-; R15a is H; R15c is H or methyl; R16c is H, halide, (C1-C4)alkyl optionally substituted with halide, or cyclopropyl; and R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3- C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5- 6-member heterocycloalkyl comprising an oxygen heteroatom. 15. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.16. A compound having the formula , wherein theabsolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 17. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 18. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 19. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 20. A compound having the formula , wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof. 21. The compound according to any of embodiments 15-20, wherein the absolute configuration at any stereocenter is a mixture of R and S; or a pharmaceutically acceptable salt thereof. 22. The compound according to any of embodiments 15-20, wherein the absolute configuration at any stereocenter is S; or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition, comprising a compound of any one of the preceding embodiments; and a pharmaceutically acceptable excipient or carrier. 24. A method of treating of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of any preceding embodiment, thereby treating or preventing the disease. 25. The method of embodiment 24, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin- induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation- induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. 26. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition of any preceding embodiment. III. PHARMACEUTICAL COMPOSITIONS In certain embodiments, the invention relates to a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable carrier. Patients, including but not limited to humans, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time. In certain embodiments, the mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors. The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti- inflammatories or other antivirals, including but not limited to nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, carriers include physiological saline and phosphate buffered saline (PBS). In certain embodiments, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. For example, enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially. Liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. IV. METHODS In certain embodiments, the present application discloses a method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition disclosed herein to thereby treat or prevent the disease. In certain embodiments, the present application discloses a compound or a pharmaceutical composition disclosed herein for use in a method of treating or preventing a disease. In certain embodiments, the present application discloses the use of a compound or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating or preventing a disease. In some embodiments, the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, flu- induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis. In certain embodiments, the present application discloses a method of treating fibrosis comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition disclosed herein to thereby treat or prevent the disease. In certain embodiments, the disease is treated or prevented by inhibiting αvβ1integrin. In certain embodiments, the subject is a mammal, e.g., a human. V. EXEMPLIFICATION Example A: Synthetic schemes and procedures for the preparation of compounds of the invention The moiety R1and R2represents appropriate substituents; L represents an appropriate linker, and X represents an appropriate halogen, such as Br, Cl or I, or another leaving group such as mesylate or tosylate. represents an appropriate optionally substituted azetidine. represents an appropriate optionally substituted tetrahydronaphthyridine. represents an appropriate optionally substituted naphthyridine. General Schemes for the synthesis of αvβ1inhibitors

[0029] General Procedures 9-BBN and Suzuki Reactions Alkene intermediates may be cross coupled to 2-halo naphthyridines or tetrahydronaphthyridines by the following procedure. To a solution of alkene (1 eq.) in dry THF (1-10 mL / mmol) under Ar was added 9-BBN (0.5M solution in THF, 1-2 eq.). The reaction was stirred at 40-80 °C for 1-4 hours, then cooled to room temperature. To this mixture was added 2-halonaphthyridine or Boc-protected 2-halotetrahydronaphthyridine (1-1.5 eq.), KOH or other base (1-5 eq), Pd(OAc)2 (0.05 to 0.1 eq.) and PCy3 (0.1 to 0.2 eq.), or another appropriate Pd / ligand combination such as Pd(PPh3)4. The reaction was stirred at 80-100 °C for 12-24 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column to give the alkyl linked naphthyridine product. Ring Annulations Naphthyridines may also be made from methyl ketones by the following procedure. A mixture of methyl ketone (1 eq.), 2-aminonicotinaldehyde (1-2 eq.) and secondary amine such as pyrrolidine or L-proline (1-2 eq) in DMF or EtOH (1-10 mL / mmol) was stirred at 70-100 °C for 2- 10 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column to give the desired naphthyridine product. Naphthyridine Reduction Naphthyridines may be reduced to tetrahydronaphthyridines by the following procedure. A mixture of an appropriate naphthyridine (1 eq.) and Pd / C (5-20 weight percent Pd, 0.05 to 0.2 eq.) in ethyl acetate or another appropriate solvent (2-10 mL / mmol) was stirred under H2balloon at room temperature to 50 °C for 2-20 hours. The reaction was filtered and concentrated in vacuo to give the desired tetrahydronaphthyridine product. Boc Deprotection Boc-protected amine (1 eq.) was treated with HCl (4-100 eq.) in 1,4-dioxane (1-50 mL / mmol amine) at room temperature to 50 °C for 1-16 hours. The reaction was concentrated in vacuo, and the amine product was used crude or after purification by silica gel column. The amine could be used crude as a dihydrochloride salt or converted to the free base by dissolving in an appropriate solvent and washing with aqueous NaHCO3. Amine alkylation: A mixture of amine (1 equiv.), alkylating agent (1-1.5 equiv.) and K2CO3or N,N- diisopropylethylamine (2-10 eq) in MeCN or DMF (3-10 mL / mmole amine) was stirred at room temperature to 80 °C for 2-16 hours. Sometimes NaI (1-2 eq.) was added to accelerate the reaction rate. The reaction was concentrated in vacuo, and the residue was purified by silica gel column to give the desired amino acetic acid ester. The amine used may be the free base or a salt such hydrochloride or dihydrochloride. If the reaction is done with a salt of the amine, additional equivalents of base may be needed. Saponification: For certain esters such as R1= Me or ethyl, the ester may be saponified under basic conditions. The ester (1 equiv.) was treated with LiOH-H2O (3-5 equiv.) in MeOH (3-10 mL / mmol ester) and water (3-10 mL / mmol ester) at room temperature to 50 °C for 1-16 hours. The reaction was concentrated in vacuo, and the residue was purified by prep HPLC to give the desired carboxylic acid product. For certain esters such as R1= tert-butyl, the ester may be saponified under acidic conditions. The ester (1 equiv.) was treated with 4 N HCl (4-100 equiv.) in 1,4-dioxane (1- 25 mL / mmol ester) or with TFA (2-20 mL / mmol) in dichloromethane (2-20 mL / mmol) at room temperature to 50 °C for 1-16 hours. The reaction was concentrated in vacuo, and the residue was purified by prep HPLC to give the desired carboxylic acid product. Petasis reaction: As an alternative to the amine alkylation / saponification sequence, a Petasis reaction can be used to prepare certain aryl analogs: A mixture of amine (1 eq.) aryl boronic acid or aryl boronate ester (1-1.5 eq.) and 2-oxoacetic acid (1.5-2 eq) in MeCN or DMF (2-10 mL / mmole amine) was stirred at 50-80 °C for 2-16 hours. The reaction was concentrated in vacuo, and the residue was purified by prep HPLC to give the desired amino acetic acid. Synthesis of Alkylating Agents: Alkylating agents can be synthesized from aryl bromides by a sequence of Negishi and bromination reactions: Negishi Reaction: To a mixture of aryl bromide, iodide or triflate (1 eq), Pd2(dba)3 or other Pd source (0.05- 0.1 eq.) and Q-phos or other appropriate ligand (0.05-0.1 eq.) in THF (2-10 mL / min) at room temperature under Ar was added (2-alkoxy-2-oxoethyl)zinc(II) bromide solution (1 M in THF, 2-5 eq.). The reaction was stirred at 40-80 °C for 1-8 hours, then quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo. The residue was purified by silica gel column to give the aryl acetate ester. Bromination Reaction: To a solution of aryl acetate ester (1 eq.) in THF (5-20 mL / mmol) at -78 °C was added dropwise lithium diisopropylamide solution (2.0 M in THF / hexanes, 2-3 eq.). The reaction was stirred at -78°C for 15-30 min.; then a solution of chlorotrimethylsilane (2-3 eq.) in THF (1-2 mL / mmol) was added, and the reaction was stirred at -78°C for another 15-30 min. Then a solution of NBS (2-3 eq.) in THF (1-5 mL / mmol) was added, and the reaction was stirred at -78°C for 0.5-2 hours, then quenched with MeOH (2 mL) and concentrated in vacuo. The residue can be purified by silica gel column to isolate the pure alkylating agent, or used crude in the next step. Analytical Methods NMR Methods Compounds were analyzed by NMR using one of the following instruments: BRUKER, AVANCE III 500MHZ, PROBHD 5 mm PABBO BB-, PULPROG zg30, TD 65536, NS 8, DS 0, SWH 10330.578 Hz, D11.00000000 sec, NUC11H, P113.72 usec, PL1W 13.34460926 W, SFO1500.1330885 MHz BRUKER, AVANCE III 400MHZ, PROBHD 5 mm PABBO BB / , PULPROG zg30, TD 65536, NS 8, DS 2, SWH 8223.685 Hz, D11.00000000 sec, SFO1400.1324710 MHz, NUC1 1H, P115.00 usec, PL1W 11.00000000 W Prep-HPLC Methods Crude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm: Prep HPLC A: column: XBridge C18, 21.2 * 250 mm, 10 µm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 20 mL / min. Prep HPLC B: column: XBridge C18, 21.2 * 250 mm, 10 µm; mobile phase: A water (10 mM formic acid), B CH3CN; gradient elution as in text; flow rate: 20 mL / min. Prep HPLC C: column: XBridge OBD C18, 19 * 100 mm, 5 µm; mobile phase: A water, B CH3CN; gradient elution as in text; flow rate: 20 mL / min. Prep HPLC D: Column Xtimate C1821.2*250mm, 10 um; Mobile Phase: A water (10 mM NH4HCO3 & 0.025% NH3·H2O),B: CAN;Gradient 5% B for 2 min, then 5%-10% B in 8 min, stop at 17 min; Flow Rate (ml / min) 30.00. Prep HPLC E: Column Welch 10 um 150A 21.2*250 mm ; Mobile Phase: A water (10 mM NH4HCO3 & NH3H20), B Acetonitrile; Gradient 25-35% B in 9 min, hold at 95% B for 4 min, back to 10% B within 0.2 min, stop at 15 min; Flow Rate (ml / min) 30.00. Prep Chiral SFC Methods Racemic products were separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm: Prep chiral SFC A: column: (R,R)-Whelk-O1, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC B: column: AD 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC C: column: AS 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC D: column: OD 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC E: column: Cellulose-SC 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC F: column: OZ 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC G: column: IC 20*250mm, 10 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC H: column: (S,S)-Whelk-O1, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC I: column: OX-H, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC J: column: IG, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC K: column: IH, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC L: column: OJ, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC M: column: Amylose-C Neo, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC N: column: ID, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Prep chiral SFC O: column: AY-H, 20*250mm, 5 µm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Analytical Chiral SFC Methods Chiral products were analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm: Chiral SFC A: column: (R,R)-Whelk-O1, 4.6*100mm, 5 µm (Decial), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC B: column: AD 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC C: column: AS 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC D: column: OD 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC E: column: Cellulose-SC 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC F: column: OZ 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C,mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC G: column: IC 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC H: column: (S,S)-Whelk-O1, 4.6*100mm, 5 µm (Decial), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC I: column: OX-H, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC J: column: IG, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC K: column: IH, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC L: column: OJ, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC M: column: Amylose-C Neo, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC N: column: ID, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Chiral SFC O: column: AY, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Stereochemical Assignments: Analysis of x-ray crystal structures of compounds bound to αvβ1 integrin or other integrin proteins has demonstrated that the S configuration of the amino acid stereocenter results in higher potency at αvβ1 integrin than the R configuration in the Fluorescence Polarization assay of Example B. Consequently, for pairs of compounds differing only in the configuration of the amino acid stereocenter, the more active compound has been assigned the S-amino acid (S-a.a.) configuration and the less active compound the R-amino acid (R- a.a.) configuration. Similarly, x-ray crystallographic analysis shows that for compounds with the tetrahydronaphthyridine (THN) group attached to the B group through the saturated ring, the S configuration results in higher potency at αvβ1 integrin than the R configuration in the Fluorescence Polarization assay of Example B. For pairs of these compounds, the more active compound has been assigned the S-THN configuration and the less active compound the R-THN configuration. Other stereocenters where the absolute configuration is known either from x-ray crystallographic analysis or from the synthetic method have been marked as “absolute”. All remaining stereocenters have been assigned an arbitrary configuration to facilitate identification of relative stereochemical configurations. Synthesis of Intermediates The following intermediates were prepared according to the procedures below for use in synthesizing the example compounds: Preparation of 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride Step 1: tert-butyl 3-(pent-4-enyloxy)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.0 g, 11.6 mmol) and 5- bromopent-1-ene (2.6 g, 17.4 mmol) in n-Heptane (50 mL) was added sodium hydroxide (50% solution in water, 10 mL) and tetrabutylammonium bromide (374 mg, 1.16 mmol). The mixture was warmed to 80 °C and stirred for 2 hours, then cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (50 mL x3). The combined organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product tert-butyl 3-(pent- 4-enyloxy)azetidine-1-carboxylate as a pale yellow oil (1.6 g, 57% yield). MS (ESI +, m / z): 185 [M+H-tBu]+ Step 2: tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate To a solution of tert-butyl 3-(pent-4-enyloxy)azetidine-1-carboxylate (14.4 g, 59.8 mmol) in THF (dry, 20 mL) under Ar was added 9-BBN (0.5 M in THF, 240 mL, 120 mmol). The reaction mixture was stirred at 50 °C for 2 hours, then cooled to room temperature. Tert- butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (32.0 g, 120 mmol), Pd(OAc)2 (672 mg, 3.0 mmol), PCy3 (1.69 g, 6.0 mmol), and KOH (5.04 g, 90 mmol) were added. The reaction mixture was warmed to 70 °C and stirred for 12 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 3:1) to give the desired product tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3- yloxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a pale yellow oil (11.6 g, 41% yield). MS (ESI +, m / z): 476 [M+H]+. Step 3: 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride A mixture of tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate (11.6 g, 24.4 mmol) in 4N HCl / dioaxne (50 mL) was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo to give 7- (5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochlorid as a pale yellow oil (8.5 g). MS (ESI +, m / z): 276 [M+H]+. Preparation of 7-(5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride Step 1: tert-butyl 3-(5-(4-methoxy-1,8-naphthyridin-2-yl)pentyloxy)azetidine-1- carboxylate To a solution of tert-butyl 3-(pent-4-enyloxy)azetidine-1-carboxylate (1.2 g, 4.98 mmol) in THF (dry, 5 mL) under Ar was added 9-BBN (0.5 M, 20 mL, 10 mmol). The reaction mixture was stirred at 50 °C for 2 hours and cooled to room temperature. 2-Chloro-4- methoxy-1,8-naphthyridine (969 mg, 4.98 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), PCy3 (140 mg, 0.5 mmol), and KOH (840 mg, 15 mmol) were added, and the reaction mixture was stirred at 70 °C for 15 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30:1) to give the desired product tert-butyl 3- (5-(4-methoxy-1,8-naphthyridin-2-yl)pentyloxy)azetidine-1-carboxylate as a pale yellow oil (0.9 g, 45% yield ). MS (ESI +, m / z): 402 [M+H]+ Step 2: tert-butyl 3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidine-1-carboxylate A mixture of tert-butyl 3-(5-(4-methoxy-1,8-naphthyridin-2-yl)pentyloxy)azetidine-1- carboxylate (900 mg, 2.24 mmol) and Pd / C (90 mg, 20 Wt %) in ethyl acetate (20 mL) was stirred under H2 balloon at 40 °C for 16 hours. The mixture was filtered and concentrated in vacuo to give the desired product tert-butyl 3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidine-1-carboxylate as a yellow oil (900 mg). MS (ESI +, m / z): 406 [M+H]+ Step 3: 7-(5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride A mixture of tert-butyl 3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidine-1-carboxylate (2 g, 4.93 mmol) in 4N HCl / dioaxne (50 mL) was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo to give 7- (5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride as a yellow oil (1.8 g, 97% yield). MS (ESI +, m / z): 306 [M+H]+ Preparation of 7-(5-(azetidin-3-yloxy)pentyl)-3,3-dimethyl-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride Step 1: 3-(bromomethyl)-2,6-dichloropyridine To a solution of (2,6-dichloropyridin-3-yl)methanol (1.0 g, 5.6 mmol) in DCM (10 mL) was added a solution of PBr3 (2.9 g, 10.7 mmol) in DCM (1.5 mL). The reaction was stirred at room temperature for 12 hours, and sat. aq. NaHCO3 (30 mL) was added. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to give the desired product 3-(bromomethyl)-2,6-dichloropyridine as a pale white solid (1.2 g). Yield 88% (ESI 240 (M+H)+). Step 2: methyl 3-(2,6-dichloropyridin-3-yl)-2,2-dimethylpropanoate To a solution of LDA (1.1 mL, 2.0 M in THF / hexanes, 2.2 mmol) in THF (2 mL) at -78 °C under Ar was added dropwise a solution of methyl isobutyrate (200 mg, 2.0 mmol) in THF (1 mL). Then a solution of 3-(bromomethyl)-2,6-dichloropyridine (518 mg, 2.2 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at room temperature for 12 hours, then poured into NH4Cl aq. solution (50 mL) and extracted with EtOAc (20 mL x3). The combined organic extracts were washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product methyl 3-(2,6-dichloropyridin-3-yl)-2,2-dimethylpropanoate as a colorless oil (401 mg). Yield 78% (ESI 262 (M+H)+). Step 3: 3-(2,6-dichloropyridin-3-yl)-2,2-dimethylpropanamide To a solution of methyl 3-(2,6-dichloropyridin-3-yl)-2,2-dimethylpropanoate (1.0 g, 3.83 mmol) in MeOH (10 mL) at 0 °C, was added LiOH-H2O (1.6 g, 38.3 mmmol) and H2O (2 mL). The reaction was warmed to room temeprature and stirred for 12 hours, then partially concentrated in vacuo and quenched with aqueous 1N HCl to pH = 5. The solid was collected by filtration and dried under vacuum to give the crude product 3-(2,6- dichloropyridin-3-yl)-2,2-dimethylpropanoic acid. This material was dissolved in DMF (10 mL). NH4Cl (2.25 g, 38.3 mmol), DIEA (1.61 g, 25 mmol), HOBt (0.8 g, 5.0 mmol), and EDCI.HCl (2.5 g, 5.0 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours, then dilued with H2O (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 1:1) to give the desired product 3-(2,6- dichloropyridin-3-yl)-2,2-dimethylpropanamide as a colorless oil (0.65 g). Yield 68% (ESI 247 (M+H)+). Step 4: 7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine To a solution of 3-(2,6-dichloropyridin-3-yl)-2,2-dimethylpropanamide (200 mg, 0.81 mmol) in THF (5 mL) at 0 °C was added dropwise a 1 M solution of BH3 in THF (8 mL). The reaction was warmed to room temeprature and stirred for 12 hours, then quenched with MeOH (8 mL) and concentrated in vacuo to give crude product 3-(2,6-dichloropyridin-3- yl)-2,2-dimethylpropan-1-amine. This material was dissolved in DMF (10 mL). Cs2CO3 (792 mg, 2.43 mmol) was added, and the mixture was warmed to 140 °C and stirred for 24 hours. The reaction mixture was cooled to room temperature, diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc= 2:1) to give the desired product 7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-1,8- naphthyridine as a yellow oil (102 mg). Yield 64% (ESI 197 (M+H)+). Step 5: tert-butyl 7-chloro-3,3-dimethyl-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate To a solution of 7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (102 mg, 0.52 mmol) in THF (10 mL) was added Boc2O (225 mg, 1.04 mmol) and DMAP (127 mg, 1.04 mmol). The mixture was warmed to 80 °C and stirred for 24 hours, then cooled to room temeprature, diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc= 5:1) to give the desired product tert-butyl 7-chloro- 3,3-dimethyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a colorless oil (90 mg). Yield 58% (ESI 241 (M+H-tBu)+). 1H NMR (400 MHz, CDCL3) δ7.28 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.50 (s, 2H), 2.53 (s, 2H), 1.54 (s, 9H), 1.02 (s, 6H). Step 6: 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3,3-dimethyl-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate To a solution of tert-butyl 3-(pent-4-enyloxy)azetidine-1-carboxylate (1.22 g, 5.07 mmol) in THF (dry, 10 mL) at 0 °C, was added 9-BBN (20.3 mL, 0.5 M in THF, 10.15 mmol). The reaction was warmed to 50 °C and stirred for 2 hrs, then cooled to room temperature. Tert-butyl 7-chloro-3,3-dimethyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.5 g, 5.07 mmol), KOH (851 mg, 15.21 mmol), Pd(OAc)2 (56 mg, 0.2 mmol) and PCy3 (140 mg, 0.5mmol) were added. The reaction mixture was warmed to 70 °C and stirred for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 3:1) to give the desired product tert-butyl 7-(5-(1-(tert- butoxycarbonyl)azetidin-3-yloxy)pentyl)-3,3-dimethyl-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate as a pale yellow oil (1.3 g). Yield 51% (ESI 504(M+H) +). Step 7: 7-(5-(azetidin-3-yloxy)pentyl)-3,3-dimethyl-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride Tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3,3-dimethyl-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.3 g, 2.6 mmol) was treated with a 4M solution of HCl in 1,4-dioxane (30 mL). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed in vacuo to give the desired product 7-(5- (azetidin-3-yloxy)pentyl)-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride as a pale yellow oil (920 mg). Yield 94% (ESI 304 (M+H)+). Preparation of 2-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride stereoisomer B Step 1: tert-butyl 3-(hept-6-enyloxy)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.8 mmol) in n- Heptane (20 mL) was added sodium hydroxide 50% solution in water (10 mL, 62.4 mmol), tetrabutylammonium bromide (86.0 mg, 0.27 mmol), and 7-bromohept-1-ene (3.06 g, 17.4 mmol). The mixture was heated to 80 °C and stirred for 2 hours, then cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (50 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product tert-butyl 3-(hept-6-enyloxy)azetidine-1-carboxylate as a colorless oil (1.2 g). Yield 80% (ESI 214 [M+H-tBu]+). Step 2: tert-butyl 3-(6-hydroxyoct-7-enyloxy)azetidine-1-carboxylate To a solution of tert-butyl 3-(hept-6-enyloxy)azetidine-1-carboxylate (1.0 g, 3.7 mmol) in THF (10 mL) and H2O (3 mL) was added sodium periodate (2.0 g, 9.25 mmol) and osmium tetroxide solution (4 wt% in water, 0.5 mL, 0.08 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with water (10 mL) and extracted with EtOAc (20 mL x3). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude product. To a solution of the crude product in tetrahydrofuran (dry, 10 mL) at 0 °C was added dropwise a solution of vinylmagnesium bromide (7.4 mL, 1 M in THF, 7.4 mmol). The mixture was stirred at room temperature overnight, then quenched with sat. NH4Cl (20 mL) and extracted with EtOAc (20mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to give the desired product tert-butyl 3-(6-hydroxyoct-7-enyloxy)azetidine-1-carboxylate as a colorless oil (310 mg). Yield 28% (ESI 244 [M+H-tBu]+). Step 3: tert-butyl 3-(8-(2-chloropyridin-3-yl)-6-oxooctyloxy)azetidine-1-carboxylate To a solution of tert-butyl 3-(6-hydroxyoct-7-enyloxy)azetidine-1-carboxylate (650 mg, 2.17 mmol), 2-chloro-3-iodopyridine (260 mg, 4.34 mmol), tetrabutylammonium chloride (30 mg, 0.11 mmol), and sodium bicarbonate (456 mg, 5.4 mmol) in DMF (10 mL) was added Pd(OAc)2 (25 mg, 0.11 mmol). The reaction was stirred under Ar at 70 °C overnight, then cooled to room temeprature and diluted with water (20 mL) and extracted with EtOAc (20 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product tert-butyl 3-(8-(2-chloropyridin-3-yl)-6-oxooctyloxy)azetidine-1- carboxylate (780 mg) as a colorless oil. Yield 85% (ESI 411 [M+H]+). Step 4: tert-butyl 3-(6-amino-8-(2-chloropyridin-3-yl)octyloxy)azetidine-1- carboxylate To a solution of tert-butyl 3-(8-(2-chloropyridin-3-yl)-6-oxooctyloxy)azetidine-1- carboxylate (780 mg, 1.9 mmol) in methanol (10 mL) was added ammonium acetate (2.2 g, 28.5 mmol). The mixture was stirred at room temperature for 5 min; then sodium cyanoborohydride (480 mg, 7.6 mmol) was added. The mixture was stirred at room temperature for 20 hours, quenched with 1 M NaOH (10 mL) and extracted with DCM (20 mL x3). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give a crude product. To a solution of the crude product in DMF (10 mL) was added Cs2CO3 (1.5 g, 4.75 mmol). The mixture was stirred at 140 °C for 20 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column (pet ether: EtOAc 1:1) to give the desired product tert-butyl 3-(5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidine-1- carboxylate as a pale yellow oil (450 mg). Yield 63% (ESI 376 [M+H]+). 1H NMR (400 MHz, CDCL3) δ 7.85 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.50-6.47 (m, 1H), 4.81 (s, 1H), 4.21-4.04 (m, 3H), 3.83-3.80 (m, 2H), 3.41-3.33 (m, 3H), 2.75-2.70 (m, 2H), 1.94- 1.92 (m, 1H), 1.59-1.35 (m, 18H). The racemic product was separated by Prep chiral SFC B to give stereoisomer A (160 mg) and stereoisomer B (150 mg) as pale yellow oils. Step 5: 2-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride stereoisomer B A solution of tert-butyl 3-(5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidine-1-carboxylate stereoisomer B (150 mg, 0.4 mmol) in 4N HCl in dioxane (5 mL) was stirred at room temperature for 12 hours. Solvent was removed in vacuo to give the desired product (S)-2-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro- 1,8-naphthyridine dihydrochloride stereoisomer B as a colorless oil (135 mg). Yield 95% (ESI 276 [M+H]+). Preparation of 7-(5-(azetidin-3-yloxy)pentyl)-3-methyl-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride stereoisomer A Step 1: methyl 3-(2,6-dichloropyridin-3-yl)-2-methylpropanoate To a solution of LDA (1.1 mL, 2.0 M in THF / hexanes, 2.2 mmol) in THF (2 mL) at -78 °C under Ar was added dropwise a solution of methyl isobutyrate (176 mg, 2.0 mmol) in THF (1 mL). Then a solution of 3-(bromomethyl)-2,6-dichloropyridine (518 mg, 2.2 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at room temperature for 12 hours, then poured onto sat. aq. NH4Cl (50 mL) and extracted with EtOAc (20 mL x3). The combined organic layer was washed with brine, concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product methyl 3- (2,6-dichloropyridin-3-yl)-2-methylpropanoate as a colorless oil (380 mg). Yield 77% (ESI 248 (M+H)+). Step 2: 3-(2,6-dichloropyridin-3-yl)-2-methylpropanamide To a solution of methyl 3-(2,6-dichloropyridin-3-yl)-2-methylpropanoate (10 g, 40.49 mmol) in MeOH (80 mL) at 0 °C was added LiOH (16 g, 404.9 mmmol) and H2O (16 mL). The reaction was stirred at room temperature for 12 hours, then partially concentrated in vacuo and adjusted to pH = 5 with aqueous HCl (1N). The solid was collected by filtration and dried in vacuo to give crude 3-(2,6-dichloropyridin-3-yl)-2-methylpropanoic acid. This material was dissolved in DMF (130 mL), and NH4Cl (21.1 g, 390.6 mmol), DIEA (15.1 g, 117.2 mmol), HOBt (7.46 g, 39.1 mmol), and EDCI-HCl (7.73 g, 46.9 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours, diluted with H2O (50 mL) and extracted with EtOAc (350 mL). The organic layer was washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 2:1) to give the desired product 3-(2,6-dichloropyridin-3-yl)-2- methylpropanamide as a colorless oil (4.68 g). Yield 52% (ESI 233 (M+H)+). Step 3: 7-chloro-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine To a solution of 3-(2,6-dichloropyridin-3-yl)-2-methylpropanamide (2.6 g, 11.2 mmol) in THF (50 mL) at -78 °C was added dropwise a 1 M solution of BH3 in THF (56 mL). The reaction was stirred at room temperature for 12 hours, then quenched with MeOH (8 mL) and concentrated in vacuo to give crude product 3-(2,6-dichloropyridin-3-yl)-2- methylpropan-1-amine. This material was dissolved in DMF (25 mL). Cs2CO3 (11 g, 33.0 mmol) was added, and the mixture was heated to 130 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with H2O (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc= 2:1) to give the desired product 7-chloro-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine as a yellow oil (1.4 g). Yield 69% (ESI 183 (M+H)+). The racemic product was separated by by Prep chiral SFC L to give stereoisomer A (425 mg) and stereoisomer B (478 mg) as white solids. Step 4: tert-butyl 7-chloro-3-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate stereoisomer A A solution of 7-chloro-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine stereoisomer A (425 mg, 2.33 mmol), Boc2O (763 mg, 3.50 mmol), and DMAP (854 mg, 7.00 mmol) in THF (15 mL) was stirred at 70 °C for 4 hours. The reaction mixture was cooled to room temperature, and diluted with EtOAc (40 mL) and H2O (10 mL). The organic layer was washed with brine, concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc = 9:1) to give the desired product (tert-butyl 7-chloro-3-methyl-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A as a colorless oil (650 mg). Yield 99% (ESI 283 (M+H)+). Step 5: tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3-methyl-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A To a solution of tert-butyl 3-(pent-4-en-1-yloxy)azetidine-1-carboxylate (758 mg, 3.14 mmol) in anhydrous THF (5 mL) under Ar was added 9-BBN (12.5 mL, 0.5M solution in THF, 6.25 mmol). The reaction was stirred at 50 °C for 2 hours, then cooled to room temperature and added to a mixture of tert-butyl 7-chloro-3-methyl-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate stereoisomer A (445 mg, 1.57 mmol), PCy3 (44mg, 0.16 mmol), Palladium acetate (18 mg, 0.08 mmol), and KOH (132.4 mg, 2.36 mmol) in 1,4- Dioxane (10 mL). The reaction was heated to 70 °C and stirred overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether / EtOAc = 0% → 30%) to give the desired product tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3- yloxy)pentyl)-3-methyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate stereoisomer A as a yellow oil (310 mg). Yield 40% (ESI 490 (M+H) +). Step 6: 7-(5-(azetidin-3-yloxy)pentyl)-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride stereoisomer A Tert-butyl 7-(5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)pentyl)-3-methyl-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate stereoisomer A (310 mg, 0.63 mmol) was was treated with 4N HCl in 1,4-dioxane (10 mL) at room temperature and stirred overnight. Solvent was removed in vacuo to give the desired product 7-(5-(azetidin-3-yloxy)pentyl)-3-methyl- 1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride stereoisomer A (225 mg). Yield 99% (ESI 290 (M+H)+). The following methods were used to prepare exemplary compounds of Formula (I). Example 1: Preparation of 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 1- E1 and 1-E2) Step 1: 4-bromo-3-methyl-1H-indazole A mixture of 1-(2-bromo-6-fluorophenyl)ethanone (5 g, 23.15 mmol) and hydrazine hydrate (2.34 g, 115.74 mmol) in iPrOH (10 mL) was warmed to 130 °C and stirred for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 1:5) to give the desired product 4-bromo-3-methyl-1H-indazole as a white solid (1.6 g). Yield 33% (ESI 211.0 (M+H) +). Step 2: 4-bromo-1-isopropyl-3-methyl-1H-indazole A mixture of 4-bromo-3-methyl-1H-indazole (525 mg, 2.5mmol), cesium carbonate (815 mg, 2.5mmol), and 2-iodopropane (425 mg, 2.5 mmol) in DMF (20 mL) was warmed to 130 °C and stirred for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 4- bromo-1-isopropyl-3-methyl-1H-indazole as a colorless oil (474 mg). Yield 75% (ESI 253.0 (M+H) +).1H NMR (400 MHz, CDCL3) δ 7.30 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.14-7.10 (m, 1H), 4.77-4.70 (m, 1H), 2.78 (s, 3H), 1.55 (d, J = 6.4Hz, 6H). Step 3: tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)acetate To a mixture of 4-bromo-1-isopropyl-3-methyl-1H-indazole (510 mg, 2.0mmol), Pd2(dba)3(73 mg, 0.1 mmol), and Q-phos (91 mg, 0.1 mmol) in THF (10 mL) was added (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (8.5 mL, 1 M in THF, 8.5 mmol) at room temperature under argon. The reaction was warmed to 60 °C and stirred for 2 hours, then quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)acetate as a yellow oil (437 mg). Yield 76% (ESI:289 (M+H) +). Step 4: tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H-indazol-4-yl)acetate To a solution of tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)acetate (378 mg, 1.31 mmol) in THF (6 mL) at -78 °C, was added lithium diisopropylamide solution (1.6 mL, 2.0 M in THF / hexanes, 3.2 mmol) dropwise. The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (283 mg, 2.6 mmol) was added, and the reaction was stirred at - 78 °C for another 30 min. Then a solution of NBS (467 mg, 2.6 mmol) in THF (2 mL) was added, and the reaction was stirred at -78 °C for 1 hour, then quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H- indazol-4-yl)acetate as a yellow oil (218 mg). Yield 45% (ESI 367 (M+H) +). Step 5: tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H-indazol-4-yl)acetate (183 mg, 0.5 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (174 mg, 0.5 mmol), and DIPEA (129 mg, 1.0 mmol) in acetonitrile (8 mL) was stirred at 50 °C for 3 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1-isopropyl-3-methyl- 1H-indazol-4-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1- yl)acetate as a yellow oil (118 mg). Yield 42% (ESI 561.0 (M+H) +). Step 6: 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 1-E1 and 1-E2) To a solution of tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (118 mg, 0.16 mmol) in DCM (2.5 mL) was added TFA (2.5 mL). The mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 1 as a white solid (80 mg). The racemic product was separated by Prep chiral SFC C to give enantiomeric compounds 1-E1 (34 mg) and 1- E2 (43 mg) as white solids. Compound 1-E1 (R-enantiomer) LC / MS ESI 506 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.57 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.37 (d, J = 7.2 Hz, 1H), 5.39 (s, 1H), 4.93-4.89 (m, 1H), 4.32– 4.30 (m, 2H), 4.06-4.00 (m, 1H), 3.91-3.86 (m, 1H), 3.65-3.62 (m, 1H), 3.42-3.36 (m, 4H), 2.92 (s, 3H), 2.70 (t, J = 6.4 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 1.89-1.86 (m, 2H), 1.68-1.52 (m, 10H), 1.43-1.39 (m, 2H). Chiral SFC C (15% MeOH), ee 100%, Rt = 1.39 min. Compound 1-E2 (S-enantiomer) LC / MS ESI 506 (M+H)+.1H NMR (400 MHz, MeOD δ 7.57 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 5.40 (s, 1H), 4.93-4.89 (m, 1H), 4.32– 4.30 (m, 2H), 4.06-4.00 (m, 1H), 3.91-3.86 (m, 1H), 3.65-3.62 (m, 1H), 3.42-3.36 (m, 4H), 2.92 (s, 3H), 2.70 (t, J = 6.4 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 1.89-1.86 (m, 2H), 1.67-1.53 (m, 10H), 1.43-1.39 (m, 2H).Chiral SFC C (15% MeOH), ee 99%, Rt = 1.75 min. Example 2: Preparation of 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 2-E1 and 2-E2) Step 1: 7-bromo-3-methyl-1H-indazole To a solution of 1-(3-bromo-2-fluorophenyl)ethan-1-one (2 g, 9.2 mmol) in ethylene glycol (10 mL) was added hydrazine monohydrate (2.3 g, 46 mmol). The reaction was stirred at 165 °C for 4 hours, then cooled to room temperature, diluted with H2O (20 mL) and extracted with DCM (20 mL x3). The combined organic extracts were dried over MgSO4, filtered, and concentration in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2:1) to give the desired product 7-bromo-3-methyl-1H-indazole as a colorless oil (1.6 g). Yield 82% (ESI 211 (M+H) +). Step 2: 7-bromo-1-(2-methoxyethyl)-3-methyl-1H-indazole To a mixture of 7-bromo-3-methyl-1H-indazole (1.63 g, 7.74 mmol) and Cs2CO3(5.04 g, 15.48 mmol) in DMF (70 mL) was added 1-bromo-2-methoxyethane (1.29 g, 9.29 mmol). The reaction mixture was heated to 80 °C and stirred overnight, then cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 7-bromo-1-(2-methoxyethyl)-3- methyl-1H-indazole as a white solid (1.21 g). Yield 58% (ESI 269 (M+H) +).1H NMR (500 MHz, CDCl3) δ7.62-7.58 (m, 2H), 7.02-6.94 (m, 1H), 4.99-4.92 (m, 2H), 3.88-3.80 (m, 2H), 3.37 (s, 3H), 2.57 (s, 3H). Step 3: tert-butyl 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-1-(2-methoxyethyl)-3-methyl-1H-indazole (1.28 g, 5.09 mmol), Pd2(dba)3(263 mg, 0.25 mmol), and Q-phos (181 mg, 0.25 mmol) in THF (10 mL) was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (26 mL, 1 M in THF, 26 mmol) at room temperature under argon. The reaction was stirred at 70 °C for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert- butyl 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)acetate as a pale red oil (1.2 g). Yield 77% (ESI 305 (M+H) +). Step 4: tert-butyl 2-bromo-2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)acetate (300 mg, 1.0 mmol) in THF (10 mL) at -78 °C, was added lithium diisopropylamide solution (1.25 mL, 2.0 M in THF / hexanes, 2.5 mmol) dropwise. The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (218 mg, 2.5 mmol) was added and the reaction was stirred at -78 °C for another 30 min. A solution of NBS (445 mg, 2.5 mmol) in THF (4 mL) was added and the reaction was stirred at -78 °C for an additional 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20mL x2). The combined organic extracts were washed with sat. aq. NaHCO3and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(1-(2-methoxyethyl)-3-methyl-1H- indazol-7-yl)acetate as a yellow oil (382 mg). Yield 93% (ESI 383.0 (M+H) +). Step 5: tert-butyl 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)acetate (383 mg, 1 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (348 mg, 1mmol), and DIPEA (288 mg, 3 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1-(2- methoxyethyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (208 mg). Yield 36 % (ESI 578 (M+H) +). Step 6: 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 2- E1 and 2-E2) To a solution of tert-butyl 2-(1-(2-methoxyethyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (208 mg, 0.36 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by prep-HPLC A (30 → 65% MeCN) to give compound 2 as a white solid (90 mg, 48% yield), which was separated by Prep chiral SFC A to give enantiomeric compounds 2-E1 (22 mg) and 2-E2 (29 mg) as white solids. Compound 2-E1 (S-enantiomer) LC / MS ESI 522.3 (M+H) +. 1H NMR (400 MHz, MeOD) δ 7.73 (d, J=8.0Hz,1H), 7.40 (d,J=6.8Hz,1H), 7.19-7.13 (m, 2H), 6.35 (d, J=7.6Hz,1H), 5.90 (s, 1H), 5.44 (s, 1H), 4.62.4.58 (m, 1H), 4.40-4.36 (m, 1H), 4.05-3.75 (m, 5H), 3.48-3.41 (m, 2H), 3.40-3.34 (m, 5H), 2.71-2.68 (m, 2H), 2.60-2.52 (m, 5H), 1.91- 1.84 (m, 2H), 1.71-1.54 (m, 4H),1.44-1.34 (m, 2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 2.26 min. Compound 2-E2 (R-enantiomer) LC / MS ESI 522.3 (M+H) +. 1H NMR (400 MHz, MeOD) δ 7.73 (d, J=8.0Hz,1H), 7.40 (d,J=6.8Hz,1H), 7.19-7.13 (m, 2H), 6.35 (d, J=7.6Hz,1H), 5.90 (s, 1H), 5.44 (s, 1H), 4.62.4.58 (m, 1H), 4.40-4.36 (m, 1H), 4.05-3.75 (m, 5H), 3.48-3.34 (m, 7H), 2.71-2.68 (m, 2H), 2.60-2.52 (m, 5H), 1.91-1.84 (m, 2H), 1.71- 1.54 (m, 4H),1.44-1.34 (m, 2H). Chiral SFC A (45% MeOH): ee 100%, Rt = 3.45 min. Example 3: Preparation of 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 3- E1 and 3-E2) Step 1: 7-bromo-1-isopropyl-3-methyl-1H-indazole To a mixture of 7-bromo-3-methyl-1H-indazole (1 g, 4.74 mmol) and Cs2CO3(3.09 g, 9.48 mmol) in DMF (40 mL) was added 2-iodopropane (967 mg, 5.69 mmol). The mixture was warmed to 80 °C and stirred overnight, then filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 7-bromo-1-isopropyl-3-methyl-1H-indazole as a white solid (987 mg). Yield 77% (ESI 253 (M+H) +).1H NMR (500 MHz, CDCl3) δ7.61-7.53 (m, 2H), 7.0-6.94 (m, 1H), 5.88-5.78 (m, 1H), 2.58 (s, 3H), 1.59 (d, 6H). Step 2: tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-1-isopropyl-3-methyl-1H-indazole (733 mg, 2.9 mmol), Pd2(dba)3(132 mg, 0.15 mmol), and Q-phos (107 mg, 0.15 mmol) in THF (3 mL) was added (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (14.5 mL, 1 M in THF, 14.5 mmol) at room temperature under Ar. The reaction was stirred at 70 °C for 2 hours. The mixture was quenched with sat. aq. NaHCO3, then filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert- butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)acetate as a pale red oil (497 mg). Yield 60% (ESI 289 (M+H) +). Step 3: tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)acetate (220 mg, 0.76 mmol) in THF (8 mL) at -78 °C was added dropwise lithium diisopropylamide solution (0.95 mL, 2.0 M in THF / hexanes, 1.9 mmol). The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (206 mg, 1.9 mmol) was added, and the reaction was stirred at - 78 °C for another 30 min. Then a solution of NBS (338 mg, 1.9 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (20 mL x2). The combined organic phase was washed with sat. aq. NaHCO3solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H-indazol-7- yl)acetate as a yellow oil (210 mg). Yield 75% (ESI 367 (M+H) +). Step 4: tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of tert-butyl tert-butyl 2-bromo-2-(1-isopropyl-3-methyl-1H-indazol-7- yl)acetate (140 mg, 0.38 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride (132 mg, 0.38 mmol), and DIPEA (147 mg, 1.14 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (93 mg). Yield 44% (ESI 562 (M+H) +). Step 5: 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 3-E1 and 3-E2) To a solution of tert-butyl 2-(1-isopropyl-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (93 mg, 0.17 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 3 as a white solid (65 mg, 70% yield), which was separated by Prep chiral SFC F to give enantiomeric compounds 3-E1 (15 mg) and 3-E2 (16 mg) as white solids. Compound 3-E1 (R-enantiomer) LC / MS ESI 506.3 (M+H) +. 1H NMR (400 MHz, MeOD) δ 7.64 (d, J=7.6Hz,1H), 7.52 (s, 1H), 7.18-7.09 (m, 2H), 6.37 (d, J=7.2Hz,1H), 5.72 (s, 1H), 4.20 (s, 1H), 4.05 (s, 1H), 3.76-3.48 (m, 2H), 3.42-3.36 (m, 4H), 2.72-2.69 (m, 2H), 2.56-2.51 (m, 5H), 1.91-1.88 (m, 2H), 1.71-1.28 (m, 14H). Chiral SFC F (45% MeOH): ee 100%, Rt = 2.27 min. Compound 3-E2 (S-enantiomer) LC / MS ESI 506.3 (M+H) +. 1H NMR (400 MHz, MeOD) δ 7.67 (d, J=8.0Hz,1H), 7.49 (s, 1H), 7.20-7.11 (m, 2H), 6.39 (d, J=7.2Hz,1H), 5.64 (s, 1H), 4.27 (s, 1H), 4.10 (s, 1H), 3.91-3.64 (m, 2H), 3.44-3.36 (m, 4H), 2.72-2.71 (m, 2H), 2.78-2.71 (m, 5H), 1.91-1.85 (m, 2H), 1.74-1.24 (m, 14H). Chiral SFC F (45% MeOH): ee 100%, Rt = 4.44 min. Example 4: Preparation of 2-(3-chloro-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 4- E1 and 4-E2) Step 1: 7-bromo-3-chloro-1-methyl-1H-indazole A mixture of 7-bromo-1-methyl-1H-indazole (1.90 g, 9.0 mmol) and NCS (1.45 g, 10.8 mmol) in DMF (15 mL) was stirred at room temperature overnight under Ar atmosphere. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 7-bromo-3-chloro-1-methyl-1H-indazole as a colorless oil (1.6 g). Yield 73% (ESI 245 (M+H) +). Step 2: tert-butyl 2-(3-chloro-1-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-3-chloro-1-methyl-1H-indazole (730 mg, 3.0 mmol), Pd2(dba)3(144 mg, 0.15 mmol), and Q-phos (111 mg, 0.15 mmol) in THF (15 mL) was added (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (15 mL, 1 M in THF, 15 mmol) at room temperature under argon. The reaction was warmed to 60 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1 → 4:1) to give the desired product tert-butyl 2-(3-chloro-1-methyl-1H-indazol-7-yl)acetate as a pale red oil (570 mg). Yield 68% (ESI 281 (M+H) +). Step 3: tert-butyl 2-bromo-2-(3-chloro-1-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(3-chloro-1-methyl-1H-indazol-7-yl)acetate (570 mg, 2.0 mmol) in THF (10 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (2.04 mL, 2.0 M in THF / hexanes, 4.08 mmol). The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (440 mg, 4.1 mmol) was added and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (730 mg, 4.1 mmol) in THF (10 mL) was added, and the reaction was stirred at -78 °C for an additional 30 min. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (20 mL ×3). The combined organic extracts were washed with sat. aq. NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(3-chloro-1-methyl-1H- indazol-7-yl)acetate as a yellow oil (450 mg). Yield 63% (ESI 359 (M+H) +). Step 4: tert-butyl 2-(3-chloro-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-chloro-1-methyl-1H-indazol-7-yl)acetate (250 mg, 0.70 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (193 mg, 0.70 mmol), and DIPEA (271 mg, 2.10 mmol) in acetonitrile (15 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(3-chloro-1-methyl- 1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1- yl)acetate as a yellow oil (290 mg). Yield 75% (ESI 554 (M+H) +). Step 5: 2-(3-chloro-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 4-E1 and 4-E2) To a solution of tert-butyl 2-(3-chloro-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (290 mg, 0.52 mmol) in DCM (4 mL), was added TFA (4 mL). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 4 as a white solid (210 mg, 81% yield). The racemic product was separated by Prep chiral SFC F to give enantiomeric compounds 4-E1 (87 mg) and 4-E2 (91 mg) as white solids. Compound 4-E1 (R-enantiomer) LC / MS ESI 498 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.25 – 7.21 (m, 2H), 6.40 (d, J = 7.2 Hz, 1H), 5.19 (s, 1H), 4.49 (s, 3H), 4.27-4.23 (m, 2H), 4.12-4.08 (m, 2H), 3.54-3.52 (m, 1H), 3.40 – 3.33 (m, 4H), 2.72 (t, J = 6.4 Hz, 2H ), 2.57 (t, J = 6.8 Hz, 2H ), 1.89 – 1.87 (m, 2H), 1.72-1.37 (m, 6H). Chiral SFC F (45% MeOH): ee 100%, Rt = 2.71min. Compound 4-E2 (S-enantiomer) LC / MS ESI 498 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.63 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.26 – 7.21 (m, 2H), 6.40 (d, J = 7.2 Hz, 1H), 5.21 (s, 1H), 4.49 (s, 3H), 4.26-4.24 (m, 2H), 4.12-4.08 (m, 2H), 3.41-3.33 (m, 5H), 2.72 (t, J = 6.4 Hz, 2H ), 2.56 (t, J = 6.8 Hz, 2H ), 1.91 – 1.85 (m, 2H), 1.72-1.41 (m, 6H). Chiral SFC F (45% MeOH): ee 99.6%, Rt = 3.85 min. Example 5: Preparation of 2-(1-methylisoquinolin-5-yl)-2-(3-((5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 5-E1 and 5- E2) Step 1: 1-methyl-5-nitroisoquinoline To a solution of 1-methylisoquinoline (10 g, 699 mmol) in H2SO4 (44 mL) at -15 °C was added in portions potasium nitrate (7 g, 699 mmol). The mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured onto ice resulting in the formation of a yellow precipitate which was collected by filtration and washed with water (60 mL x3) to give the desired product 1-methyl-5-nitroisoquinoline (11.7 g). Yield 89% (ESI 189 (M+H) +). Step 2: 1-methylisoquinolin-5-amine A mixture of 1-methylisoquinoline (7.7 g, 41 mmol) and Pd / C (10%, 770 mg) in EtOAc (60 mL) was stirred under H2 at room temperature for 16 hours. The mixture was filtered and concentrated in vacuo to give the desired product 1-methylisoquinolin-5-amine as a yellow solid (6.2 g). Yield 96% (ESI 159.0 (M+H) +). Step 3: 5-bromo-1-methylisoquinoline To a mixture of 1-methylisoquinolin-5-amine (760 mg, 4.8 mmol) and CuBr (1.37 g, 9.6 mmol) in CH3CN (30 mL) was added amyl nitrite (1.12 g, 9.6 mmol). The reaction was stirred at 60 °C for 2 hours, then concentrated in vacuo and diluted with EtOAc (50 mL). Sat. aq. NaHCO3 solution was added to adjust to pH = 8-9, and the organic layer was separated and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product 5-bromo-1-methylisoquinoline as a pale yellow oil (460 mg). Yield 43% (ESI 222 (M+H) +). Step 4: tert-butyl 2-(1-methylisoquinolin-5-yl)acetate To a mixture of 5-bromo-1-methylisoquinoline (460 mg, 2.1 mmol), Pd2(dba)3(55 mg, 0.06 mmol), and Q-phos (43 mg, 0.06 mmol) in THF (3 mL) was added (2-tert-butoxy-2- oxoethyl)zinc(II) bromide solution (10.5 mL, 1 M in THF, 10.5 mmol) at room temperature under Ar. The reaction was warmed to 50 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 3:1) to give the desired product tert-butyl 2-(1-methylisoquinolin-5-yl)acetate as a pale red oil (400 mg). Yield 78% (ESI 258.0 (M+H) +). Step 5: tert-butyl 2-bromo-2-(1-methylisoquinolin-5-yl)acetate To a solution of tert-butyl 2-(1-methylisoquinolin-5-yl)acetate (258 mg, 1.0 mmol) in THF (10 mL) at -78 °C, was added lithium diisopropylamide solution (1.0 mL, 2.0 M in THF / hexanes, 2.0 mmol) dropwise. The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (217 mg, 2.0 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for an additional 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL x2). The combined organic extracts were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(1-methylisoquinolin-5-yl)acetate as a yellow oil (240 mg). Yield 72% (ESI 336.0 (M+H) +). Step 6: tert-butyl 2-(1-methylisoquinolin-5-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1-methylisoquinolin-5-yl)acetate (240 mg, 0.71 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (247 mg, 0.71 mmol), and DIPEA (279 mg, 2.16 mmol) in acetonitrile (8 mL) was stirred at room temperature for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1- methylisoquinolin-5-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (220 mg). Yield 58% (ESI 531.0 (M+H) +). Step 7: 2-(1-methylisoquinolin-5-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 5-E1 and 5-E2) To a solution of tert-butyl 2-(1-methylisoquinolin-5-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (220 mg, 0.42 mmol) in DCM (6.0 mL) was added TFA (3.0 mL). The reaction mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 5 as a white solid (150 mg, 75% yield), which was separated by Prep chiral SFC D to give enantiomeric compounds 5-E1 (34 mg) and 5-E2 (30 mg) as white solids. Compound 5-E1 (R-enantiomer) LC / MS ESI 475.4 (M+H)+.1H NMR (400 MHz, MeOD) δ 8.39-8.33 (m, 2H), 8.25 (d, J = 6.3 Hz, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 5.37 (s, 1H), 4.33 - 4.19 (m, 2H), 3.92 - 3.63 (m, 3H), 3.41-3.32 (m, 4H), 2.99 (s, 3H), 2.70 (t, J = 6.3 Hz, 2H), 2.58 - 2.52 (m, 2H), 1.93 - 1.83 (m, 2H), 1.73 - 1.55 (m, 4H), 1.46 - 1.37 (m, 2H). Chiral SFC D (25% MeOH): ee 100%, Rt = 2.68 min. Compound 5-E2 (S-enantiomer) LC / MS ESI 475.4 (M+H) +. 1H NMR (400 MHz, MeOD) δ 8.39-8.33 (m, 2H), 8.25 (d, J = 6.2 Hz, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 6.39 (d, J = 7.3 Hz, 1H), 5.37 (s, 1H), 4.30-4.21 (m, 2H), 3.90 - 3.59 (m, 3H), 3.43 - 3.35 (m, 4H), 2.99 (s, 3H), 2.70 (t, J = 6.2 Hz, 2H), 2.58- 2.55 (m, 2H), 1.91 - 1.83 (m, 2H), 1.72 - 1.55 (m, 4H), 1.47 - 1.38 (m, 2H). Chiral SFC D (25% MeOH): ee 99%, Rt = 4.14 min. Example 6: Preparation of 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 6-E1 and 6-E2) Step 1: 7-bromo-1,3-dimethyl-1H-indazole To a mixture of 7-bromo-3-methyl-1H-indazole (2.5 g, 11.9 mmol) and Cs2CO3(7.8 g, 23.8 mmol) in DMF (30 mL) was added MeI (3.4 g, 23.8 mmol). The reaction mixture was warmed to 80 °C and stirred overnight, then filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 7- bromo-1,3-dimethyl-1H-indazole as a white solid (1.4 g). Yield 53% (ESI 225 (M+H) +).1H NMR (400 MHz, CDCl3) δ7.56 (d, J=8.0Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 6.93 (t, J=8.0Hz, 1H), 4.34 (s, 3H), 2.53 (s, 3H). Step 2: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-1,3-dimethyl-1H-indazole (1.63 g, 7.28 mmol), Pd2(dba)3(375 mg, 0.36 mmol), and Q-phos (259 mg, 0.36 mmol) in THF (10 mL) was added (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (40 mL, 1 M in THF, 40 mmol) at room temperature under Ar. The reaction was warmed to 70 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)acetate as a pale red oil (1.1 g). Yield 58% (ESI 261 (M+H) +). Step 3: tert-butyl 2-bromo-2-(1,3-dimethyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)acetate (260 mg, 1.0 mmol) in THF (8 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (1 mL, 2.0 M in THF / hexanes, 2.0 mmol). The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (216 mg, 2.0 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (2 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 8:1) to give the desired product tert-butyl 2-bromo-2-(1,3-dimethyl-1H- indazol-7-yl)acetate as a yellow oil (170 mg). Yield 89% (ESI 339.0 (M+H)+). Step 4: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1,3-dimethyl-1H-indazol-7-yl)acetate (170 mg, 0.5 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (189 mg, 0.5 mmol), DIPEA (129 mg, 1.0 mmol), and NaI (38 mg, 0.25 mmol) in acetonitrile (5 mL) was warmed to 50 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, diluted with H2O (5 mL), and extracted with ethyl acetate (10 mL x3). The combined organic extracts were concentrated in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (150 mg). Yield 53% (ESI 564.2 (M+H)+). Step 5: 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 6-E1 and 6-E2) To a solution of tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (150 mg, 0.27 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 6 as a white solid (80 mg, 58% yield). The racemic product was separated by Prep chiral SFC F to give enantiomeric compounds 6-E1 (25 mg) and 6-E2 (23 mg) as white solids. Compound 6-E1 (R-enantiomer) LC / MS ESI 508.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ7.66 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.33 (s,1H), 5.13 (s,2H), 4.43 (s, 3H), 4.24–4.21 (m, 1H), 3.98-3.96 (m, 1H), 3.89 (s,3H), 3.79- 3.70 (m, 2H), 3.45-3.38 (m, 3H), 3.36-3.31 (m, 1H), 2.63-2.58 (m, 4H), 2.57 (s, 3H), 1.88- 1.30 (m, 8H). Chiral SFC F (45% MeOH), ee 100%, Rt = 3.54 min. Compound 6-E2 (S-enantiomer) LC / MS ESI 508.2 (M+H)+.1H NMR (400 MHz, MeOD) δ7.64-7.55 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.27 (s,1H), 5.03 (s,2H), 4.43(s, 3H), 4.21– 4.19 (m, 1H), 3.96-3.90 (m, 1H), 3.86 (s,3H), 3.70-3.60 (m, 2H), 3.55-3.51 (m, 2H), 3.36- 3.31 (m, 2H), 2.59-2.56 (m, 4H), 2.55 (s,3H), 1.88-1.30 (m, 8H). Chiral SFC F (45% MeOH), ee 99%, Rt = 5.95 min. Example 7: Preparation of 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(6,6-dimethyl- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 7-E1 and 7-E2) Step 1: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(6,6-dimethyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1,3-dimethyl-1H-indazol-7-yl)acetate (170 mg, 0.5 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-3,3-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (188 mg, 0.5 mmol), DIPEA (129 mg, 1.0 mmol), and NaI (37.5 mg, 0.25 mmol) in acetonitrile (5 mL) was warmed to 50 °C and stirred for 4 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x3). The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product tert-butyl 2-(1,3-dimethyl-1H- indazol-7-yl)-2-(3-(5-(6,6-dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (100 mg). Yield 36% (ESI 563.2 (M+H)+). Step 2: 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(6,6-dimethyl-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 7-E1 and 7-E2) A solution of tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(6,6-dimethyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (100 mg, 0.18 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 7 as a white solid (80 mg, 88% yield). The racemic product was separated by Prep chiral SFC F to give enantiomeric compounds 7-E1 (30 mg) and 7-E2 (40 mg) as white solids . Compound 7-E1 (R-enantiomer) LC / MS ESI 506.4 (M+H) +. 1H NMR (400 MHz, MeOD) δ7.76 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.56 (s, 1H), 4.45 (s, 3H), 4.35 (s, 2H), 4.25– 3.70 (m, 3H), 3.50-3.48 (m, 2H), 3.19 (s, 2H), 2.67-2.63 (m, 2H), 2.54-2.50 (m,5H), 1.74- 1.60 (m, 4H), 1.47-1.31 (m, 2H), 1.03 (s, 6H). Chiral SFC F (45% MeOH), ee 100%, Rt = 2.80 min. Compound 7-E2 (S-enantiomer) LC / MS ESI 506.4 (M+H) +. 1H NMR (400 MHz, MeOD) δ7.77 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 5.68 (s, 1H), 4.45 (s, 3H), 4.35–3.80 (m, 4H), 3.50-3.48 (m, 2H), 3.19 (s, 2H), 2.67-2.63 (m, 2H), 2.54-2.50 (m,5H), 1.74-1.60 (m, 4H), 1.47-1.31 (m, 2H), 1.03 (s, 6H). Chiral SFC F (45% MeOH), ee 100%, Rt = 5.23 min. Example 9: Preparation of 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 9-E1 and 9-E2) Step 1: (2-bromo-6-fluorophenyl)(cyclopropyl)methanol To a solution of 2-bromo-6-fluorobenzaldehyde (2.0 g, 9.9 mmol) in THF (20 mL) at -78 °C under Ar was added cyclopropylmagnesium bromide (19.8 mL, 1 M in THF, 19.8 mmol). The reaction was stirred at room temperature for 3 hours and then quenched with sat. aq. NH4Cl (5 mL), diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product (2-bromo-6-fluorophenyl)(cyclopropyl)methanol as a yellow oil (2.3 g). Yield 95% (ESI 227.0 (M+H-H2O) +). Step 2: (2-bromo-6-fluorophenyl)(cyclopropyl)methanone To a solution of (2-bromo-6-fluorophenyl)(cyclopropyl)methanol (2.3 g, 9.58 mmol) in dichloromethane at 0 °C (10 mL) was added Dess-Martin reagent (6.1 g, 14.37 mmol) in portions. The reaction was stirred at room temperature for 2 hours, then quenched with sat. aq. NaHCO3 (5 mL), diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product (2-bromo-6- fluorophenyl)(cyclopropyl)methanone as a yellow oil (1.1 g). Yield 47% (ESI 243.0 (M+H) +). Step 3: 4-Bromo-3-cyclopropyl-1-methyl-1H-indazole To a solution of (2-bromo-6-fluorophenyl)(cyclopropyl)methanone (1.1 g, 4.55 mmol) in i-PrOH (10 mL) was added methylhydrazine (419 mg, 9.1 mmol). The reaction was stirred at 120 °C overnight. The mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC to give the desired product 4-bromo-3-cyclopropyl-1-methyl-1H-indazole as a yellow oil (160 mg). Yield 14% (ESI 251.0 (M+H) +). Step 4: Tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)acetate A mixture of 4-bromo-3-cyclopropyl-1-methyl-1H-indazole (160 mg, 0.64 mmol), (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (3.2 mL, 1.0 M in THF, 3.2 mmol), Pd2(dba)3 (34 mg, 0.032 mmol), and Q-phos (23 mg, 0.032 mmol) in THF (5 mL) was warmed to 80 °C and stirred overnight. The reaction mixture was poured into sat. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (100 mL x3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(3-cyclopropyl-1- methyl-1H-indazol-4-yl)acetate as a red oil (120 mg). Yield 66 % (ESI 287 [M+H]+). Step 5: Tert-butyl 2-bromo-2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)acetate To a solution of tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)acetate (120 mg, 0.33 mmol) in THF (10 mL) at -78 °C, was added lithium diisopropylamide solution (0.42 mL, 2.0 M in THF / hexanes, 0.825 mmol) dropwise. The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (89 mg, 0.825 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (147 mg, 0.825 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (20 mL x3). The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product tert-butyl 2-bromo-2-(3-cyclopropyl-1- methyl-1H-indazol-4-yl)acetate as a yellow oil (120 mg, ESI 365 (M+H)+). Step 6: Tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)acetate (120 mg, 0.33 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (115 mg, 0.33 mmol), NaI (50 mg), and DIPEA (128 mg, 0.99 mmol) in acetonitrile (10 mL) was stirred at 50 °C overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 5:1) to give the desired product tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (110 mg). Yield 60% (ESI 560 (M+H) +). Step 7: 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 9-E1 and 9-E2) To a solution of tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-4-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (110 mg, 0.20 mmol) in DCM (3.0 mL) was added TFA (3.0 mL). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 9 (30 mg) as a white solid, which was separated by Prep chiral SFC D to give enantiomeric compounds 9-E1 (13 mg) and 9-E2 (12 mg) as white solids. Compound 9-E1 (R-enantiomer) LC / MS ESI 504.3 (M+H)+. 1H NMR (500 MHz, MeOD) δ 7.55-7.45 (m, 1H), 7.43-7.40 (m,.1H), 7.38-7.25 (m, 1H), 7.15 (d, J=7.5Hz, 1H), 6.35 (d, J=7.5Hz, 1H), 5.76 (s, 1H), 4.45-4.20 (m, 2H), 4.02-3.85 (m, 4H), 3.83-3.75 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.31 (m, 4H), 2.78-2.60 (m, 3H), 2.51 (t, J=7.5 Hz, 2H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 4H), 1.43-1.30 (m, 3H), 1.22-1.02 (m, 2H), 0.90-0.70 (m, 1H). Chiral SFC D (25% MeOH), ee 100%, Rt = 2.37 min. Compound 9-E2 (S-enantiomer) LC / MS ESI 504.3 (M+H)+.1H NMR (500 MHz, MeOD) δ 7.58-7.50 (m, 1H), 7.48-7.40 (m,.1H), 7.35-7.25 (m, 1H), 7.14 (d, J=7.0Hz, 1H), 6.36 (d, J=7.0Hz, 1H), 5.79 (s, 1H), 4.45-4.20 (m, 2H), 4.02-3.85 (m, 4H), 3.83-3.75 (m, 1H), 3.70- 3.60 (m, 1H), 3.45-3.30 (m, 4H), 2.75-2.65 (m, 2H), 2.63-2.55 (m, 1H), 2.51 (t, J=7.5 Hz, 2H), 1.95-1.80 (m, 2H), 1.75-1.50 (m, 4H), 1.42-1.30 (m, 3H), 1.20-1.00 (m, 2H), 0.85- 0.75 (m, 1H). Chiral SFC D (25% MeOH), ee 100%, Rt = 3.09 min. Example 10: Preparation of 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)-2-(3-((5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 10-E1 and 10-E2) Step 1: 7-bromo-1-isopropyl-1H-indazole To a solution of 7-bromo-1H-indazole (1.5 g, 7.6 mmol) and 2-iodopropane (1.55 g, 9.1 mmol) in DMF (30 mL) was added Cs2CO3 (4.9 g, 15.2 mmol). The mixture was warmed to 80 °C and stirred under nitrogen for 18 hours, then diluted with water (30 mL) and extracted with EtOAc (50mL x3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 7-bromo-1-isopropyl-1H-indazole as a yellow oil (1 g). Yield 55% (ESI 239 (M+H) +).1H NMR (400 MHz, CDCL3) δ8.02 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 5.89-5.82 (m, 1H), 1.59 (d, J = 6.4 Hz, 6H). Step 2: 7-bromo-3-fluoro-isopropyl-1H-indazole To a solution of 7-bromo-1-isopropyl-1H-indazole (1 g, 4.2 mmol) in CH3CN (15 mL) and AcOH (1 mL) was added selectfluor (3 g, 8.4 mmol). The mixture was warmed to 90 °C and stirred for 2 hours, then poured into sat. aq. NaHCO3 solution (20 mL) and extracted with EtOAc (20 mL x3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 7-bromo-3-fluoro-isopropyl-1H-indazole as a red oil (590 mg). Yield 55 % (ESI 257 [M+H]+). Step 3: tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate To a mixture of 5-bromo-1-methylisoquinoline (590 mg, 2.3 mmol), Pd2(dba)3(55 mg, 0.06 mmol), and Q-phos (43 mg, 0.06 mmol) in THF (5 mL) at room temeprature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (10.5 mL, 1 M in THF, 10.5 mmol). The reaction was warmed to 50 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3 solution, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate as a pale oil (440 mg). Yield 71% (ESI 293.0 (M+H) +). Step 4: tert-butyl 2-bromo-2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate (220 mg, 0.75 mmol) in THF (5 mL) at -78 °C was added dropwise lithium diisopropylamide solution (0.75 mL, 2.0 M in THF / Hexanes, 1.5 mmol). The reaction was stirred at -78 °C for 30 min. Then a solution of chlorotrimethylsilane (162 mg, 1.5 mmol) in THF (1 mL) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (270 mg, 1.5 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate as a colorless oil (210 mg). Yield 76% (ESI 371 [M+H]+). Step 5: tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)acetate (210 mg, 0.72 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (250 mg, 0.72 mmol), and DIPEA( 279 mg, 2.16 mmol) in acetonitrile (8 mL) was stirred at room temperature for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (190 mg). Yield 49% (ESI 566.0 (M+H) +). Step 6: 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 10-E1 and 10-E2) To a solution of tert-butyl 2-(3-fluoro-1-isopropyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (190 mg, 0.34 mmol) in dichloromethane (6.0 mL) was added TFA (3.0 mL). The reaction mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 10 as a white solid (110 mg, 64% yield), which was separated by Prep chiral SFC F to give enantiomeric compounds 10-E1 (15 mg) and 10-E2 (14 mg) as white solids. Compound 10-E1 (R-enantiomer) LC / MS ESI 510 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.63 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 7.3 Hz, 1H), 5.60 (s, 1H), 5.02 (s, 1H), 4.26-4.24 (m, 1H), 4.02- 3.91 (m, 2H), 3.53 – 3.35 (m, 4H), 2.74 (m, 2H), 2.60 (m, 2H), 1.93 - 1.86 (m, 2H), 1.80 - 1.32 (m, 14H). Chiral SFC F (45% MeOH): ee 100%, Rt = 1.29 min. Compound 10-E2 (S-enantiomer) LC / MS ESI 510 (M+H)1H NMR (400 MHz, MeOD) δ 7.62 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 7.3 Hz, 1H), 5.63 (s, 1H), 4.91 (s, 1H), 4.22 (m, 1H), 4.00-3.85 (m, 2H), 3.40-3.35 (m, 4H), 2.74 (m, 2H), 2.63 - 2.54 (m, 2H), 1.90-1.88 (m, 2H), 1.79 - 1.32 (m, 14H). Chiral SFC F (45% MeOH): ee 97%, Rt = 1.80 min. Example 11: Preparation of 2-(6-fluoro-1,3-dimethyl-1H-indazol-4-yl)-2-(3-((5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 11-E1 and 11-E2) Step 1: 1-(2-bromo-4,6-difluorophenyl)ethan-1-one A mixture of 1-bromo-3,5-difluoro-2-iodobenzene (2.5 g, 7.9 mmol), tributyl(1- ethoxyvinyl)stannane (4.3 g, 11.9 mmol), Pd(PPh3)4 (460 mg, 0.4 mmol), and LiCl (1 g, 23.7 mmol) in dioxane (40 mL) was stirred at 100 °C under Ar for 18 hours. The reaction was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in THF (30 mL) and a 1 M aq. solution of HCl (15 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with water (30 mL) and extracted with EtOAc (50mL x3). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 20:1) to give the desired product 1-(2-bromo-4,6-difluorophenyl)ethan-1-one as a pale yellow oil (1.2 g). Yield 65% (ESI 181 (M+H) +). Step 2: 4-bromo-6-fluoro-1,3-dimethyl-1H-indazole A mixture of 1-(2-bromo-4,6-difluorophenyl)ethan-1-one (1.2 g, 5.1 mmol) and methylhydrazine (1.8 g, 15.3 mmol) in propan-2-ol (25 mL) in a sealed tube was warmed to 130 °C and stirred overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 4- bromo-6-fluoro-1,3-dimethyl-1H-indazole as a white solid (540 mg). Yield 43% (ESI 245 (M+H) +). Step 3: tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate To a mixture of 4-bromo-6-fluoro-1,3-dimethyl-1H-indazole (540 mg, 2.2 mmol), Pd2(dba)3(55 mg, 0.06 mmol), and Q-phos (43 mg, 0.06 mmol) in THF (5 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (11 mL, 1 M in THF, 11 mmol). The reaction was warmed to 50 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3 solution, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate as a pale red oil (280 mg). Yield 52% (ESI 279.0 (M+H) +). Step 4: tert-butyl 2-bromo-2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate To a solution of tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate (280 mg, 1 mmol) in THF (5 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (1 mL, 2.0 M in THF / Hexanes, 2 mmol). The reaction was stirred at -78 °C for 30 min. Then a solution of chlorotrimethylsilane (216 mg, 2 mmol) in THF (1 mL) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2 mmol) in THF (5 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo- 2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate as colorless oil (270 mg). Yield 76% (ESI 357 [M+H]+). Step 5: tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazol-4-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl) acetate A mixture of 2-bromo-2-(6-fluoro-1,3-dimethyl-1H-indazole-4-yl)acetate (270 mg, 0.76 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (260 mg, 0.76 mmol), and DIPEA (279 mg, 2.16 mmol) in acetonitrile (8 mL) was stirred at room temperature for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazol-4-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (310 mg). Yield 74% (ESI 552.0 (M+H) +). Step 6: 2-(6-fluoro-1,3-dimethyl-1H-indazol-4-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 11-E1 and 11-E2) To a solution tert-butyl 2-(6-fluoro-1,3-dimethyl-1H-indazol-4-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (310 mg, 0.56 mmol) in DCM (6.0 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 11 as a white solid (130 mg, 47% yield), which was separated by Prep chiral SFC F to give enantiomeric compounds 11-E1 (12 mg) and 11- E2 (16 mg) as white solids. Compound 11-E1 (R-enantiomer) LC / MS ESI 496 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.26-7.22 (m, 2H), 7.09 (dd, J = 10.3, 2.0 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 5.23 (s, 1H), 4.33 - 4.16 (m, 2H), 4.04 - 3.97 (m, 1H), 3.95 (s, 3H), 3.84-3.82 (m, 1H), 3.92-3.60 (m, 1H), 3.46 - 3.36 (m, 4H), 2.86 (s, 3H), 2.72 (t, J = 6.2 Hz, 2H), 2.56-2.54 (m, 2H), 1.93 - 1.85 (m, 2H), 1.73 - 1.56 (m, 4H), 1.44 (m, 2H). Chiral SFC F (45% MeOH): ee 100%, Rt = 2.09 min. Compound 11-E2 (S-enantiomer) LC / MS ESI 496 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.25-7.22 (m, 2H), 7.09 (dd, J = 10.3, 2.0 Hz, 1H), 6.41 (d, J = 7.3 Hz, 1H), 5.22 (s, 1H), 4.32 - 4.16 (m, 2H), 4.03 - 3.92 (m, 4H), 3.83-3.80 (m, 1H), 3.58-3.56 (m, 1H), 3.45 - 3.36 (m, 4H), 2.86 (s, 3H), 2.72 (t, J = 6.3 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 1.93 - 1.84 (m, 2H), 1.73 - 1.57 (m, 4H), 1.43 (m, 2H). Chiral SFC F (45% MeOH): ee 99%, Rt = 2.77 min. Example 14: Preparation of 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 14-E1 and 14- E2) Step 1: 5-Bromo-1-ethylisoquinoline To a mixture of 5-bromo-1-chloroisoquinoline (2.0 g, 8.29 mmol) and Pd(PPh3)4(479 mg, 0.41 mmol) in THF (30 mL) at 0 °C under Ar was added dropwise Et2Zn (6.5 mL, 6.5 mmol). The reaction was warmed to room temperature and stirred for 2 hours, then quenched with sat. aq. NH4Cl (5 mL), diluted with H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product 5-bromo-1-ethylisoquinoline as a white solid (550 mg). Yield 28% (ESI 236.0 (M+H) +). Step 2: Tert-butyl 2-(1-ethylisoquinolin-5-yl)acetate A mixture of 5-bromo-1-ethylisoquinoline (550 mg, 2.24 mmol), (2-tert-butoxy-2- oxoethyl)zinc(II) bromide solution (11.7 mL, 1.0 M in THF, 11.7 mmol), Pd2(dba)3 (123 mg, 0.117 mmol) and Q-phos (83 mg, 0.117 mmol) in THF (15 mL) was stirred at 80 °C overnight. The reaction mixture was poured into sat. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (100 mL x3). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(1-ethylisoquinolin-5-yl)acetate as a red oil (230 mg). Yield 38 % (ESI 272 [M+H]+). Step 3: Tert-butyl 2-bromo-2-(1-ethylisoquinolin-5-yl)acetate To a solution of tert-butyl 2-(1-ethylisoquinolin-5-yl)acetate (230 mg, 0.85 mmol) in THF (20 mL) at -78 °C was added lithium diisopropylamide solution (1.06 mL, 2.0 M in THF / hexanes, 2.125 mmol) dropwise. The reaction was stirred at -78 °C for 30 min, and then chlorotrimethylsilane (230 mg, 2.125 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (378 mg, 2.125 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (30mL x3). The combined oragnic phase was washed with sat. aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product tert-butyl 2-bromo-2-(1- ethylisoquinolin-5-yl)acetate as a yellow oil (296 mg, ESI 350 (M+H) +). Step 4: Tert-butyl 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (297 mg, 0.85 mmol), tert-butyl 2-bromo-2-(1-ethylisoquinolin-5- yl)acetate (296 mg, 0.85 mmol), NaI (100 mg), and DIPEA (329 mg, 2.55 mmol) in acetonitrile (8 mL) was warmed to 50 °C and stirred overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 5:1) to give the desired product tert-butyl 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (300 mg). Yield 65% (ESI 545 (M+H) +). Step 5: Tert-butyl 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (compounds 14-E1 and 14-E2) To a solution of tert-butyl 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (300 mg, 0.55 mmol) in DCM (3.0 mL) was added TFA (3.0 mL). The mixture was stirred at room temeprature overnight, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (33 → 65% MeCN) to give compound 14 (60 mg) as a white solid, which was separated by Prep chiral SFC B to give enantiomeric compounds 14-E1 (39 mg) and 14-E2 (39 mg) as white solids. Compound 14-E1 (R-enantiomer) LC / MS ESI 489.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 8.43-8.37 (m, 2H), 8.26-8.24 (m, 1H), 7.97-7.96 (m, 1H), 7.75-7.71 (m, 1H), 7.20 (d, J=7.2Hz, 1H), 6.39 (d, J=7.6Hz, 1H), 5.36 (s, 1H), 4.40-4.18 (m, 2H), 3.95-3.58 (m, 3H), 3.42-3.31 (m, 6H), 2.70 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 1.89-1.80 (m, 2H), 1.78-1.50 (m, 4H), 1.45-1.35 (m, 5H). Chiral SFC B (30% MeOH): ee 100%, Rt = 1.02 min. Compound 14-E2 (S-enantiomer) LC / MS ESI 489.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ 8.43-8.37 (m, 2H), 8.26-8.24 (m, 1H), 7.98-7.96 (m, 1H), 7.76-7.72 (m, 1H), 7.19 (d, J=7.2Hz, 1H), 6.38 (d, J=7.6Hz, 1H), 5.37 (s, 1H), 4.40-4.18 (m, 2H), 3.90-3.58 (m, 3H), 3.42-3.31 (m, 6H), 2.70 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 1.95-1.81 (m, 2H), 1.75-1.50 (m, 4H), 1.42-1.35 (m, 5H). Chiral SFC B (30% MeOH): ee 100%, Rt = 2.09 min. Example 15: Preparation of 2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyloxy)azetidin-1-yl)-2-(1-methylisoquinolin-5-yl)acetic acid (compounds 15- E1 and 15-E2) Step 1: tert-butyl 2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1-methylisoquinolin-5-yl)acetate A mixture of tert-butyl 2-bromo-2-(1-methylisoquinolin-5-yl)acetate (200 mg, 0.60 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (227 mg, 0.60 mmol), and DIPEA (154 mg, 1.19 mmol) in acetonitrile (8 mL) was stirred at room temperature for 3 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1-methylisoquinolin-5-yl)acetate as a yellow oil (130 mg). Yield 39% (ESI 561.0 (M+H) +). Step 2: 2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1-methylisoquinolin-5-yl)acetic acid (compounds 15-E1 and 15-E2) To a solution of tert-butyl 2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1-methylisoquinolin-5-yl)acetate (130 mg, 0.23 mmol) in DCM (2.5 mL) was added TFA (2.5 mL). The reaction mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by Prep- HPLC A (30 → 65% MeCN) to give compound 15 as a white solid (80 mg, 69% yield). The racemic product was separated by Prep chiral SFC B to give enantiomeric compounds 15-E1 (30 mg) and 15-E2 (30 mg) as white solids. Compound 15-E1 (R-enantiomer) LC / MS ESI 505.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ8.34-8.27 (m, 3H), 7.98 (d, J = 7.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 6.34 (s, 1H), 5.08 (s, 1H), 4.24-4.21 (m, 1H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 3.69-3.65 (m, 1H), 3.59- 3.56 (m, 1H), 3.42-3.37 (m, 3H), 3.33-3.31 (m, 2H), 2.97 (s, 3H), 2.62-2.55 (m, 4H), 1.86- 1.81 (m, 2H), 1.79-1.58 (m, 4H), 1.49-1.41 (m, 2H). Chiral SFC B (35% MeOH), ee 100%, Rt = 1.02 min. Compound 15-E2 (S-enantiomer) LC / MS ESI 505.2 (M+H)+. 1H NMR (400 MHz, MeOD δ8.34-8.26 (m, 3H), 7.98 (d, J = 7.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 6.34 (s, 1H), 5.06 (s, 1H), 4.24-4.21 (m, 1H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 3.69-3.65 (m, 1H), 3.59- 3.56 (m, 1H), 3.42-3.37 (m, 3H), 3.33-3.31 (m, 2H), 2.97 (s, 3H), 2.62-2.56 (m, 4H), 1.84- 1.81 (m, 2H), 1.73-1.58 (m, 4H), 1.46-1.42 (m, 2H). Chiral SFC B (35% MeOH), ee 99%, Rt = 2.11 min. Example 16: Preparation of 2-(1-methylisoquinolin-5-yl)-2-(3-(5-((S)-1,2,3,4- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 16- E1, 16-E2, 16-E3 and 16-E4) Step 1: tert-butyl 2-(1-methylisoquinolin-5-yl)-2-(3-(5-((S)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate THN stereoisomer B A mixture of 2-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride stereoisomer B (200 mg, 0.58 mmol), tert-butyl 2-bromo-2-(1- methylisoquinolin-5-yl)acetate (202 mg, 0.58 mmol), DIPEA (260 mg, 2.0 mmol) and NaI (50 mg) in acetonitrile (20 mL) was stirred at 40 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1- methylisoquinolin-5-yl)-2-(3-(5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetate THN stereoisomer B as a pale yellow oil (260 mg). Yield 85% (ESI 531 [M+H]+). Step 2: 2-(1-methylisoquinolin-5-yl)-2-(3-(5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetic acid THN stereoisomer B (compounds 16-E1 and 16- E2) To a solution of tert-butyl 2-(1-methylisoquinolin-5-yl)-2-(3-(5-((S)-1,2,3,4-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate THN stereoisomer B (260 mg, 0.49 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 24 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN / H2O) to give compound 16 as a white solid (102 mg, 50% yield). The product was separated by Prep chiral SFC B to give diastereomeric compounds 16-E1 (50 mg) and 16-E2 (51 mg) as white solids. Compound 16-E1 (R-a.a., R-THN diastereomer) LC / MS ESI 475 (M+H) +.1H NMR (400 MHz, MeOD) δ 8.40-8.26 (m, 3H), 7.98 (d, J=7.2Hz, 1H), 7.77-7.66 (m, 2H), 7.30-7.28 (m, 1H), 6.55-6.51 (m, 1H), 5.41 (s, 1H), 4.32-4.29 (m, 2H), 3.90-3.61 (m, 3H), 3.38-3.32 (m, 3H), 3.01 (s, 3H), 2.77 -2.75 (m, 2H), 1.90-1.88 (m, 1H), 1.72-1.32 (m, 9H). Chiral SFC B (30% MeOH), ee 100%, Rt = 1.49 min. Compound 16-E2 (S-a.a., R-THN diastereomer) LC / MS ESI 475 (M+H) +.1H NMR (400 MHz, MeOD) δ 8.43-8.26 (m, 3H), 7.98 (d, J=7.2Hz, 1H), 7.76-7.68 (m, 2H), 7.30-7.28 (m, 1H), 6.54-6.51 (m, 1H), 5.41 (s, 1H), 4.32-4.29 (m, 2H), 3.90-3.62 (m, 3H), 3.39-3.32 (m, 3H), 3.00(s, 3H), 2.78 -2.75 (m, 2H), 1.90-1.87 (m, 1H), 1.74-1.31 (m, 9H). Chiral SFC B (30% MeOH), ee 100%, Rt = 3.17 min. Step 3: 2-(1-methylisoquinolin-5-yl)-2-(3-(5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetic acid THN stereoisomer A (compounds 16-E3 and 16- E4) 2-(1-methylisoquinolin-5-yl)-2-(3-(5-((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetic acid THN stereoisomer A (diastereomeric compounds 16-E3 and 16-E4) was synthesized from tert-butyl 3-(5-(1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidine-1-carboxylate stereoisomer A by the same procedures as for stereoisomer B. Compound 16-E3 (R-a.a., S-THN diastereomer) LC / MS ESI 475 (M+H) +.1H NMR (400 MHz, MeOD) δ 8.41-8.25 (m, 3H), 7.98 (d, J=7.2Hz, 1H), 7.77-7.66 (m, 2H), 7.30-7.28 (m, 1H), 6.55-6.51 (m, 1H), 5.48 (s, 1H), 4.32-4.29 (m, 2H), 3.90-3.61 (m, 3H), 3.45-3.38 (m, 3H), 2.99 (s, 3H), 2.77 -2.74 (m, 2H), 1.90-1.88 (m, 1H), 1.65-1.32 (m, 9H). Chiral SFC B (30% MeOH), ee 100%, Rt = 1.24 min. Compound 16-E4 (S-a.a., S-THN diastereomer) LC / MS ESI 475 (M+H) +.1H NMR (400 MHz, MeOD) δ 8.43-8.24 (m, 3H), 7.98 (d, J=7.2Hz, 1H), 7.76-7.68 (m, 2H), 7.30-7.28 (m, 1H), 6.54-6.52 (m, 1H), 5.47 (s, 1H), 4.32-4.29 (m, 2H), 3.90-3.62 (m, 3H), 3.39-3.32 (m, 3H), 2.99 (s, 3H), 2.78 -2.75 (m, 2H), 1.90-1.87 (m, 1H), 1.74-1.31 (m, 9H). Chiral SFC B (30% MeOH), ee 100%, Rt = 2.08 min. Example 17: Preparation of 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 17-E1, 17-E2 and 17-E3) Step 1: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate methyl stereoisomer A A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-3-methyl-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride stereoisomer A (127 mg, 0.35 mmol), tert-butyl 2-bromo-2- (1,3-dimethyl-1H-indazol-7-yl)acetate (119 mg, 0.35mmol), and DIPEA (136 mg, 1.05 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate methyl stereoisomer A as a pale yellow oil (160 mg). Yield 83% (ESI 548.0 (M+H) +). Step 2: 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid methyl stereoisomer A (compound 17-E1) To a solution of tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate methyl stereoisomer A (160 mg, 0.29 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 17-E1 (mixture of two stereoisomers) as a white solid (8.6 mg, 6% yield). Compound 17-E1 (racemic a.a., R-Me stereochemistry) LC / MS ESI 492.3 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.62 (d, J=7.6Hz,1H), 7.35 (d, J=7.2Hz 1H), 7.08-6.98 (m, 2H), 6.53 (s, 1H), 6.23 (d, J=7.2Hz, 1H), 4.32 (s, 3H), 4.12 (s, 1H), 3.91-3.84 (m, 1H), 3.31-3.25 (m, 6H), 2.87-2.79 (m, 1H), 2.65-2.58 (m, 1H), 2.47-2.36 (m, 5H), 2.30-2.22 (m, 1H) , 1.91-1.80 (m, 1H), 1.62-1.40 (m, 7H), 0.95 (d, J=6.4Hz, 3H). Step 3: 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-((5-(6-methyl-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid methyl stereoisomer B (compounds 17-E2 and 17-E3 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(6-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyloxy)azetidin-1-yl)acetic acid methyl stereoisomer B was synthesized from 7- chloro-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine stereoisomer B by the same procedures as for stereoisomer A. The racemic product was separated by Prep chiral SFC B to give diastereomeric compounds 17-E2 and 17-E3 as white solids. Compound 17-E2 (R-a.a., S-Me diastereomer) LC / MS ESI 492.4 (M+H)+1H NMR (400 MHz, MeOD) δ 7.72 (d, J=8.0Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.25 – 7.07 (m, 2H), 6.38 (d, J=7.2Hz, 1H), 5.40 (s, 1H), 4.44 (s, 3H), 4.34 – 4.13 (m, 2H), 4.06 – 3.82 (m, 2H), 3.74 – 3.59 (m, 1H), 3.44 – 3.34 (m, 3H), 3.01 – 2.92 (m, 1H), 2.80 – 2.70 (m, 1H), 2.58 – 2.56 (m, 5H), 2.42 – 2.31 (m, 1H), 2.06 – 1.90 (m, 1H), 1.75 – 1.56 (m, 4H), 1.45 – 1.34 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H). Chiral SFC B (30% EtOH): ee 100%, Rt = 1.19 min. Compound 17-E3 (S-a.a., S-Me diastereomer) LC / MS ESI 492.4 (M+H)+1H NMR (400 MHz, MeOD) δ 7.72 (d, J=8.0Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.25 – 7.07 (m, 2H), 6.38 (d, J=7.2Hz, 1H), 5.38 (s, 1H), 4.44 (s, 3H), 4.31 – 4.13 (m, 2H), 4.01 – 3.79 (m, 2H), 3.67 – 3.57 (m, 1H), 3.45 – 3.36 (m, 3H), 3.01 – 2.91 (m, 1H), 2.79 – 2.70 (m, 1H), 2.58 – 2.49 (m, 5H), 2.40 – 2.30 (m, 1H), 2.04 – 1.93 (m, 1H), 1.74 – 1.55 (m, 4H), 1.46 – 1.34 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H). Chiral SFC B (30% EtOH): ee 100%, Rt = 1.58 min. Example 18: Preparation of 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1,3,4-trimethyl-1H-indazol-7-yl)acetic acid (compounds 18-E1 and 18-E2) Step 1: 1-(3-bromo-2-fluoro-6-methylphenyl)ethan-1-ol To a stirred solution of diisopropylamine (8.3 mL, 58.2 mmol) in tetrahydrofuran (25 mL) at -78 °C was added slowly n-butyllithium (2.5M solution in hexanes, 21.2 mL, 52.9 mmol). After 20 min a solution of 1-bromo-2-fluoro-4-methylbenzene (5 g, 26.5 mmol) in tetrahydrofuran (50 mL) was added. After 30 min acetaldehyde (7.47 mL, 132 mmol) was added. After 15 min the mixture was added to saturated aqueous ammonium chloride, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography ( 2–20% ethyl acetate in heptane) gave 1-(3-bromo-2-fluoro-6- methylphenyl)ethan-1-ol (2.908 g). Yield: 47%.1H NMR (400 MHz, Chloroform-d) δ 7.32 (dd, J = 8.2, 7.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.17 (p, J = 7.0 Hz, 1H), 2.36 (s, 3H), 2.21 (dd, J = 8.1, 5.4 Hz, 1H), 1.63 – 1.55 (m, 3H). Step 2: 1-(3-bromo-2-fluoro-6-methylphenyl)ethan-1-one To a solution of 1-(3-bromo-2-fluoro-6-methylphenyl)ethan-1-ol (3363 mg, 14.43 mmol) in dichloromethane (67 mL) was added water (1.5 mL) followed by Dess-Martin periodinane (9.17 g, 21.64 mmol). After 1 h, additional Dess-Martin periodinane (3.06 g, 7.21 mmol) and dichloromethane (60 mL) were added. After 1 h, the mixture was added to saturated aqueous sodium hydrogencarbonate, diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with sodium thiosulfate (saturated solution in water), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (2–20% ethyl acetate in heptane) gave 1-(3- bromo-2-fluoro-6-methylphenyl)ethan-1-one (2.008 g). Yield: 60%.1H NMR (400 MHz, Chloroform-d) δ 7.47 (dd, J = 8.2, 7.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 2.56 (d, J = 2.8 Hz, 3H), 2.29 (s, 3H). Step 3: 7-bromo-3,4-dimethyl-1H-indazole Hydrazine monohydrate (4.1 mL, 83 mmol) and 1-(3-bromo-2-fluoro-6- methylphenyl)ethan-1-one (1.92 g, 8.32 mmol) were heated to 150 °C in a sealed vial for 16 hours. The reaction was cooled to room temperature, diluted with water and extracted three times weith ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7-bromo-3,4-dimethyl-1H-indazole (1.804 g). Yield: 96%.1H NMR (400 MHz, Chloroform-d) δ 9.91 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 2.72 (s, 3H), 2.65 (s, 3H). Step 4: 7-bromo-1,3,4-trimethyl-1H-indazole To a solution of 7-bromo-3,4-dimethyl-1H-indazole (1.01 g, 4.46 mmol) in N,N- dimethylformamide (20 mL) at 0 °C was added sodium hydride (60% (w / w) dispersion in mineral oil, 357 mg, 8.93 mmol). After 10 min., methyl iodide (0.84 mL, 13.39 mmol) was added. After 10 min., the mixture was added to saturated aqueous ammonium chloride, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium thiosulfate, three times with water and once with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography ( 2–20% ethyl acetate in heptane) gave 7-bromo-1,3,4-trimethyl-1H- indazole (752 mg). Yield: 70%.1H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 4.31 (s, 3H), 2.66 (s, 3H), 2.62 (s, 3H). Step 5: Tert-butyl 2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate A mixture of 7-bromo-1,3,4-trimethyl-1H-indazole (700 mg, 2.94 mmol), (2-tert-butoxy- 2-oxoethyl)zinc(II) bromide solution (1.0 M in THF, 14.7 mL, 14.7 mmol), Pd2(dba)3 (154 mg, 0.147 mmol), and Q-phos (104 mg, 0.147 mmol) in THF (10 mL) was stirred at 80 °C overnight. The reaction mixture was poured into sat. NaHCO3 solution (20 mL) and extracted with EtOAc (50 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(1,3,4-trimethyl-1H-indazol-7- yl)acetate as a red oil (440 mg). Yield 55 % (ESI 275 [M+H]+). Step 6: Tert-butyl 2-bromo-2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate (240 mg, 0.88 mmol) in THF (10 mL) at -78 °C was added dropwise lithium diisopropylamide solution 2.0 M in THF / hexanes (1.1 mL, 2.2 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (238 mg, 2.2 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (392 mg, 2.2 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (30 mL x3). The combined organic phase was washed with sat. aq. NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product tert-butyl 2-bromo-2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate as a yellow oil (310 mg). Yield 100% (ESI 353 (M+H) +). Step 7: Tert-butyl 2-(1-ethylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (306 mg, 0.88 mmol), tert-butyl 2-bromo-2-(1,3,4-trimethyl-1H-indazol- 7-yl)acetate (310 mg, 0.88 mmol), NaI (50 mg), and DIPEA(341 mg, 2.64 mmol) in acetonitrile (8 mL) was heated to 50 °C and stirred overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 5:1) to give the desired product tert-butyl 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate as a pale yellow oil (450 mg). Yield 93% (ESI 548 (M+H) +). Step 8: 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)-2- (1,3,4-trimethyl-1H-indazol-7-yl)acetic acid (compounds 18-E1 and 18-E2) To a solution of tert-butyl 2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)-2-(1,3,4-trimethyl-1H-indazol-7-yl)acetate (450 mg, 0.82 mmol) in DCM (3.0 mL) was added TFA (3.0 mL). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 18 (150 mg) as a white solid, which was separated by Prep chiral SFC H to give enantiomeric compounds 18-E1 (48 mg) and 18-E2 (60 mg) as white solids. Compound 18-E1 (R-enantiomer) LC / MS ESI 492.3 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.21 (d, J=7.6Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.26 (d, J=7.2Hz, 1H), 5.27 (s, 1H), 4.29 (s, 3H), 4.20-4.02 (m, 2H), 4.00-3.82 (m, 1H), 3.80-3.65 (m, 1H), 3.58-3.42 (m, 1H), 3.38-3.22 (m, 4H), 2.62-2.50 (m, 9H), 2.45-2.35 (m, 2H), 1.85-1.70 (m, 2H), 1.62-1.38 (m, 4H), 1.35-1.20 (m, 2H). Chiral SFC B (45% EtOH), ee 100%, Rt = 2.10 min. Compound 18-E2 (S-enantiomer) LC / MS ESI 492.3 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.41 (d, J=7.2Hz, 1H), 7.19 (d, J=7.2Hz, 1H), 6.78 (d, J=7.2Hz, 1H), 6.43 (d, J=7.2Hz, 1H), 5.55 (s, 1H), 4.30-4.05 (m, 5H), 4.00-3.90 (m, 1H), 3.80-3.65 (m, 1H), 3.40- 3.25 (m, 4H), 2.78-2.62 (m, 2H), 2.60-2.50 (m, 8H), 1.90-1.75 (m, 2H), 1.60-1.40 (m, 4H), 1.38-1.20 (m, 2H). Chiral SFC B (30% MeOH), ee 100%, Rt = 4.90 min. Example 20: Preparation of 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 20-E1 and 20-E2) Step 1: 7-bromo-3-iodo-1-methyl-1H-indazole To a solution of 7-bromo-3-iodo-1H-indazole (2.50 g, 7.75 mmol) in N,N- dimethylformamide (50 mL) at 0 °C was added sodium hydride (60% (w / w) dispersion in mineral oil, 620 mg, 15.5 mmol). After 10 min., methyl iodide (1.45 mL, 23.24 mmol) was added. After 10 min, the reaction was allowed to warm to room temperature, added to saturated aqueous sodium hydrogencarbonate, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium thiosulfate, three times with water and once with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1–10% diisopropyl ether in heptane) gave 7-bromo-3-iodo-1-methyl-1H-indazole (1.982 g). Yield: 76%.1H NMR (400 MHz, Chloroform-d) δ 7.63 – 7.58 (m, 1H), 7.43 (dd, J = 8.1, 0.9 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 4.44 (s, 3H). Step 2: 7-bromo-1-methyl-1H-indazole-3-carbaldehyde To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (1.98 g, 5.88 mmol) in tetrahydrofuran (40 mL) in an ice / salt bath was added isopropylmagnesium chloride (2M in THF, 4.4 mL, 8.8 mmol). After 10 min, N,N-dimethylformamide (1.37 mL, 17.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2.5 hours, then added to saturated aqueous ammonium chloride, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography ( 2–20% ethyl acetate in heptane) gave 7-bromo-1-methyl-1H- indazole-3-carbaldehyde (1.247 g). Yield: 89%.1H NMR (400 MHz, Chloroform-d) δ 10.18 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 4.51 (s, 3H). Step 3: 7-bromo-3-(difluoromethyl)-1-methyl-1H-indazole To a solution of 7-bromo-1-methyl-1H-indazole-3-carbaldehyde (1.21 g, 5.05 mmol) in dichloromethane (25 mL) in an ice / salt bath was added DAST (1.23 mL, 10.10 mmol). After 30 min, the mixture was allowed to warm to room temperature and stirred for 22 h, then added to saturated aqueous sodium hydrogencarbonate, diluted with water and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (1– 10% ethyl acetate in heptane) gave 7-bromo-3-(difluoromethyl)-1-methyl-1H-indazole (817 mg). Yield: 62%.1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.12 – 6.76 (m, 2H), 4.44 (s, 3H). Step 4: tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-3-(difluoromethyl)-1-methyl-1H-indazole (522 mg, 2.0 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), and Q-phos (43 mg, 0.06 mmol) in THF (4 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (10 mL, 1 M in THF, 10 mmol). The reaction was stirred at 60 °C for 1 hour, then quenched with sat. aq. NaHCO3 solution, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 100:1 → 4:1) to give the desired product tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate as a pale red oil (503 mg). Yield 85% (ESI 297 (M+H) +). Step 5: tert-butyl 2-bromo-2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate (296 mg, 1.0 mmol) in THF (5mL) at -78 °C was added dropwise lithium diisopropylamide solution (1.0 mL, 2.0 M in THF / hexanes, 2.0 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (217 mg, 2.0 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (10mL x3). The combined oragnic phase was washed with sat. aq. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product tert-butyl 2-bromo-2-(3- (difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate as a yellow oil (375mg, purity 65%). Yield 65% (ESI 375 (M+H) +). Step 6: tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)acetate (375 mg, 1.0 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (348 mg, 1.0 mmol) and DIPEA( 388 mg, 3.0 mmol) in acetonitrile (16 mL) was stirred at room temperature for 30 min. Solvent was removed in vacuo, and the residue was diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH=100:1 → 10:1) to give the desired product tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (270 mg). Yield 47% (ESI 570.0 (M+H) +). Step 7: 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 20-E1 and 20- E2) To a solution of tert-butyl 2-(3-(difluoromethyl)-1-methyl-1H-indazol-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (270 mg, 0.47mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 20 as a white solid (171 mg, 71% yield). The racemic product was separated by Prep chiral SFC I to give enantiomeric compounds 20-E1 (64 mg) and 20-E2 (63 mg) as white solids. Compound 20-E1 (R-enantiomer) LC / MS ESI 514.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J=7.6Hz, 1H), 7.56 (d, J=6.8Hz, 1H), 7.28-7.22 (m, 2H), 7.03 (t, J=14.4Hz, 1H), 6.39 (d, J=7.6Hz, 1H), 5.30 (s, 1H), 4.57 (s, 3H), 4.27-4.11 (m, 2H), 3.93- 3.59 (m, 3H), 3.41–3.36 (m, 4H), 2.71 (m, 2H), 2.56 (m, 2H), 1.90-1.84 (m, 2H), 1.71 – 1.55 (m, 4H), 1.45–1.39 (m, 2H). Chiral SFC I (35% MeOH), ee 100%, Rt = 2.94 min. Compound 20-E2 (S-enantiomer) LC / MS ESI 514.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J=7.6Hz, 1H), 7.57 (d, J=6.8Hz, 1H), 7.27-7.22 (m, 2H), 7.03 (t,J=14.4Hz, 1H), 6.39 (d, J=7.6Hz, 1H), 5.26 (s, 1H), 4.57 (s, 3H), 4.25-4.11 (m, 2H), 3.88-3.55 (m, 3H), 3.41–3.36 (m, 4H),2.71 (m, 2H), 2.55 (m, 2H), 1.90-1.85 (m, 2H), 1.71 –1.55 (m, 4H), 1.44–1.38 (m, 2H). Chiral SFC I (35% MeOH), ee 100%, Rt = 4.42 min. Example 21: Preparation of 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 21-E1 and 21-E2) Step 1: 1-(5-bromo-4-chloropyridin-3-yl)ethan-1-ol To a solution of 5-bromo-4-chloronicotinaldehyde (4.86 g, 22.04 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 °C was added methylmagnesium chloride (22% (w / w) in THF, 8.9 mL, 26.4 mmol). After 20 min, the mixture was added to saturated aqueous ammonium chloride, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 1-(5-bromo-4-chloropyridin-3-yl)ethan-1-ol (5.284 g). Yield: 100%.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.67 (s, 1H), 5.36 – 5.25 (m, 1H), 2.29 (d, J = 3.9 Hz, 1H), 1.55 (d, J = 6.4 Hz, 3H). Step 2: 1-(5-bromo-4-chloropyridin-3-yl)ethan-1-one To a solution of 1-(5-bromo-4-chloropyridin-3-yl)ethan-1-ol (4.69 g, 19.8 mmol) in dichloromethane (100 mL) and water (2.5 mL) at 0 °C was added in portions Dess-Martin periodinane (16.84 g, 39.7 mmol). After 10 min, the mixture was allowed to warm to room temperature, stirred for 16 hours, added to saturated aqueous sodium hydrogencarbonate, diluted with water and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 1-(5-bromo-4- chloropyridin-3-yl)ethan-1-one (4.510 g). Yield: 97%.1H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.61 (s, 1H), 2.68 (s, 3H). Step 3: 7-bromo-3-methyl-1H-pyrazolo[4,3-c]pyridine To a solution of 1-(5-bromo-4-chloropyridin-3-yl)ethan-1-one (4.40 g, 18.8 mmol) in 1,2- dimethoxyethane (22 mL) was added hydrazine monohydrate (3.7 mL, 75 mmol). The reaction was heated to 120 °C for 22 hours, then added to water, basified with saturated sodium hydrogencarbonate, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo to give 7-bromo-3-methyl-1H-pyrazolo[4,3-c]pyridine (2.965 g).1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 9.05 (s, 1H), 8.46 (s, 1H), 2.59 (s, 3H). Step 4: 7-bromo-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridine To a solution of 7-bromo-3-methyl-1H-pyrazolo[4,3-c]pyridine (271 mg, 1.28 mmol) in N,N-dimethylformamide (5.5 mL) at 0 °C was added sodium hydride (60% (w / w) dispersion in mineral oil (102 mg, 2.56 mmol). After 10 min, methyl iodide (0.24 mL, 3.83 mmol) was added. After 10 min, the reaction was allowed to warm to room temperature, added to saturated aqueous sodium hydrogencarbonate, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium thiosulfate, three times with water and once with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10–100% ethyl acetate in heptane) gave 7-bromo-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridine (120 mg). Yield: 41%.1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.46 (s, 1H), 4.32 (s, 3H), 2.61 (s, 3H). Step 5: tert-butyl 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetate To a mixture of zinc (578 mg, 8.85 mmol, prepared with heating with a heatgun under a flow of argon) in anhydrous tetrahydrofuran (5 mL) was added 1,2-dibromoethane (0.019 mL, 0.22 mmol), followed by trimethylsilylchloride (0.028 mL, 0.22 mmol). After 10 min, a solution of tert-butyl 2-bromoacetate (863 mg, 4.42 mmol) in anhydrous tetrahydrofuran (5 mL) was added. The mixture was heated in a warm water bath (~60 °C) for 20 min, then added to a mixture of 7-bromo-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridine (500 mg, 2.21 mmol), bis(dibenzylideneacetone)palladium (127 mg, 0.221 mmol) and tri-tert- butylphosphine tetrafluoroborate (71 mg, 0.24 mmol) in anhydrous tetrahydrofuran (10 mL) under argon. The mixture was heated to 60 °C for 45 min, then cooled to room temperature, added to saturated aqueous ammonium chloride, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (15– 100% ethyl acetate in heptane) gave tert-butyl 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin- 7-yl)acetate (525 mg). Yield: 91%.1H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.33 (s, 1H), 4.16 (s, 3H), 3.94 (s, 2H), 2.61 (s, 3H), 1.44 (s, 9H). Step 6: tert-butyl 2-bromo-2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetate To a solution of tert-butyl 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetate (261 mg, 1.0 mmol) in THF (10 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (1.0 mL, 2.0 M in THF / hexanes, 2.0 mmol). The reaction was stirred at -78 °C for 30 min. Then chlorotrimethylsilane (217 mg, 2.0 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30min. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL x3). The combined oragnic phase was washed with sat. aq. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product tert-butyl 2-bromo-2-(1,3- dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetate as a yellow oil (340 mg, purity 62%). Yield 61% (ESI 340 (M+H) +). Step 7: tert-butyl 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)acetate (340 mg, 1.0 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (348 mg, 1.0 mmol), and DIPEA (388 mg, 3.0 mmol) in acetonitrile (15 mL) was stirred at room temperature for 30 min. Solvent was removed in vacuo, and the residue was diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH=100:1 → 9:1) to give the desired product tert-butyl 2- (1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a pale yellow oil (220 mg). Yield 41% (ESI 535 (M+H) +). Step 8: 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 21-E1 and 21- E2) To a solution of tert-butyl 2-(1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (220 mg, 0.41mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction was stirred at room temperature for 4 hours, then concentrated in vacuo, and the residue was purified by Prep- HPLC A (30 → 65% MeCN) to give compound 21 as white solid (97 mg, 49% yield). The racemic product was separated by Prep chiral SFC B to give enantiomeric compounds 21- E1 (32 mg) and 21-E2 (25 mg) as white solids. Compound 21-E1 (S-enantiomer) LC / MS ESI 479.3 (M+H)+. 1H NMR (400 MHz, MeOD) 8.92 (s, 1H), 8.39 (s, 1H), 7.32 (d, J=7.6Hz, 1H), 6.44 (d, J=7.6Hz, 1H), 4.85 (s, 1H), 4.46 (s, 3H), 4.20-4.18 (m, 1H), 3.96-3.94 (m, 1H), 3.62-3.59 (m, 2H), 3.40-3.38 (m, 5H), 2.74-2.72 (m, 2H), 2.64-2.58 (m, 5H), 1.92-1.86 (m, 2H), 1.76 –1.68 (m, 2H), 1.63 – 1.56 (m, 2H), 1.48–1.42 (m, 2H). Chiral SFC B (25% MeOH), ee 100%, Rt = 1.23 min. Compound 21-E2 (R-enantiomer) LC / MS ESI 479.3 (M+H)+. 1H NMR (400 MHz, MeOD) 8.91 (s, 1H), 8.39 (s, 1H), 7.31 (d, J=7.6Hz, 1H), 6.44 (d, J=7.6Hz, 1H), 4.82 (s, 1H), 4.48 (s, 3H), 4.19-4.17 (m, 1H), 3.96-3.94 (m, 1H), 3.60-3.56 (m, 2H), 3.40-3.38 (m, 5H), 2.74-2.72 (m, 2H), 2.64-2.58 (m, 5H), 1.92-1.86 (m, 2H), 1.75 –1.65 (m, 2H), 1.62 – 1.56 (m, 2H), 1.48–1.41(m, 2H). Chiral SFC B (25% MeOH), ee 100%, Rt = 2.48 min. Example 22: Preparation of 2-(7-fluoro-1-methylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 22- E1 and 22-E2) Step 1: 5-bromo-7-fluoroisoquinoline 2-oxide To a solution of 5-bromo-7-fluoroisoquinoline (897 mg, 3.97 mmol) in dichloromethane (18 mL) was added m-CPBA (1.27 g, 5.16 mmol). After 1 hour, sodium hydroxide (1N solution in water) and water were added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5-bromo-7-fluoroisoquinoline 2-oxide (912 mg). Yield: 95%.1H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 7.4, 1.7 Hz, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.65 (dd, J = 8.0, 2.3 Hz, 1H), 7.33 (dd, J = 8.5, 2.3 Hz, 1H). Step 2: 5-bromo-7-fluoro-1-methylisoquinoline A mixture of 5-bromo-7-fluoroisoquinoline 2-oxide (875 mg, 3.61 mmol), potassium tert- butoxide (811 mg, 7.23 mmol) and methyltriphenylphosphonium iodide (4.38 g, 10.84 mmol) in MTBE (32 mL) was heated to 110 °C for 1 hour in a sealed vial. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in diethyl ether (100 mL), filtered and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (2–20% ethyl acetate in heptane) afforded 5-bromo-7-fluoro-1-methylisoquinoline (340 mg). Yield: 39%. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 6.1 Hz, 1H), 7.80 (dd, J = 7.9, 2.4 Hz, 1H), 7.73 (dd, J = 9.2, 2.4 Hz, 1H), 2.94 (s, 3H). Step 3: tert-butyl 2-(7-fluoro-1-methylisoquinolin-5-yl)acetate To a mixture of 5-bromo-7-fluoro-1-methylisoquinoline (325 mg, 1.35 mmol), Pd2(dba)3 (43mg, 0.047 mmol), and Q-phos (34 mg, 0.047 mmol) in THF (4 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (6.75 mL, 1 M in THF, 6.75 mmol). The reaction was stirred at 60 °C for 1 hour, then cooled to room temperature, quenched with sat. aq. NaHCO3 solution, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1 → 2:1) to give the desired product tert-butyl 2-(7-fluoro-1-methylisoquinolin-5-yl)acetate as a pale red oil (332 mg). Yield 89% (ESI 276 (M+H) +). Step 4: tert-butyl 2-bromo-2-(7-fluoro-1-methylisoquinolin-5-yl)acetate To a solution of tert-butyl 2-(7-fluoro-1-methylisoquinolin-5-yl)acetate (275 mg, 1.0 mmol) in THF (5 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (1.0 mL, 2.0 M in THF / hexanes, 2.0 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (217 mg, 2.0 mmol) was added, and the reaction was stirred at - 78 °C for another 30 min. Then a solution of NBS (356 mg, 2.0 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL x3). The combined organic phase was washed with sat. aq. NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the desired product tert-butyl 2-bromo-2-(7-fluoro-1- methylisoquinolin-5-yl)acetate as a pale yellow oil (352 mg, purity 68%). Yield 68% (ESI 354.0 (M+H) +). Step 5: tert-butyl 2-(7-fluoro-1-methylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(7-fluoro-1-methylisoquinolin-5-yl)acetate (352 mg, 1.0 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (348 mg, 1.0 mmol), and DIPEA (388 mg, 3.0 mmol) in acetonitrile (16 mL) was stirred at room temperature for 2 hours. Solvent was removed in vacuo, and the residue was diluted with water (5 mL) and EtOAc (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 100:1 → 9:1) to give the crude product, which was purified by Prep-HPLC A (30 → 65% MeCN) to give the desired product tert-butyl 2-(7-fluoro-1- methylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetate as a pale yellow oil (210 mg). Yield 38% (ESI 549.1 (M+H) +). Step 6: 2-(7-fluoro-1-methylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 22-E1 and 22-E2) To a solution of tert-butyl 2-(7-fluoro-1-methylisoquinolin-5-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (210 mg, 0.38 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction was stirred at room temperature for 8 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 22 as a white solid (141 mg, 75% yield). The racemic product was separated by Prep chiral SFC B to give enantiomeric compounds 22-E1 (59 mg) and 22-E2 (62 mg) as white solids. Compound 22-E1 (R-enantiomer) LC / MS ESI 493.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 8.33-8.27 (m, 2H), 7.92 (dd, J=1.6Hz, J=9.6Hz, 1H), 7.83 (d, J=9.6Hz, 1H), 7.29 (d, J=7.2Hz, 1H), 6.42 (d, J=7.2Hz, 1H), 5.09 (s, 1H), 4.24-4.22 (m, 1H), 4.06-4.02 (m, 1H), 3.73-3.71 (m, 1H), 3.56-3.52 (m, 1H), 3.40-3.37 (m, 5H), 2.93 (s, 2H), 2.73-2.70 (m, 2H), 2.60-2.56 (m, 2H), 1.90-1.85 (m, 2H), 1.69 –1.55 (m, 4H), 1.43–1.39 (m, 2H). Chiral SFC B (25% MeOH), ee 100%, Rt = 2.32 min. Compound 22-E2 (S-enantiomer) LC / MS ESI 493.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 8.33-8.27 (m, 2H), 7.92 (dd, J=1.6Hz, J=9.6Hz, 1H), 7.84 (d, J=9.6Hz, 1H), 7.28 (d, J=7.2Hz, 1H), 6.42 (d, J=7.2Hz, 1H), 5.06 (s, 1H), 4.24-4.22 (m, 1H), 4.06-4.02 (m, 1H), 3.70-3.68 (m, 1H), 3.54-3.52 (m, 1H), 3.40-3.36 (m, 5H), 2.92 (s, 2H), 2.73-2.70 (m, 2H), 2.60-2.56 (m, 2H), 1.90-1.85 (m, 2H), 1.69 –1.55 (m, 4H), 1.45–1.39 (m, 2H). Chiral SFC B (25% MeOH), ee 100%, Rt = 4.26 min. Example 23: Preparation of 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 23-E1 and 23-E2) Step 1: 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-ol A mixture of i-PrMgBr (44.6 mL, 1N in THF, 44.6 mmol) and ZnCl2 (6.08 g, 44.6 mmol) in anhydrous THF (25 mL) was stirred at room temperature for 1 hour under Ar atmophere; then a solution of 3-bromo-2-fluorobenzaldehyde (3 g, 14.8 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours, then poured into sat. aq. NH4Cl (10 mL) and extracted with EtOAc (50 mL x2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1 → 5:1) to give the desired product 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-ol as a colorless oil (1.61 g). Yield 44% (ESI 229 (M+H-18) +). Step 2: 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-one A mixture of 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-ol (1.61 g, 6.52 mmol) and Dess-Martin reagent (5.52 g, 13.0 mmol) in DCM (30 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into sat. aq. NaHCO3 soltion (50 mL) and extracted with DCM (50 mL x2). The combined organic extracts were washed with sat. aq. NaHSO3 (30 mL x2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 20:1 → 10:1) to give the desired product 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-one as a light yellow oil (1.22 g). Yield 76% (ESI 245 (M + H) +). Step 3: 7-bromo-3-isopropyl-1-methyl-1H-indazole A mixture of 1-(3-bromo-2-fluorophenyl)-2-methylpropan-1-one (1.22 g, 4.98 mmol) and methylhydrazine hydrochloride (2.0 g, 40% in H2O, 10.0 mmol) in i-PrOH (30 mL) was stirred at 120 °C for 6 hours in a sealed tube. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 20:1 → 10:1) to give the desired product 7-bromo-3-isopropyl-1-methyl-1H-indazole as a yellow oil (0.82 g). Yield 65% (ESI 253 (M + H) +). Step 4: tert-butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-3-isopropyl-1-methyl-1H-indazole (820 mg, 3.23 mmol), Pd2(dba)3(156 mg, 0.16 mmol), and Q-phos (120 mg, 0.16 mmol) in THF (8 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (16 mL, 1 M in THF, 16 mmol). The reaction was heated to 60 °C and stirred for 2 hours, then quenched with sat. aq. NaHCO3 , filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1 → 4:1) to give the desired product tert- butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)acetate as a pale red oil (660 mg). Yield 71% (ESI 289 (M + H) +). Step 5: tert-butyl 2-bromo-2-(3-isopropyl-1-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)acetate (660 mg, 2.29 mmol) in THF (10 mL) at -78 °C was added dropwise lithium diisopropylamide solution (2.29 mL, 2.0 M in THF / hexanes, 4.58 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (492 mg, 4.58 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (816 mg, 4.58 mmol) in THF (10 mL) was added, and the reaction was stirred at -78 °C for 30 min., then quenched with H2O (10 mL) and extracted with EtOAc (20mL ×3). The combined organic phase was washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(3-isopropyl-1-methyl-1H-indazol-7-yl)acetate as a yellow oil (640 mg). Yield 76% (ESI 367 (M + H) +). Step 6: tert-butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (210 mg, 0.60 mmol), tert-butyl 2-bromo-2-(3-isopropyl-1-methyl-1H- indazol-7-yl)acetate (220 mg, 0.60 mmol) and DIPEA (232 mg, 1.80 mmol) in acetonitrile (15 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyloxy)azetidin-1-yl)acetate as a colorless oil (150 mg). Yield 44% (ESI 562 (M + H) +). Step 7: 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 23-E1 and 23-E2) To a solution of tert-butyl 2-(3-isopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (150 mg, 0.27 mmol) in DCM (4 mL) was added TFA (4 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (20 → 65% MeCN) to give compound 23 as a white solid (120 mg, 88% yield). The racemic product was separated by Prep chiral SFC E to give enantiomeric compounds 23- E1 (50 mg) and 23-E2 (37 mg) as white solids. Compound 23-E1 (R-enantiomer) LC / MS ESI 506 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.68 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 5.38 (s, 1H), 4.35 (s, 3H), 4.17 – 4.15 (m, 2H), 3.94 – 3.79 (m, 3H), 3.31 – 3.25 (m, 5H), 2.62 – 2.42 (m, 4H), 1.79 – 1.76 (m, 2H), 1.53 – 1.35 (m, 4H), 1.29 – 1.27 (m, 8H). Chiral SFC E (45% MeOH): ee 100%, Rt = 2.81min. Compound 23-E2 (S-enantiomer) LC / MS ESI 506 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.63 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.24 (d, J = 7.6 Hz, 1H), 5.09 (s, 1H), 4.34 (s, 3H), 4.12 – 4.01 (m, 2H), 3.70 – 3.54 (m, 2H), 3.28 – 3.20 (m, 6H), 2.59 – 2.38 (m, 4H), 1.78 – 1.72 (m, 2H), 1.56 – 1.43 (m, 4H), 1.32 – 1.29 (m, 8H). Chiral SFC E (45% MeOH): ee 98%, Rt = 3.47 min. Example 24: Preparation of 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 24-E1 and 24-E2) Step 1: (3-bromo-2-fluorophenyl)(cyclopropyl)methanol To a solution of 3-bromo-2-fluorobenzaldehyde (3 g, 14.78 mmol) in anhydrous THF (25 mL) at 0 °C under Ar was added dropwise cyclopropylmagnesium bromide (22.17 mL, 1N in THF, 22.17 mmol). The reaction was stirred at 0 °C for 30 min, then warmed to room temperature for 2 hours, poured into sat. aq. NH4Cl soltion (10 mL) and extracted with EtOAc (50 mL x2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1 → 5:1) to give the desired product (3-bromo-2- fluorophenyl)(cyclopropyl)methanol as a colorless oil (1.45 g). Yield 40% (ESI 227 (M- 17) +). Step 2: (3-bromo-2-fluorophenyl)(cyclopropyl)methanone A mixture of (3-bromo-2-fluorophenyl)(cyclopropyl)methanol (1.45 g, 5.92 mmol) and Dess-Martin reagent (5.03 g, 11.84 mmol) in DCM (40 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into sat. aq. NaHCO3 (50 mL) and extracted with DCM (50 mL x2). The combined organic phase was washed with sat. aq. NaHSO3 (30 mL x2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 20:1 → 10:1) to give the desired product (3-bromo-2-fluorophenyl)(cyclopropyl)methanone as a light yellow oil (1.14 g). Yield 79% (ESI 225 (M-17) +). Step 3: 7-bromo-3-cyclopropyl-1-methyl-1H-indazole A mixture of (3-bromo-2-fluorophenyl)(cyclopropyl)methanone (1.14 g, 4.69 mmol) and methylhydrazine (1.08 g, 40% in H2O, 9.38 mmol) in i-PrOH (30 mL) was stirred at 120 °C for 6 hours in a sealed tube. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1 → 5:1) to give the desired product 7-bromo-3-cyclopropyl-1-methyl-1H-indazole as a yellow oil (0.74 g). Yield 63% (ESI 251 (M + H) +). Step 4: tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-3-cyclopropyl-1-methyl-1H-indazole (740 mg, 2.94 mmol), Pd2(dba)3 (146 mg, 0.15 mmol), and Q-phos (112 mg, 0.15 mmol) in THF (10 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (15 mL, 1 M in THF, 15 mmol). The reaction was stirred at 60 °C for 2 hours, then quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1 → 4:1) to give the desired product tert-butyl 2-(3- cyclopropyl-1-methyl-1H-indazol-7-yl)acetate as a pale red oil (705 mg). Yield 84% (ESI 287 (M + H) +). Step 5: tert-butyl 2-bromo-2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)acetate To a solution of tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)acetate (705 mg, 2.47 mmol) in THF (10 mL) at -78 °C, was added dropwise lithium diisopropylamide solution (2.47 mL, 2.0 M in THF / hexanes, 4.94 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (533 mg, 4.94 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (879 mg, 4.94 mmol) in THF (10 mL) was added, and the reaction was stirred at -78 °C for 30 min. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (20mL ×3). The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(3-cyclopropyl-1-methyl-1H-indazol- 7-yl)acetate as a pale yellow oil (570 mg). Yield 63% (ESI 365 (M + H) +). Step 6: tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)acetate (220 mg, 0.60 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (210 mg, 0.60 mmol) and DIPEA (232 mg, 1.80 mmol) in acetonitrile (15 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2- (3-cyclopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyloxy)azetidin-1-yl)acetate as a colorless oil (190 mg). Yield 56% (ESI 560 (M + H) +). Step 7: 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 24-E1 and 24-E2) To a solution of tert-butyl 2-(3-cyclopropyl-1-methyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (190 mg, 0.34 mmol) in DCM (4 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 12 hours., then concentrated in vacuo, and the residue was purified by Prep-HPLC A (20 → 65% MeCN) to give compound 24 as a white solid (110 mg, 64% yield). The racemic product was separated by Prep chiral SFC B to give enantiomeric compounds 24-E1 (25 mg) and 24-E2 (42 mg) as white solids. Compound 24-E1 (R-enantiomer) LC / MS ESI 504 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.20 – 7.12 (m, 2H), 6.38 (d, J = 7.2 Hz, 1H), 5.42 (s, 1H), 4.41 (s, 3H), 4.28 – 4.21 (m, 2H), 4.01 – 3.92 (m, 2H), 3.88 – 3.84 (m, 1H), 3.66 – 3.31 (m, 4H), 2.72 – 2.52 (m, 4H), 2.24 – 2.22 (m, 1H), 1.88 – 1.61 (m, 8H), 1.05 – 1.02 (m, 4H). Chiral SFC B (20% MeOH): ee 100%, Rt = 2.59 min Compound 24-E2 (S-enantiomer) LC / MS ESI 504 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.80 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.19 – 7.12 (m, 2H), 6.38 (d, J = 7.2 Hz, 1H), 5.41 (s, 1H), 4.41 (s, 3H), 4.27 – 4.21 (m, 2H), 4.18 – 4.02 (m, 2H), 4.00 – 3.87 (m, 1H), 3.66 – 3.31 (m, 4H), 2.72 – 2.52 (m, 4H), 2.25 – 2.21 (m, 1H), 1.89 – 1.57 (m, 8H), 1.05 – 0.99 (m, 4H). Chiral SFC B (20% MeOH): ee 100%, Rt = 3.53 min Example 25: Preparation of 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 25-E1 and 25-E2) Step 1: 7-bromo-1-(tert-butyl)-3-methyl-1H-indazole To a solution of 1-(3-bromo-2-fluorophenyl)ethan-1-one (2 g, 9.2 mmol) and tert- butylhydrazine hydrochloride (7.3 g, 58.9 mmol) in NMP (10 mL) was added DBU (2.3 g, 18.4 mmol), K2CO3 (3.2 g, 23 mmol) and CuO (15 mg, 0.18 mmol). The reaction was stirred at 130 °C for 17 hours, then cooled to room temperature, diluted with H2O (50 mL) and extracted with ethyl acetate (2x 100 mL). The combined organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product 7-bromo-1-(tert-butyl)-3-methyl-1H-indazole (1.7 g) as a colorless oil. Yield 69% (ESI 267 (M+H) +). Step 2: ethyl 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)acetate To a mixture of 7-bromo-1-(tert-butyl)-3-methyl-1H-indazole (500 mg, 1.9 mmol), Pd2(dba)3 (150 mg, 0.05 mmol) and Q-phos (103 mg, 0.05 mmol) in THF (3 mL) at room temperature under Ar was added (2-ethoxy-2-oxoethyl)zinc(II) bromide solution in THF (0.5 M, 11.4 mL, 5.7 mmol). The reaction was stirred at 60 °C for 2 hours, then quenched with aqueous NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1~2:1) to give the desired product ethyl 2-(1-(tert- butyl)-3-methyl-1H-indazol-7-yl)acetate as a pale red oil (420 mg). Yield 81% (ESI 275 (M+H) +). Step 3: ethyl 2-bromo-2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)acetate To a solution of ethyl 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)acetate (200 mg, 0.73 mmol) in THF (8 mL) at -78°C was added dropwise lithium diisopropylamide solution (2.0 M in THF / hexanes, 0.9 mL, 1.8 mmol). The reaction was stirred at -78°C for 30 min; then chlorotrimethylsilane (198 mg, 1.83 mmol) was added, and the reaction was stirred at - 78 °C for another 30 min. Then a solution of NBS (325 mg, 1.83 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min, then diluted with H2O (10 mL) and extracted with EtOAc (2x 20mL). The combined oragnic phase was washed with sat. aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired ethyl 2-bromo-2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)acetate as a pale yellow oil (229 mg). Yield 90% (ESI 353 (M+H) +). Step 4: ethyl 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of ethyl 2-bromo-2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)acetate (150 mg, 0.42 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (229 mg, 0.66 mmol) and DIPEA (246 mg, 1.97 mmol) in acetonitrile (10 mL) was stirred at 60 °C for 15 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product ethyl 2-(1- (tert-butyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)azetidin-1-yl)acetate as a pale yellow oil (150 mg). Yield 42% (ESI 548.0 (M+H) +). Step 5: 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 25-E1 and 25-E2) To a solution of ethyl 2-(1-(tert-butyl)-3-methyl-1H-indazol-7-yl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (150 mg, 0.55 mmol) in MeOH ( 4.5 mL) was added H2O ( 1.5 mL) and LiOH (220 mg, 11 mmol). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (30-65% MeCN) to give compound 25 as a white solid (80 mg). The racemic product was separated by Prep chiral SFC J to give enantiomeric compounds 25-E1 (11 mg) and 25-E2 (16 mg) as white solids. Compound 25-E1 (R-enantiomer) LC / MS ESI 520 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.73 (d, J=7.6Hz,1H), 7.52 (d, J=7.2Hz,1H), 7.21-7.15 (m, 2H), 6.37 (d, J=7.6Hz,1H), 5.64 (s, 1H), 4.27-4.16 (m, 2H), 4.01 (s, 1H), 3.75 (s, 1H), 3.60 (s, 1H), 3.40-3.34 (m, 4H), 2.74-2.67 (m, 2H), 2.56-2.48 (m, 5H), 1.96-1.83 (m, 11H), 1.72-1.38 (m, 6H). Chiral SFC J (45% MeOH): ee 100%, Rt = 1.79 min. Compound 25-E2 (S-enantiomer) LC / MS ESI 520 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.72 (d, J=7.2Hz,1H), 7.53 (d, J=6.8Hz,1H), 7.22-7.13 (m, 2H), 6.36 (d, J=7.6Hz,1H), 5.60 (s, 1H), 4.25-4.11 (m, 2H), 3.94 (s, 1H), 3.71 (s, 1H), 3.56 (s, 1H), 3.42-3.34 (m, 4H), 2.74-2.67 (m, 2H), 2.56-2.46 (m, 5H), 1.98-1.83 (m, 11H), 1.70-1.34 (m, 6H). Chiral SFC J (45% MeOH): ee 95%, Rt = 2.43 min. Example 28: Preparation of 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 28- E1 and 28-E2) Step 1: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate To a solution of tert-butyl 2-bromo-2-(1,3-dimethyl-1H-indazol-7-yl)acetate (300 mg, 0.88 mmol) in acetonitrile (10 mL) was added 7-(5-(azetidin-3-yloxy)pentyl)- 1,2,3,4-tetrahydro-1,8-naphthyridine (242 mg, 0.88 mmol) and DIPEA (340 mg, 2.64 mmol). The reaction was stirred for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (20-80% EtOAc in pet ether) to afford the title compound (280 mg, 59% yield) as a yellow oil. LC / MS ESI 534.3 [M+H]+. Step 2: 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 28-E1 and 28-E2) Tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyloxy)azetidin-1-yl)acetate (290 mg, 0.54 mmol) was treated with TFA (2 mL) in DCM (5 mL) at 25 °C for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC and Prep chiral SFC M to give enantiomeric compounds 28- E1 (65 mg, 24% yield) and 28-E2 (74 mg, 29% yield). Compound 28-E1 (R-enantiomer) LC / MS ESI 477.3 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.69 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.39 (d, J = 7.3 Hz, 1H), 5.33 (s, 1H), 4.45 (s, 3H), 4.30 – 4.23 (m, 1H), 4.22 – 4.16 (m, 1H), 3.95-3.94 (m, 1H), 3.81-3.80 (m, 1H), 3.58-3.56 (m, 1H), 3.39-3.36 (m, 4H), 2.70 (t, J = 6.2 Hz, 2H), 2.57 – 2.48 (m, 5H), 1.91 – 1.83 (m, 2H), 1.66-1.60 (m, 4H), 1.42-1.37 (m, 2H). Chiral SFC M: ee 100%, Rt = 1.91 min Compound 28-E2 (S-enantiomer) LC / MS ESI 477.3 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.72 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 5.40 (s, 1H), 4.45 (s, 3H), 4.27-4.21 (m, 2H), 4.01-3.99(m, 1H), 3.88-3.86 (m, 1H), 3.67-3.66 (m, 1H), 3.45 – 3.35 (m, 4H), 2.71 (t, J = 6.1 Hz, 2H), 2.59 – 2.48 (m, 5H), 1.91-1.87 (m, 2H), 1.72 – 1.55 (m, 4H), 1.43-1.41 (m, 2H). Chiral SFC M: ee 100%, Rt = 2.97 min Example 30: Preparation of 2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin- 1-yl)acetic acid (compounds 30-E1 and 30-E2) Step 1: 2-cyclopropyl-3-nitrophenol A mixture of 2-bromo-3-nitrophenol (10 g, 45.9 mmol), cyclopropylboronic acid (5.92 g, 68.85 mmol), Pd(OAc)2(773 mg, 3.44 mmol), tricyclohexylphosphine (2.04 g, 6.88 mmol) and potassium carbonate (19 g, 137.7 mmol) in toluene (60 mL) and water (7.5 mL) was heated to 110 °C and stirred overnight. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 2-cyclopropyl-3-nitrophenol as a colorless oil (6.4 g). Yield 77% (ESI 180.0 (M+H) +). Step 2: 4-(2-cyclopropyl-3-nitrophenoxy)tetrahydro-2H-pyran To a mixture of 2-cyclopropyl-3-nitrophenol (6.4 g, 35.6 mmol), tetrahydro-2H-pyran-4-ol (4.36 g, 42.72 mmol) and triphenylphosphine (9.33 g, 35.6 mmol) in THF (dry, 40 mL) at 0 °C under Ar was added DIAD (7.2 g, 35.6 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 4-(2-cyclopropyl-3-nitrophenoxy)tetrahydro-2H-pyran as a colorless oil (5.1 g). Yield 54% (ESI 264.0 (M+H) +). Step 3: 2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)aniline To a mixture of 2-cyclopropyl-1-isopropoxy-3-nitrobenzene (3.7 g, 14.1 mmol) and NH4Cl (3.8 g, 70.5 mmol) in EtOH (20 mL) and H2O (5 mL) was added Fe (1.7 g, 70.5 mmol) at 20 °C. The mixture was warmed to 90 °C and stirred for 2 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated in vacuo. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL x4). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 6:1) to give the desired product 2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)aniline as a yellow oil (2.4 g). Yield 73% (ESI 234.0 (M+H) +). Step 4: 4-(3-bromo-2-cyclopropylphenoxy)tetrahydro-2H-pyran A mixture of 2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)aniline (1.16 g, 5.0 mmol), tert-butyl nitrite (773 mg, 7.5 mmol), and CuBr (1.07 g, 7.5 mmol) in acetonitrile (20 mL) was heated to 65 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 4-(3-bromo-2-cyclopropylphenoxy) tetrahydro-2H-pyran as a yellow oil (480 mg). Yield 32% (ESI 297.0 (M+H) +). Step 5: tert-butyl 2-(2,4-dicyclopropylpyrimidin-5-yl)acetate A mixture of 1-bromo-2-cyclopropyl-3-isopropoxybenzene (480 mg, 1.62 mmol), (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (13 mL, 0.5 M in THF, 6.5 mmol), Pd2(dba)3 (74 mg, 0.08 mmol), and Q-phos (114 mg, 0.16 mmol) in THF (10 mL) was stirred at 65 °C for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate as a yellow oil (380 mg). Yield 70% (ESI 333.0 (M+H) +). Step 6: tert-butyl 2-bromo-2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate To a solution of tert-butyl 2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy) phenyl) acetate (380 mg, 1.14 mmol) in THF (6 mL) at -78 °C was added lithium diisopropylamide solution (1.5mL, 2.0 M in THF / hexanes, 2.85 mmol) dropwise. The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (308 mg, 2.85 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (508 mg, 2.85 mmol) in THF (8 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 4:1) to give the desired product tert-butyl 2-bromo-2-(2-cyclopropyl-3-isopropoxyphenyl)acetate as a yellow oil (300 mg). Yield 64% (ESI 412 (M+H) +). Step 7: tert-butyl 2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy) phenyl)acetate (300 mg, 0.73 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro- 1,8-naphthyridine (200 mg, 0.73 mmol), and DIEA (283 mg, 2.19 mmol) in acetonitrile (8 mL) was warmed to 60 °C and stirred for 16 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine as a yellow oil (150 mg). Yield 38% (ESI 606 (M+H) +). Step 8: 2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 30- E1 and 30-E2) Tert-butyl 2-(2-cyclopropyl-3-isopropoxyphenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (150 mg, 0.24 mmol) was treated with a 4M solution of HCl in 1,4-dioxane (5 mL) at 25 °C for 2 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 30 as a white solid (105 mg, 70% yield). The racemic product was separated by Prep chiral SFC I to give enantiomeric compounds 30-E1 (26 mg) and 30-E2 (51mg) as white solids. Compound 30-E1 (R-enantiomer) LC / MS ESI 550 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.24 – 6.97 (m, 4H), 6.37 (d, J = 7.2 Hz, 1H), 5.64 (s, 1H), 4.61 – 4.57 (m, 1H), 4.34 – 4.31 (m, 2H), 4.02-3.98 (m, 3H), 3.81 – 3.79 (m, 1H), 3.68 – 3.58 (m, 3H), 3.50 – 3.32 (m, 5H), 2.61 – 2.57 (m, 2H), 2.52-2.49 (m, 2H), 2.04 – 2.02 (m, 2H), 1.94 – 1.55 (m, 9H), 1.48 – 1.09 (m, 5H), 0.58 – 0.56 (m, 1H).Chiral SFC I (45% MeOH:MeCN=3:2): ee 100 %, Rt = 2.55min. Compound 30-E2 (S-enantiomer) LC / MS ESI 550 (M+H) +.1H NMR (400 MHz, MeOD) ) δ 7.24 – 6.97 (m, 4H), 6.37 (d, J = 7.2 Hz, 1H), 5.64 (s, 1H), 4.61 – 4.57 (m, 1H), 4.44 – 4.32 (m, 2H), 4.04-3.98 (m, 3H), 3.81 – 3.79 (m, 1H), 3.68 – 3.58 (m, 3H), 3.48 – 3.30 (m, 5H), 2.61 – 2.57 (m, 2H), 2.52-2.49 (m, 2H), 2.04 – 2.00 (m, 2H), 1.94 – 1.55 (m, 9H), 1.48 – 1.09 (m, 5H), 0.58 – 0.56 (m, 1H).Chiral SFC I (45% MeOH:MeCN=3:2): ee 100 %, Rt = 5.46min. Example 31: Preparation of 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(4-methoxy- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 31-E1 and 31-E2) Step 1: 2-cyclopropyl-3-methoxyaniline A mixture of 2-bromo-3-methoxyaniline (10.0 g, 49.5 mmol), cyclopropylboronic acid (8.51 g, 99.0 mmol), Pd(OAc)2(556 mg, 2.48 mmol), tricyclohexylphosphine (1.39 g, 4.95 mmol) and tripotassium phosphate (31.5g, 148.5 mmol) in toluene (100 mL) and water (10 mL) was heated to 120 °C and stirred overnight. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 2-cyclopropyl-3-methoxyaniline as a colorless oil (7.2 g). Yield 89% (ESI 164 (M+H) +). Step 2: 2-cyclopropyl-1-iodo-3-methoxybenzene To a mixture of p-TsOH·H2O (1.719 g, 9 mmol) and 2-cyclopropyl-3-methoxyaniline (489 mg, 3 mmol) in MeCN (12 mL) at 0 °C was added dropwise a solution of NaNO2 (414 mg, 6 mmol) and KI (1.24 g, 7.5 mmol) in H2O (2 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with H2O (50 mL) and adjusted to pH = 9–10 with sat. aq. NaHCO3 (1M). A 2M aq. solution of Na2S2O3 (6 mL) was added, and the crude product was extracted with EtOAc (50 mL x2). The combined organic extracts were dried over Na2SO4 and filtered. The solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 2-cyclopropyl-1-iodo-3-methoxybenzene as a pale yellow oil (500 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 3.74 (s, 3H), 1.64-1.58 (m, 1H), 1.01-0.96 (m, 2H), 0.69- 0.63 (m, 2H). Step 3: tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)acetate A mixture of 2-cyclopropyl-1-iodo-3-methoxybenzene (274 mg, 1.0 mmol), (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (8 mL, 0.5 M in THF, 4.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol) and Q-phos (71 mg, 0.10 mmol) in THF (5 mL) was warmed to 65 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)acetate as a red oil (220 mg). Yield 84% (ESI 285 (M+Na) +). Step 4: tert-butyl 2-bromo-2-(2-cyclopropyl-3-methoxyphenyl)acetate To a solution of tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)acetate (220 mg, 0.84 mmol) in THF (5 mL) at -78 °C was added dropwise lithium diisopropylamide solution (1.1 mL, 2.0 M in THF / hexanes, 2.2 mmol). The reaction was stirred at -78 °C for 30 min, then chlorotrimethylsilane (239 mg, 2.2 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (392 mg, 2.2 mmol) in THF (5 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2-(2-cyclopropyl-3- methoxyphenyl)acetate as a yellow oil (220 mg). Yield 77% (ESI 363 (M+Na) +). Step 5: tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(2-cyclopropyl-3-methoxyphenyl)acetate (170 mg, 0.5 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-5-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (188 mg, 0.5 mmol), DIPEA (129 mg, 1.0 mmol), and NaI (37.5 mg, 0.25 mmol) in acetonitrile (5 mL) was warmed to 50 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, diuled with H2O (5 mL) and extracted with ethyl acetate (10mL x3). The combined organic extracts were concentrated in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a yellow oil (120 mg). Yield 42% (ESI 566 (M+H) +). Step 6: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(4-methoxy-5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 31-E1 and 31- E2) A solution of tert-butyl 2-(1,3-dimethyl-1H-indazol-7-yl)-2-(3-(5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (120 mg, 0.21 mmol) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 31 as a white solid (95 mg, 89% yield). The racemic product was separated by Prep chiral SFC J to give enantiomeric compounds 31-E1 (41 mg) and 31- E2 (42mg) as white solids. Compound 31-E1 (R-enantiomer) LC / MS ESI 510.3 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.25 (t, J = 8.0 Hz, 1H), 7.00-6.95 (m, 2H), 6.22 (s, 1H), 5.62 (s, 1H), 4.38-4.29 (m, 2H), 4.02–3.96 (m, 1H), 3.83-3.79 (m, 7H), 3.70-3.62 (m, 1H), 3.43-3.41 (m, 2H), 3.38- 3.36 (m, 2H), 2.59-2.51 (m, 7H), 1.87-1.58 (m, 7H), 1.43-1.10 (m, 5H), 0.62-0.59 (m, 1H). Chiral SFC J (45% EtOH), ee 100%, Rt = 2.91 min. Compound 31-E2 (S-enantiomer) LC / MS ESI 510.3 (M+H)+.1H NMR (400 MHz, MeOD δ 7.24 (t, J = 8.0 Hz, 1H), 7.00-6.95 (m, 2H), 6.22 (s, 1H), 5.59 (s, 1H), 4.36-4.29 (m, 2H), 4.02–3.96 (m, 1H), 3.83-3.79 (m, 7H), 3.70-3.62 (m, 1H), 3.43-3.41 (m, 2H), 3.38-3.36 (m, 2H), 2.59-2.51 (m, 7H), 1.87-1.58 (m, 7H), 1.43-1.10 (m, 5H), 0.62-0.59 (m, 1H). Chiral SFC J (45% EtOH), ee 100%, Rt = 4.44 min. Example 34: Preparation of 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 34-E1 and 34-E2) Step 1: 1-bromo-3-methoxy-2-(prop-1-en-2-yl)benzene To a solution of 1-(2-bromo-6-methoxyphenyl)ethanone (100 mg, 0.44 mmol) in THF (2 mL) was added dropwise a solution of methyl magnesium chloride (0.88 mL, 1 M in THF, 0.88 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in toluene (5 mL). TsOH (30 mg) was added, and the reaction mixture was warmed to 80 °C and stirred for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to give the desired product 1- bromo-3-methoxy-2-(prop-1-en-2-yl)benzene as a colorless oil (65 mg). Yield 60% (ESI 227 / 229 [M+H]+). Step 2: 1-bromo-3-methoxy-2-(1-methylcyclopropyl)benzene To a solution of diethyl zinc (18 mL, 1 M in hexane, 18 mmol) in anhydrous DCM (20 mL) at 0 °C was added TFA (2.05 g, 18.0 mmol). The reaction was stirred at 0 °C for 30 min, and a solution of diiodomethane (4.82 g, 18.0 mmol) in DCM (10 mL) was added dropwise. The reaction was stirred at 0 °C for 30 min. Then a solution of 1-bromo-3-methoxy-2- (prop-1-en-2-yl)benzene (693 mg, 3.0 mmol) in dichloromethane (5 mL) was added. The reaction was stirred at room temperature for 3 hours, then quenched with sat. aq. NH4Cl (20 mL) and extracted with DCM (20 mL x3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 20:1) to give the desired product 1-bromo-3-methoxy-2-(1- methylcyclopropyl)benzene (610 mg) as a colorless oil. Yield 86% (ESI 241 / 243 [M+H]+). Step 3: tert-butyl 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)acetate A mixture of 1-bromo-3-methoxy-2-(1-methylcyclopropyl)benzene (610 mg, 2.5 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (30 mL, 0.5 M in THF, 15 mmol), Pd2(dba)3 (152 mg, 0.15 mmol), and Q-phos (105 mg, 0.15 mmol) in THF (2 mL) was warmed to 80 °C and stirred for 2 hours. The mixture was quenched with sat. aq. NaHCO3 solution, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-(3-methoxy-2-(1- methylcyclopropyl)phenyl)acetate as a pale red oil (310 mg). Yield 44% (ESI 299 [M+Na]+). Step 4: tert-butyl 2-bromo-2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)acetate To a solution of tert-butyl 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)acetate (320 mg, 1.16 mmol) in THF (5 mL) at -78 °C was added dropwise lithium diisopropylamide solution (1.45 mL, 2.0 M in THF / hexanes, 2.9 mmol). The reaction was stirred at -78 °C for 30 min. Then a solution of chlorotrimethylsilane (310 mg, 2.9 mmol) in THF (1mL) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (511 mg, 2.9 mmol) in THF (10 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)acetate as a pale yellow oil (350 mg). Yield 80% (ESI 299 [M+H-tBu]+). Step 5: tert-butyl 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate A mixture of tert-butyl 2-bromo-2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)acetate (350 mg, 1.0 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (348 mg, 1.0 mmol), DIPEA ( 450 mg, 3.0 mmol), and NaI (50 mg) in acetonitrile (20 mL) was warmed to 40 °C and stirred for 12 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM / MeOH 0% → 10%) to give the desired product tert-butyl 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a colorless oil (210 mg). Yield 38 % (ESI 550 [M+H]+). Step 6: 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 34-E1 and 34-E2) To a solution of tert-butyl 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate (210 mg, 0.38 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 24 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give the desired product compound 34 (65 mg, 35% yield). The racemic product was separated by Prep chiral SFC J to give enantiomeric compounds 34-E1 (25mg) and 34-E2 (24 mg) as white solids. Compound 34-E1 (R-enantiomer) LC / MS ESI 494 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.24 (t, J=8.0Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 6.96-6.92 (m, 2H), 6.35 (d, J=7.2Hz, 1H), 5.52-5.50 (m, 1H), 4.32-4.30 (m, 2H), 4.01-3.31 (m, 10H), 2.71 -2.49 (m, 4H), 1.85-1.50 (m, 7H), 1.45-1.21 (m, 4H), 1.01-0.61 (m, 4H). Chiral SFC J (45% MeOH): ee 100%, Rt = 1.37min. Compound 34-E2 (S-enantiomer) LC / MS ESI 494 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.24 (t, J=8.0Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 6.96-6.92 (m, 2H), 6.35 (d, J=7.2Hz, 1H), 5.52-5.50 (m, 1H), 4.32-4.30 (m, 2H), 4.01-3.31 (m, 10H), 2.71 -2.50 (m, 4H), 1.87-1.52 (m, 7H), 1.44-1.20 (m, 4H), 1.02-0.60 (m, 4H). Chiral SFC J (45% MeOH): ee 100%, Rt = 1.92min. Example 36: Preparation of 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-((5-(6-methyl- 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compounds 36-E1, 36-E2 and 36-E3) Step 1: tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(6-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate methyl stereoisomer A A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-3-methyl-1,2,3,4-tetrahydro-1,8- naphthyridine dihydrochloride stereoisomer A (127 mg, 0.35 mmol), tert-butyl 2-bromo-2- (2-cyclopropyl-3-methoxyphenyl)acetate (119 mg, 0.35mmol), and DIPEA (136 mg, 1.05 mmol) in acetonitrile (10 mL) was heated to 40 °C and stirred for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(6- methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate methyl stereoisomer A as a pale yellow oil (100 mg). Yield 52% (ESI 550 (M+H) +). Step 2: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-((5-(6-methyl-5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid methyl stereoisomer A (compound 36-E1) To a solution of tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(6-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate methyl stereoisomer A (100 mg, 0.18 mmol) in DCM (5 mL) was added TFA (2.5 mL). The mixture was stirred at room temperature for 18 hours. Solvent was removed in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 36-E1 (mixture of two stereoisomers) as a white solid (6.7 mg, 7% yield). Compound 36-E1 (racemic a.a., R-Me stereochemistry) LC / MS ESI 494.3 (M+H) +.1H NMR (500 MHz, MeOD) δ 7.26-7.21 (m, 1H), 7.13 (d, J=7.0 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.36 (d, J=7.5 Hz 1H), 5.51 (s, 1H), 4.33-4.25 (m, 2H), 3.92- 3.82 (m, 4H), 3.69 (s, 1H), 3.59-3.50 (m, 1H), 3.45-3.39 (m, 3H), 3.01-2.96 (m, 1H), 2.76- 2.72 (m, 1H) , 2.54-2.50 (m, 2H), 2.40-2.34 (m, 1H), 2.0 (s, 1H) , 1.82-1.77 (m, 1H), 1.69- 1.57 (m, 4H), 1.43-1.38 (m, 2H), 1.18-104 (m, 6H), 0.63-0.59 (m, 1H). Step 3: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-((5-(6-methyl-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid methyl stereoisomer B (compounds 36-E2 and 36-E3) 2-(2-cyclopropyl-3-methoxyphenyl)-2-(3-(5-(6-methyl-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid methyl stereoisomer B was synthesized from 7-chloro-3-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine stereoisomer B by the same procedures as for stereoisomer A. The racemic product was separated by Prep chiral SFC J to give diastereomeric compounds 36-E2 and 36-E3 as white solids. Compound 36-E2 (R-a.a., S-Me diastereomer) LC / MS ESI 494.3 (M+H)+1H NMR (400 MHz, MeOD) δ 7.29 – 7.20 (m, 1H), 7.13 (d, J=7.2Hz, 1H), 7.01 – 6.92 (m, 2H), 6.39 – 6.32 (m, 1H), 5.67 (s, 1H), 4.43 – 4.25 (m, 2H), 4.04 – 3.94 (m, 1H), 3.87 – 3.74 (m, 4H), 3.72 – 3.61 (m, 1H), 3.46 – 3.34 (m, 3H), 3.01 – 2.93 (m, 1H), 2.79 – 2.68 (m, 1H), 2.56 – 2.47 (m, 2H), 2.41 – 2.30 (m, 1H), 2.04 – 1.92 (m, 1H), 1.81 – 1.72 (m, 1H), 1.69 – 1.54 (m, 4H), 1.45 – 1.34 (m, 2H), 1.18 – 1.01 (m, 6H), 0.66 – 0.55 (m, 1H). Chiral SFC J (45% MeOH): ee 100%, Rt = 1.38 min. Compound 36-E3 (S-a.a., S-Me diastereomer) LC / MS ESI 494.3 (M+H)+1H NMR (400 MHz, MeOD) δ 7.26 – 7.19 (m, 1H), 7.12 (d, J=7.6Hz, 1H), 7.04 – 6.91 (m, 2H), 6.35 (d, J=7.6Hz, 1H), 5.53 (s, 1H), 4.38 – 4.20 (m, 2H), 3.98 – 3.81 (m, 4H), 3.79 – 3.53 (m, 2H), 3.44 – 3.35 (m, 3H), 3.01 – 2.91 (m, 1H), 2.77 – 2.69 (m, 1H), 2.55 – 2.47 (m, 2H), 2.41 – 2.29 (m, 1H), 2.05 – 1.92 (m, 1H), 1.82 – 1.72 (m, 1H), 1.69 – 1.54 (m, 4H), 1.44 – 1.34 (m, 2H), 1.18 – 1.02 (m, 6H), 0.65 – 0.56 (m, 1H). Chiral SFC J (45% MeOH): ee 100%, Rt = 1.88 min. Example 37: Preparation of 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 37-E1 and 37-E2) Step 1: 4-(3-bromo-5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran To a solution of tetrahydro-2H-pyran-4-ol (860 mg, 8.44 mmol) in anhydrous THF (20 mL) at 0 °C under Ar was added dropwise a 1 M solution of LiHMDS in THF (8.5 mL). The mixture was stirred at 0 °C for 1 hour; then 1-bromo-3,5-difluoro-2-nitrobenzene (2 g, 8.44 mmol) was added, and the reaction was sttirred at room temperature for 12 hours. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 4-(3-bromo-5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (1.8 g, 67% yield) as a yellow oil. (ESI 320 (M+H) +). Step 2: tert-butyl 2-(5-fluoro-2-nitro-3-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)acetate A mixture of 4-(3-bromo-5-fluoro-2-nitrophenoxy)tetrahydro-2H-pyran (5 g, 15.67 mmol), (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (1 M in THF, 79 mL, 79 mmol), Pd2(dba)3 (810 mg, 0.79 mmol), and Q-phos (560 mg, 0.79 mmol) in THF (15 mL) was stirred at 70 °C for 3 hours. The reaction mixture was poured into sat. aq. NaHCO3 solution (150 mL) and extracted with EtOAc (150 mL x3). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(5-fluoro-2-nitro- 3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate as a yellow oil (3.1 g). Yield 56 % (ESI 356 [M+H]+). Step 3: tert-butyl 2-(2-amino-5-fluoro-3-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)acetate A mixture of tert-butyl 2-(5-fluoro-2-nitro-3-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)acetate (500 mg, 1.41 mmol), Fe (789 mg, 14.1 mmol), and NH4Cl (750 mg, 14.1 mmol) in EtOH (15 mL) and H2O (5 mL) was stirred at 90 °C for 2 hours. The mixture was filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(2-amino-5-fluoro- 3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate as a yellow oil (310 mg). Yield 68% (ESI 326 [M+H]+). Step 4: tert-butyl 2-(2-bromo-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate To a solution of tert-Butyl nitrite (38 mg, 0.37 mmol) in MeCN (5 mL) was added CuBr- S(CH3)2 (64 mg, 0.31 mmol) and LiBr (27 mg, 0.31 mmol). The reaction was stirred at 60 °C for 10 min; then a solution of tert-butyl 2-(2-amino-5-fluoro-3-(tetrahydro-2H-pyran- 4-yloxy)phenyl)acetate (100 mg, 0.31 mmol) in MeCN (1 mL) was added. The reaction was warmed to 60 °C and stirred for 24 hours, then cooled to room temperature, quenched with aqueous 5% HBr solution (10 mL) and extracted with EtOAc (10 mL x3). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(2-bromo-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate as a colorless oil (20 mg). Yield 16% (ESI 411 (M+Na) +). Step 5: tert-butyl 2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate To a solution of tert-butyl 2-(2-bromo-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate (90 mg, 0.25 mmol) in dioxane / H2O (5 mL / 1 mL) under Ar was added cyclopropylboronic acid (43 mg, 0.5 mmol), Pd(OAc)2 (3 mg, 0.013 mmol), PCy3 (7 mg, 0.025 mmol) and K3PO4 (160 mg, 0.75 mmol). The reaction was stirred at 80 °C for 12 hours, then concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-(2-cyclopropyl-5-fluoro-3- (tetrahydro-2H-pyran-4-yloxy)phenyl)acetate as a yellow oil (51 mg). Yield 63% (ESI 373 (M+Na) +). Step 6: tert-butyl 2-bromo-2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate To a solution of tert-butyl 2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate (110 mg, 0.3 mmol) in THF (3 mL) at -78 °C was added dropwise lithium diisopropylamide solution (0.375 mL, 2.0 M in THF / hexanes, 0.75 mmol). The reaction was stirred at -78 °C for 30 min. Then a solution of chlorotrimethylsilane (85 mg, 0.75 mmol) in THF (1 mL) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (150 mg, 0.75 mmol) in THF (2 mL) was added, and the reaction was stirred at -78 °C for 1 hour. The reaction was quenched with MeOH (2 mL) and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5:1) to give the desired product tert-butyl 2-bromo-2-(2-cyclopropyl-5-fluoro-3- (tetrahydro-2H-pyran-4-yloxy)phenyl)acetate as a colorless oil (109 mg). Yield 81% (ESI 451 (M+Na) +). Step 7: tert-butyl 2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin- 1-yl)acetate A mixture of tert-butyl 2-bromo-2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate (130 mg, 0.3 mmol), 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4- tetrahydro-1,8-naphthyridine dihydrochloride (110 mg, 0.3 mmol), DIPEA (120 mg, 0.9 mmol) and NaI (50 mg) in acetonitrile (10 mL) was stirred at 40 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH 20:1) to give the desired product tert-butyl 2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetate as a colorless oil (101 mg). Yield 51% (ESI 624 (M+H) +). Step 8: 2-(3-methoxy-2-(1-methylcyclopropyl)phenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 37-E1 and 37-E2) To a solution of tert-butyl 2-(2-cyclopropyl-5-fluoro-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)-2-(3-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1- yl)acetate (101 mg, 0.2 mmol) in DCM (5 mL) was added TFA ( 2.5 mL). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (40 → 70% MeCN / H2O) to give compound 37 (61 mg, 66% yield). The racemic product was separated by Prep chiral SFC K to give enantiomeric compounds 37-E1 (19 mg) and 37-E2 (23 mg) as white solids. Compound 37-E1 (S-enantiomer) LC / MS ESI 568 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.15 (d, J = 7.2Hz, 1H), 6.80-6.78 (m, 2H), 6.37 (d, J = 7.2 Hz, 1H), 5.56 (s, 1H), 4.63- 4.62 (m, 1H), 4.33-4.31 (m, 2H), 4.02-3.98 (m, 3H), 3.81-3.31 (m, 8H), 2.72 -2.50 (m, 4H), 2.08-2.04 (m, 2H), 1.91-1.20 (m, 14H), 0.62-0.60 (m, 1H). Chiral SFC K (15% MeOH), ee 100%, Rt = 2.57 min. Compound 37-E2 (R-enantiomer) LC / MS ESI 568 (M+H) +.1H NMR (400 MHz, MeOD) δ 7.15 (d, J = 7.2Hz, 1H), 6.80-6.77 (m, 2H), 6.37 (d, J = 7.2 Hz, 1H), 5.54(s, 1H), 4.63- 4.62 (m, 1H), 4.33-4.31 (m, 2H), 4.02-3.98 (m, 3H), 3.81-3.31 (m, 8H), 2.72 -2.51 (m, 4H), 2.08-2.04 (m, 2H), 1.91-1.20 (m, 14H), 0.62-0.60 (m, 1H). Chiral SFC K (15% MeOH), ee 100%, Rt = 3.73 min. Example 38: Preparation of 2-(2-(1-methylcyclopropyl)phenyl)-2-(3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compound 38) Step 1: 1-bromo-2-(prop-1-en-2-yl)benzene To a solution of 1-(2-bromophenyl)ethanone (2.97 g, 15 mmol) in THF (30 mL) at 0 °C was added dropwise MeMgBr (10 mL, 3M in THF, 30 mmol). The mixture was warmed to room temperature and stirred for 16 hours, then quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (60 mL x3). The combined organic phase was concentrated in vacuo to give the crude product 2-(2-bromophenyl)propan-2-ol as a yellow solid (2.8 g). This material was dissolved in toluene (30 mL). TsOH (3.4 g, 19.6 mmol) was added, and the reaction mixture was warmed to 80 °C and stirred for 16 hours, then concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 20:1) to give the desired product1-bromo-2-(prop-1-en-2-yl)benzene as a yellow solid (2.1 g). Yield 82% (ESI:N / A). Step 2: 1-bromo-2-(1-methylcyclopropyl)benzene To a solution of diethyl zinc (60 mL, 1 M in hexane, 60 mmol) in DCM (100 mL) was added TFA (6.8 g, 60 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min; then CH2I2 (16 g, 60 mmol) was added. The mixture was stirred at 0 °C for 30 min., and 1-bromo-2-(prop-1-en-2-yl)benzene (1.96 g, 10 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hours, then quenched with sat. aq. NH4Cl solution (20 mL) and extracted with DCM (50 mL x3). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 1-bromo-2-(1- methylcyclopropyl)benzene as a yellow oil (2 g). Yield 95% (ESI:N / A). Step 3: tert-butyl 2-(2-(1-methylcyclopropyl)phenyl)acetate To a mixture of 1-bromo-2-(1-methylcyclopropyl)benzene (1.26 g, 6.0 mmol), Pd2(dba)3 (219 mg, 0.3 mmol), and Q-phos (274 mg, 0.3 mmol) in THF (20 mL) at room temperature under Ar was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (18 mL, 1 M in THF, 18.0 mmol). The reaction was warmed to 65 °C and stirred for 2 hours, then quenched with sat. aq. NaHCO3, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert-butyl 2-(1- methylisoquinolin-5-yl)acetate as a red oil (1.42 g). Yield 96% (ESI 190.0 (M-56) +). Step 4: tert-butyl 2-bromo-2-(2-(1-methylcyclopropyl)phenyl)acetate To a solution of tert-butyl 2-(2-(1-methylcyclopropyl)phenyl)acetate (200 mg, 0.8 mmol) in THF (2 mL) at -78 °C was added dropwise lithium diisopropylamide solution (1 mL, 2.0 M in THF / hexanes, 2 mmol). The reaction was stirred at -78 °C for 30 min; then chlorotrimethylsilane (217.5 mg, 2 mmol) was added, and the reaction was stirred at -78 °C for another 30 min. Then a solution of NBS (356 mg, 2 mmol) in THF (4 mL) was added, and the reaction was stirred at -78 °C for 30 min., then quenched with H2O (10 mL) and extracted with EtOAc (20mL x2). The combined organic extracts were washed with sat. aq. NaHCO3and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product tert- butyl 2-bromo-2-(2-(1-methylcyclopropyl)phenyl)acetate as a yellow oil (230 mg). Yield 88 % (ESI 325 (M+H) +). Step 5: tert-butyl 2-(2-(1-methylcyclopropyl)phenyl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate A mixture of 7-(5-(azetidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine dihydrochloride (108 mg, 0.31 mmol), tert-butyl 2-bromo-2-(2-(1- methylcyclopropyl)phenyl)acetate (100 mg, 0.31mmol), and DIPEA (120.2 mg, 0.93 mmol) in acetonitrile (10 mL) was stirred at 40 °C for 4 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product tert-butyl 2-(2-(1-methylcyclopropyl)phenyl)-2-(3-((5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate as a yellow oil (150 mg). Yield 93% (ESI 520 (M+H) +). Step 6: 2-(2-(1-methylcyclopropyl)phenyl)-2-(3-((5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetic acid (compound 38) To a solution of tert-butyl 2-(2-(1-methylcyclopropyl)phenyl)-2-(3-((5-(5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl)pentyl)oxy)azetidin-1-yl)acetate (150 mg, 0.29 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by Prep-HPLC A (30 → 65% MeCN) to give compound 38 (mixture of two stereoisomers) as a white solid (22 mg, 16.5% yield). Compound 38 (racemate) LC / MS ESI 464.3 (M+H) +. 1H NMR (400 MHz, MeOD) δ 7.49 (d, J=7.6Hz,1H), 7.39-7.24 (m, 3H), 7.14 (d, J=7.2Hz 1H), 6.36 (d, J=7.2Hz 1H), 5.45 (s, 1H), 4.45-4.29 (m, 2H), 4.04-3.98 (m, 1H), 3.95-3.88 (m, 1H), 3.63 (s, 1H), 3.48-3.37 (m, 4H), 2.73-2.68 (m, 2H), 2.55-2.49 (m, 2H), 1.92-1.85 (m, 2H), 1.70-1.32 (m, 10H) , 0.96-0.79 (m, 3H). Example 39: Preparation of 2-(2-(3-methyltetrahydrofuran-3-yl)phenyl)-2-(3-(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyloxy)azetidin-1-yl)acetic acid (compounds 39-E1, 39-E2 and 39-E3) Step 1: methyl 2-(2-bromophenyl)propanoate To a solution of LDA (2 M in toluene, 22 mL, 44 mmol) in THF (50 mL) at -78 °C was added dropwise a solution of methyl 2-(2-bromophenyl)acetate (10.0 g, 44 mmol) in THF (20 mL). The reaction mixture stirred at -78 °C for 1 hour; then a solution of iodomethane (6.23 g, 44 mmol) in THF (10 mL) was added dropwise at -78 °C. The reaction mixture was stirred at room temperature for 12 hours, then quenched with sat. ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 20:1) to give the desired product methyl 2-(2-bromophenyl)propanoate (5.1 g) as a pale yellow oil. Yield 48% (ESI 243 (M+H) +). Step 2: 4-tert-butyl 1-methyl 2-(2-bromophenyl)-2-methylsuccinate To a solution of LDA (2 M in toluene, 13mL, 26 mmol) in THF (50 mL) at -78 °C was added dropwise a solution of methyl 2-(2-bromophenyl)propanoate (4.2 g, 17.4 mmol) in THF (20 mL). The reaction mixture was stirred at -78 °C for 1 hour; then a solution ...

Claims

CLAIMS 1. A compound of formula (I): A-B-C (I) wherein:Z is CH2; a is 0; b is 0; B is –(CH2)5-O*-; * denotes the point of attachment of B to C; C isn is 0; Rais H; R2is substituted or unsubstituted bicyclic heterocyclyl, bicyclic aryl, bicyclic heteroaryl, C6aryl, or 6-member heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound that is2. The compound of claim 1, wherein R2is a 9-10 member bicyclic heteroaryl.

3. The compound of claim 2, wherein R2is selected from:wherein: W is CR7or N; R7is H, halide, or alkyl each R15is independently alkyl or halide; each R16is independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl; when substituted, alkyl is substituted with one or more halide; or R16is halide; R17a, and R17c are each independently substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl; x is 0, 1, or 2; and y is 0 or 1.

4. The compound of claim 3, wherein W is CH.

5. The compound of claim 4, wherein R2is:wherein W is CR7or N R7is H or halide; R15a is H; R15c is H or alkyl; R16c is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, when substituted, alkyl is substituted with one or more halide; or R16cis H or halide; andR17a is substituted or unsubstituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocycloalkyl, when substituted, alkyl is substituted with one or more halide, and alkoxyalkyl is substituted with alkyl.

6. The compound of claim 5, wherein W is CH.

7. The compound of claim 6, wherein R16cis lower alkyl.

8. The compound of claim 7, wherein R15cis H.

9. The compound of claim 8, wherein R17ais substituted or unsubstituted (C1-C4)alkyl, methoxy(C1-C4)alkyl, (C3-C6)cycloalkyl, 5-6-member heterocyclyl comprising an oxygen heteroatom, or 5-6-member heterocycloalkyl comprising an oxygen heteroatom.

10. The compound of claim 9, wherein R17ais (C1-C4)alkyl.

11. The compound of any of claims 1-10, wherein C in Formula (I) is12. The compound of claim 1, wherein R2is selected fromeach of c and d is independently 0, 1 or 2, provided that c+d is 1 or 2; z is 0, 1, 2, or 3; R24is H or alkyl; each R25is independently alkyl or halide; each R26a and R26aˈ is independently alkyl, H, or halide; and each R26d and R26dˈ is independently H, alkyl, or halide.

13. A compound having the formula, wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

14. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

15. A compound having the formula ,wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

16. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

17. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

18. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

19. A compound of formula (I): A-B-C (I) wherein: A is; Z is -CH2-; a is 0; b is 0; B is –(CH2)4O-; C isn is 0; Rais H;R2is substituted or unsubstituted bicyclic heterocyclyl, bicyclic aryl, bicyclic heteroaryl, C6aryl, 6-member heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof provided that the compound is not a compound that is20. A compound having the formula, wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

21. A compound having the formula, wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

22. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

23. A compound having the formula, wherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

24. A compound having the formulawherein the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

25. The compound according to any of claims 1-24, wherein the absolute configuration at any stereocenter is a mixture of R and S; or a pharmaceutically acceptable salt thereof.

26. The compound according to any of claims 1-24, wherein the absolute configuration at any stereocenter is S; or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition, comprising a compound of any one of the preceding claims; and a pharmaceutically acceptable excipient or carrier.

28. A method of treating of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of any preceding claim, thereby treating or preventing the disease.

29. The method of claim 28, wherein the disease is idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease,nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, pulmonary arterial hypertension, or cardiac fibrosis.

30. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof or pharmaceutical composition of any preceding claim.

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