Inhibiting alpha-v beta-8 integrin

Abstract

Disclosed are small molecule inhibitors of αvβ8 integrin, and methods of using them to treat a number of diseases and conditions.

Description

[0001] MTX-03225

[0002] Inhibiting Alpha-V Beta-8 Integrin

[0003] RELATED APPLICATION

[0004] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 681,312, filed August 9, 2024.

[0005] TECHNICAL FIELD

[0006] This disclosure relates to novel chemical compounds and methods useful for inhibiting ocv8 integrin.

[0007] BACKGROUND

[0008] In the tumor microenvironment av08 is expressed on immune cells, mainly antigen presenting cells (APCs) and regulatory T cells (Tregs) as well as on the tumor cells and cancer associated fibroblast. The major function of ocv08 is activation of growth factor TGF-01 and 3. The TGF-0S are biosynthesized and stored in tissues as latent forms. The TGF-0 homodimer is kept latent by association with its dimeric prodomain (pro-TGFb). The prodomain-derived homodimer prevents TGFb from binding TGFb receptor and is called latency-associated peptide (LAP). The latent TGFb complex is stored in the extracellular matrix or on the cell surface for subsequent, integrin-dependent activation. The integrin ocv08 heterodimer binds arginine-glycine-aspartic acid motifs (RGD domain) of the latent-TGFb-1 and 3 to liberate the active TGFb cytokine from latent complex.

[0009] TGFb is a pleiotropic cytokine mediating multiple biological processes, including development and homeostasis. TGFb is a key player in cell growth, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production contributing to tissue repair processes. In the immune system TGF-0 is necessary for the development of distinct immune cell types, as well to promote immunosuppression. Homeostatic role of TGFb on immunity is critical to prevent excessive inflammatory responses and essential for maintaining tolerance to self-antigens to prevent autoimmunity. As TGFb is ubiquitously expressed it activity needs to be tightly regulated and when exacerbated lead to disease states. Dysregulation of TGFb signaling is involved in multiple disorders, especially cancer and fibrosis.

[0010] In cancer, the TGF-0 pathway has been implicated in many human neoplastic diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-0 acts 1

[0011] Foley HoagUS13043895.1 MTX-03225 as a tumor suppressor; however, in tumor cells, TGF-0 loses its anti-proliferative response and promotes cancer progression. The TGFb-promoted tumorigenesis is mainly driven by downregulation of anti-tumor immunity. The immunosuppressive effect leads to tumor immune tolerance. Additionally, TGFb facilitates epithelial to mesenchymal transition (EMT) and angiogenesis to increase tumor invasiveness. The integrin ocv8 expression in cancers correlates with TGFb activity. It modulates inflammatory phenotype of the APCs and Tregs, the main cell types fundamental for T / NK cell driven anti-tumor activity. The av08 integrin locally activates TGFb to regulate cross-talk between APCs and effector cells to skew immunity from inflammation to tolerance.

[0012] Inhibition of the integrin av08-driven TGFb activation is proposed to reverse tumor tolerance and enhance anti-tumor T / NK cell responses. In agreement with TGFb blockage, av08 inhibition can enhance outcomes in checkpoint inhibitors regimens or reverse checkpoint inhibitor resistance.Ubiquitous expression and multifunctionality of TGFb limits application of strategies based on TGFb systemic blockage, as those approaches result is unwanted side effects. Blockage of TGFb activity by antagonizing the integrin ocv08 increases the safety and has therapeutic advantage over global TGFb inhibition. It allows for tissue localized and isoform selective TGFb blockage in specific immunological milieu. Therefore, there remains a need for therapeutic compounds for inhibiting ocv08 integrin.

[0013] SUMMARY

[0014] In certain embodiments, the invention discloses a compound of Formula I:

[0015] A-B-C (I) wherein:

[0016] Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-

[0017] OH, NO2, -N(H)R, or NH2;

[0018] 2

[0019] Foley HoagUS13043895.1 MTX-03225 each Ra3 is independently H, alkyl, -alkylene-OH, -alkylene-alkoxy, heterocyclyl, or heterocycloalkyl; each Ri and Ri’ is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; a is 0, 1 or 2; b is 0, 1, 2, 3 or 4; each b’ is independently 0, 1, 2 or 3;

[0020] B is -alkylene-O-*, where * represents the point of attachment to C;

[0021] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0022] Ra is H; each R3 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; n is 0, 1, 2, 3, 4, 5 or 6;

[0023] R2is a monocyclic aryl or 5- to 6-membered monocyclic heteroaryl optionally substituted with R4 and optionally substituted with one or more R5, wherein when R2is not substituted with R4, R2is substituted with at least one R5;

[0024] R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-heterocycloalkyl,-O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl , -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and -alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each R4bis halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, - 3

[0025] Foley HoagUS13043895.1 MTX-03225 alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy;

[0026] Ra is H, (Ci-C6)alkyl, -(Ci-C6)alkylene-O-(Ci-C6)alkyl, or -(Ci-C6)alkylene-O- C(O)O(Ci-C6)alkyl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0027] 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.

[0028] DETAILED DESCRIPTION

[0029] In certain aspects, the present disclosure relates to compounds that inhibit ocvP8 integrin. The compounds are useful for the treatment of fibrosis and conditions related to the inhibition of ocvP8 integrin.

[0030] DEFINITIONS

[0031] 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.

[0032] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0033] The articles “a” and “an” are used herein to refer to one or 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.

[0034] 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

[0035] 4

[0036] Foley HoagUS13043895.1 MTX-03225 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.

[0037] 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.

[0038] 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 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.

[0039] 5

[0040] Foley HoagUS13043895.1 MTX-03225

[0041] 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.

[0042] 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.

[0043] 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 cisand trans-isomers, R- and 5-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.

[0044] 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.

[0045] 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.

[0046] 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

[0047] 6

[0048] Foley HoagUS13043895.1 MTX-03225 reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0049] 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.

[0050] 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.)

[0051] 7

[0052] Foley HoagUS13043895.1 MTX-03225

[0053] 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).

[0054] 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.

[0055] 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).

[0056] 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.

[0057] 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 8

[0058] Foley HoagUS13043895.1 MTX-03225

[0059] “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.

[0060] “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-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted.

[0061] 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, which 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.

[0062] "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.

[0063] 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.

[0064] “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 9

[0065] Foley HoagUS13043895.1 MTX-03225 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).

[0066] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0067] 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 “alkoxy!” or “alkoxy” as used herein refers to an alkyl group, as defined below, having an oxygen moiety attached thereto. Representative alkoxy 1 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, -0-(CH2)m-Rio, where m and Rio are described below.

[0068] 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 Rn, R12 and R13 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m- R10, or Rn and R12 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rio represents 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 Rn or R12 can be a carbonyl, e.g., Rn, R12, and the nitrogen together do not form an imide. In even more certain embodiments, Rn and R12 (and optionally R13) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-

[0069] 10

[0070] Foley HoagUS13043895.1 MTX-03225

[0071] Rio. 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 Rn and R12 is 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.

[0072] The term “amide”, as used herein, refers to a group wherein each R14 independently represent a hydrogen or hydrocarbyl group, or two R14 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0073] 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,

[0074] 11

[0075] Foley HoagUS13043895.1 MTX-03225 cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, 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-C12 aryl and in certain embodiments, the aryl group can be a substituted C5-C10 aryl.

[0076] 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.

[0077] 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.

[0078] The term “heterocycloalkyl” refers to a non-aromatic monocyclic heterocyclyl.

[0079] The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:

[0080] Foley HoagUS13043895.1 MTX-03225 wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-Rio or a pharmaceutically acceptable salt, Ri6 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rio, where m and Rio are as defined above. Where X’ is an oxygen and R15 or Rig is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and Rie is 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 R15 or Rig is not hydrogen, the formula represents a “thioester” group. Where X’ is a sulfur and R15 is a hydrogen, the formula represents a “thiocarboxylic acid” group. Where X’ is a sulfur and Ri6 is a hydrogen, the formula represents a “thioformate” group. On the other hand, where X’ is a bond, and R15 is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15 is a hydrogen, the above formula represents an “aldehyde” group.

[0081] 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.

[0082] 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”

[0083] 13

[0084] Foley HoagUS13043895.1 MTX-03225 means -NCO; the term “thiocyanate” means -SCN; the term “isothiocyanate” means -NCS; and the term “cyanato” means -OCN.

[0085] The term “sulfamoyl” is art-recognized and includes a moiety that can be represented by the formula: in which Rn and R12 are as defined above.

[0086] The term “sulfate” is art recognized and includes a moiety that can be represented by the formula: in which R15 is as defined above.

[0087] The term “sulfonamide” is art recognized and includes a moiety that can be represented by the formula: in which Rn and Ri6 are as defined above.

[0088] The term “sulfonate” is art-recognized and includes a moiety that can be represented by the formula: o ij— s-ox

[0089] OR15 in which R54 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0090] The terms “sulfoxido” or “sulfinyl”, as used herein, refers to a moiety that can be represented by the formula: in which R17 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0091] The term “urea” is art-recognized and may be represented by the general formula

[0092] Foley HoagUS13043895.1 MTX-03225 wherein each Ris independently represents hydrogen or a hydrocarbyl, such as alkyl, or any occurrence of Ris taken together with another and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0093] 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.

[0094] 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 sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from Ci-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are 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

[0095] 15

[0096] Foley HoagUS13043895.1 MTX-03225 moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0097] 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.

[0098] EXEMPLARY COMPOUNDS

[0099] One embodiment is a compound of formula (I):

[0100] A-B-C (I) wherein:

[0101] Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; each Ra3 is independently H, alkyl, -alkylene-OH, -alkylene-alkoxy, heterocyclyl, or heterocycloalkyl; each Ri and Ri’ is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; a is 0, 1 or 2; b is 0, 1, 2, 3 or 4; each b’ is independently 0, 1, 2 or 3;

[0102] B is -alkylene-O-*, where * represents the point of attachment to C; wherein n is 0;

[0103] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0104] 16

[0105] Foley HoagUS13043895.1 MTX-03225

[0106] Ra is H;

[0107] R2 is a monocyclic aryl or 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more R4 and optionally substituted with one or more R5, wherein when R2 is not substituted with R4, R2 is substituted with at least one R5; each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O- heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each Rib, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, wherein

[0109] Rbi and Rb2 are each H; p is 0, 1, 2 or 3; and

[0110] L is -O-.

[0111] In further embodiments, B isqwherein q is 1, 2 or 3.

[0112] In an aspect of these embodiments, q is 2 or 3.

[0113] In further embodiments,

[0114] 17

[0115] Foley HoagUS13043895.1 MTX-03225

[0116] In further embodiments,

[0117] In an aspect of the embodiments and aspects disclosed herein, R4, independently, is cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib.

[0118] In an aspect of the embodiments and aspects disclosed herein, each Rib, independently, is halide or lower alkyl.

[0119] In an aspect of the embodiments and aspects disclosed herein, R4 is (C3 -Cecycloalkyl, (C3- Ce)heterocycloalkyl, -O-(C3-Ce)heterocycloalkyl, monocyclic aryl, -(Ci-C3)alkylene-(Cs- Ce)heteroaryl-(C3-Ce)cycloalkyl, a 10 to 11 membered spirocyclic cycloalkyl, a 10 to 11 membered spirocyclic heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib.

[0120] In an aspect of the embodiments and aspects disclosed herein, R2 is substituted with one R4 group.

[0121] In an aspect of the embodiments and aspects disclosed herein, R2 is substituted with one or two R5 groups.

[0122] In an aspect of the embodiments and aspects disclosed herein, the cycloalkyl in R4 (e.g., in alkylene-heteroaryl-cycloalkyl) and Rib is Cecycloalkyl and the heterocycloalkyl in R4 (e.g., in - O-heterocycloalkyl) and Rib is a 6-membered heterocycloalkyl comprising at least one oxygen heteroatom.

[0123] In an aspect of the embodiments and aspects disclosed herein, R5 is halide, alkyl, or cycloalkyl.

[0124] In an aspect of the embodiments and aspects disclosed herein, R4 is selected from

[0125] Foley HoagUS13043895.1 MTX-03225

[0126] In an aspect of the embodiments and aspects disclosed herein, R4 is selected from

[0127] In an aspect of the embodiments and aspects disclosed herein, R4 is selected from

[0128] 19

[0129] Foley HoagUS13043895.1 MTX-03225

[0130] In an aspect of the embodiments and aspects disclosed herein, R2 is selected from:

[0131] In an aspect of the embodiments and aspects disclosed herein, wherein R2 is selected from:

[0132] In an aspect of the embodiments and aspects disclosed herein, R2 is wherein m is 1 or 2.

[0133] In an aspect of the embodiments and aspects disclosed herein, R4 is

[0134] Another embodiment is a compound of formula (I):

[0135] A-B-C (I) wherein:

[0136] 20

[0137] Foley HoagUS13043895.1 MTX-03225

[0138] B is selected from the group consisting of:

[0139] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0140] R2 is is selected from: each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O- heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib;

[0141] 21

[0142] Foley HoagUS13043895.1 MTX-03225 each R4b, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; each Rs is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0143] In an aspect of the embodiments and aspects disclosed herein, Rc is methyl.

[0144] In an aspect of the embodiments and aspects disclosed herein, each R5, independently, is F, Cl, CF3, -OMe, or -OEt.

[0145] Another embodiment is a compound selected from any one of Tables 1A, IB, 2A, 2B, 3A, 3B, 4A, 4B, 5 or 6, or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the invention relates to a compound of Formula I:

[0147] A-B-C (I) wherein:

[0148] Z is CRalRa2; each Rai and Ra2 is independently H; a = 0; b = 0; b’ = 0;

[0149] Foley HoagUS13043895.1 MTX-03225

[0150] Rbi and Rb2 are each H;

[0151] L is -0-; n is 0;

[0152] Rc is lower alkyl (e.g., methyl);

[0153] R2 is a monocyclic aryl or 5- to 6-membered monocyclic heteroaryl optionally substituted with R4 and optionally substituted with one or more R5, wherein when R2 is not substituted with R4, R2 is substituted with at least one R5;

[0154] R4 is independently selected from lower alkyl optionally substituted with one or more halide, cycloalkyl, -O-heterocycloalkyl, aryl , -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, heterocycloalkyl optionally substituted with one or more Rib, -O-(lower alkyl), or alkylene-heterocycloalkyl optionally substituted with one or more Rib, -O-(lower alkyl);

[0155] Rib is halide, cycloalkyl optionally substituted with halide, (Ci-Ce)alkyl, or heterocycloalkyl optionally substituted with halide or lower alkyl;

[0156] Rs is halide (e.g., F, Cl), alkoxy (e.g., OCH3), or (Ci-Ce)alkyl optionally substituted with one or more halide (e.g., CF3);

[0157] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, A in the compounds of formula (I) comprises substitution of each Rl, Rl ', Rai and Ra2 independently as H or alkoxy (e.g., methoxy). In some embodiments, A in the compounds of formula (I) comprises substitution of each Rl, Rl ', Rai and Ra2 are each H. In some embodiments, A in the compounds of formula (I), Z is CRaiRa2, and each of Ri, Ri', Rai and Ra2 is independently H.

[0159] In some embodiments, B in the compounds of formula (I) (e.g., in combination with Z being CRaiRa2, and each of Ri,Ri', Rai and Ra2 is independently H) is a linear, unbranched alkylene-O- having 3 to 5 carbon atoms (e.g., -(CH2)3-O-, -(CH2)4-O- or -(CH2)s-O-).

[0160] 23

[0161] Foley HoagUS13043895.1 MTX-03225

[0162] In some embodiments, C in the compounds of formula (I) is unsubstituted (n is 0) (e.g., in combination with Z being CRaiRa2, and each of Ri, R / , Rai and B being a linear, unbranched alkylene-O- having 3 to 5 carbon atoms) comprises R2 that is substituted or unsubstituted 5-6 member aryl or heteroaryl.

[0163] In some embodiments, R2 in any formula for C above can be a substituted or unsubstituted 6-membered aryl or heteroaryl selected from: osed above, and m is 0, 1, 2, or 3.

[0164] In some embodiments, R2 in any formula for C above can be a substituted or unsubstituted 5-membered aryl or heteroaryl selected from: , wherein R4, Rs are as disclosed above, and m is 0, 1, 2, or 3.

[0165] In certain embodiments, the invention relates to a compound of Formula I:

[0166] A-B-C (I) wherein:

[0167] Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-

[0168] OH, NO2, -N(H)R, or NH2;

[0169] 24

[0170] Foley HoagUS13043895.1 MTX-03225 each Ra3 is independently H, alkyl, -alkylene-OH, -alkylene-alkoxy, heterocyclyl, or heterocycloalkyl; each R / and Ri is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene- OH, NO2, -N(H)R, or NH2; a is 0, 1 or 2; b is 0, 1, 2, 3 or 4; each b’ is independently 0, 1, 2 or 3; wherein p is 0, 1, 2 or 3;

[0171] L is -O-;

[0172] Rbi and Rb2 are each H; each R3 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; n is 0, 1, 2, 3, 4, 5 or 6;

[0173] R2 is selected from the group consisting of:

[0174] R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, - alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl or heterocycloalkyl in R4 is optionally substituted with one or more Rib;

[0175] 25

[0176] Foley HoagUS13043895.1 MTX-03225 each R4b is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide); each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, - alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; m is 0, 1, 2, 3, or 4 in R2, as permitted by the applicable valence requirements of R2;

[0177] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0178] In certain embodiments, the invention relates to a compound of Formula I:

[0179] A-B-C (I) wherein:

[0180] Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene- OH, NO2, -N(H)R, or NH2; each Ri ' is independently H, halide or alkyl; each Ri is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, - N(H)R, or NH2; a is 0, 1 or 2; b is 0, 1, 2, 3 or 4; each b’ is independently 0, 1, 2 or 3;

[0181] 26

[0182] Foley HoagUS13043895.1 MTX-03225 n is 0;

[0183] R2 is selected from:

[0184] R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, - alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl;

[0185] Rs is F;

[0186] Ra is H; m is 0 or 1 ; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0187] In certain embodiments, the invention relates to a compound of Formula I:

[0188] A-B-C (I) wherein:

[0189] 27

[0190] Foley HoagUS13043895.1 MTX-03225

[0191] Z is NRas; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene- OH, NO2, -N(H)R, or NH2;

[0192] R is H, alkyl, or aryl; each Ra3 is independently H, alkyl, or alkylene-OH; each Ri ' and Ri is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; a is 0, 1, or 2; b is 0, 1, 2, 3 or 4 (permitting optional single or double substitution on each ring carbon outside of Z); each b’ is independently 0, 1, 2 or 3;

[0193] B is -alkylene-O-*, where * represents the point of attachment to C; each R3 is independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; n is independently 0, 1, 2, 3, 4, 5 or 6 (permitting optional single or double substitution on cyclobutyl with R3 in C);

[0194] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0195] R2 is selected from:

[0196] Foley HoagUS13043895.1 MTX-03225

[0197] R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-alkyl, - alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; each Rj is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene- cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene- aryl-cycloalkyl, -alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; m is 0, 1, 2, 3 or 4 as permitted by the applicable valance state;

[0198] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, the invention relates to a compound of Formula I:

[0200] A-B-C (I) wherein:

[0201] Ri is H, or alkoxy;

[0202] B is a-alkylene-O-*, where * represents the point of attachment to C;

[0203] Foley HoagUS13043895.1 MTX-03225 each R3 is independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; n is independently 0, 1, 2, 3, 4, 5 or 6 (permitting optional single or double substitution on cyclobutyl with R3 in C);

[0204] Rc is H or alkyl;

[0205] R2 is selected from: each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; n is independently 0, 1, 2, 3, 4, 5 or 6 (permitting optional single or double substitution on cyclobutyl with R3 in C);

[0206] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0207] In certain embodiments, the invention relates to a compound of Formula I:

[0208] A-B-C (I) wherein:

[0209] 30

[0210] Foley HoagUS13043895.1 MTX-03225

[0211] Ri is H;

[0212] B is -alkylene-O-*, where * represents the point of attachment to C; each R3 is independently selected from H, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; n is independently 0, 1, 2, 3, 4, 5 or 6 (permitting optional single or double substitution on cyclobutyl with R3 in C);

[0213] Rc is H or lower alkyl;

[0214] R2 is selected from: each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy;

[0215] 31

[0216] Foley HoagUS13043895.1 MTX-03225 n is independently 0, 1, 2, 3, 4, 5 or 6 (permitting optional single or double substitution on cyclobutyl with R3 in C);

[0217] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0218] In certain embodiments, the invention relates to a compound of Formula I:

[0219] A-B-C (I) wherein:

[0220] Ri is H;

[0221] B is -alkylene-O-*, where * denotes the point of attachment of B to C; n is 0;

[0222] Rc is H or lower alkyl (e.g., methyl);

[0223] R2 is selected from:

[0224] Foley HoagUS13043895.1 MTX-03225 each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; m is 0, 1, 2, or 3;

[0225] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0226] In certain embodiments, the invention relates to a compound of Formula I:

[0227] A-B-C (I) wherein:

[0228] Ri is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; n is 0;

[0229] Rc is lower alkyl;

[0230] 33

[0231] Foley HoagUS13043895.1 MTX-03225

[0232] R2 is selected from: each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; each Rj is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; m is 0, 1, 2, or 3; and

[0233] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0234] In certain embodiments, the invention relates to a compound of Formula I:

[0235] A-B-C (I)

[0236] 34

[0237] Foley HoagUS13043895.1 MTX-03225 wherein:

[0238] Ri is H;

[0239] B is -alkylene-(O)*-, where * denotes the point of attachment of B to C; and n is 0;

[0240] Rc is lower alkyl;

[0241] R2 is substituted or unsubstituted Ce aryl or 5- to 6-membered heteroaryl;

[0242] Ra is H; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0243] In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (Ila)

[0244] Foley HoagUS13043895.1 MTX-03225

[0245] (Ila), wherein

[0246] Z is CRaiRa2or NRa3; each of Rai, Ra2 and Ra3 is H; p is 0, 1, 2 or 3;

[0247] -L- is -O-;

[0248] R3 is H, lower alkyl or halide; each Rbi and Rb2is H;

[0249] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0250] R2 is substituted or unsubstituted aryl or heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0251] In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (IIa-1) or Formula (IIa-2)

[0252] (IIa-2), wherein

[0253] Z is CRalRa2 or NRa3; each of Rai, R 2 and Ra3 is H; p is 0, 1, 2 or 3;

[0254] R2 is substituted or unsubstituted aryl or heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof;

[0255] 36

[0256] Foley HoagUS13043895.1 MTX-03225 or a pharmaceutically acceptable salt thereof.

[0257] In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; and Rc is methyl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; and Z is -CH2-. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6- membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; Z is -CH2-; and Rc is methyl.

[0258] In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; Rc is methyl, and Z is -O-.

[0259] In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIa-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. Rc is methyl, and Z is -NH-.

[0260] In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (Ila)

[0261] (lib), wherein

[0262] Z is CRaiRa2 or NRa3; each of Rai, R 2 and Ra3 is H; p is 0, 1, 2 or 3;

[0263] -L- is -O-;

[0264] Foley HoagUS13043895.1 MTX-03225

[0265] Rs is H, lower alkyl or halide; each Rbi and Rb2 is H;

[0266] Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;

[0267] R2 is substituted or unsubstituted aryl or heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0268] In certain embodiments, the invention relates to compounds of Formula (I) that are described by Formula (lib- 1 ) or Formula (IIb-2) wherein

[0269] Z is CRalRa2 or NRa3; each of Rai, R 2 and Ra3 is H; p is 0, 1, 2 or 3;

[0270] R2 is substituted or unsubstituted aryl or heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0271] In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (lib- 1 ) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; and Rc is methyl. In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted

[0272] 38

[0273] Foley HoagUS13043895.1 MTX-03225

[0274] 9- or 10-membered bicyclic heteroaryl. In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; and Z is -CH2-. In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6- membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIa-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; Z is -CH2-; and Rc is methyl.

[0275] In certain embodiments, R2 in Formula (IIa-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; Rc is methyl, and Z is -O-.

[0276] In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl. In certain embodiments, R2 in Formula (IIb-1) or Formula (IIb-2) is substituted or unsubstituted 6-membered aryl or heteroaryl; Rc is methyl, and Z is -NH-.

[0277] In certain embodiments, the invention relates to any compounds of Formula (I), Formula

[0278] (Ila) or Formula (lib), wherein each Z, a, b, Ri and Ri ' is defined above. In certain embodiments, the invention relates to any compounds of Formula (I), Formula

[0279] (Ila) or Formula (lib), wherein each Z, a, b, Ri and Ri ' is defined above. In certain embodiments, the invention relates to any compounds of Formula (I), Formula

[0280] (Ila) or Formula (lib), wherein each Ri is defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein A is each Ri is defined above. In certain embodiments, the invention relates

[0281] 39

[0282] Foley HoagUS13043895.1 MTX-03225 to any one of the aforementioned compounds, wherein each Z, a, b, Ri and Rf is defined above. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein defined above. In some embodiments, provided that A is not halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R", or NH2; R” is H, alkyl, or aryl.

[0283] In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein B is -alkylene-(O). In some embodiments, wherein -alkylene-(O)- is - (CH2)3-O-. In some embodiments, wherein -alkylene-(O)- is -(CH2)4-O-. In some embodiments, wherein -alkylene-(O)- is -(CH2)s-O-.

[0284] In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein B is selected from the group consisting of: , . some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some

[0285] 40

[0286] Foley HoagUS13043895.1 MTX-03225 embodiments, wherein p is 0, 1, 2 or 3; L is -O-; and Rbi and Rb2 are each H. In some embodiments, wherein p is 1 ; L is -O-; and

[0287] Rbi and Rb2 are each independently H. In some embodiments, wherein p is 2; L is -O-; and Rbi and Rb2 are each independently H. In some embodiments, B is , wherein p is 3; L is -O-; and Rbi and Rb2 are each H.

[0288] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R in B is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R in B is alkyl. In some embodiments, alkyl in R is methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R is aryl.

[0289] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein Ri is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is alkyl. In certain embodiments, Ri is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is alkoxy. In some embodiments, alkoxy is methoxy, ethoxy, iso-propyloxy, iso-butyloxy, or tert-butyloxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is alkylene-OH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is NO2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein Ri is -N(H)Ra. In certain embodiments, the invention

[0290] Foley HoagUS13043895.1 MTX-03225 relates to any one of the aforementioned compounds, wherein Ri is NH2. In some embodimemts, at least one instance of Ri is alkyl, halide, OMe, OH, alkylene-OH, or NH2. In some embodimemts, at least one instance of Ri is OMe. In some embodimemts, all instances of Ri are H.

[0291] In certain embodiments, C in Formula (I) is selected from: wherein R2 is substituted or unsubstituted 6- member aryl or heteroaryl.

[0292] In certain embodiments, C in Formula (I) is selected from: or unsubstituted 6- member aryl or heteroaryl.

[0293] In certain embodiments, C in Formula (I) is selected from: wherein R2 is substituted or unsubstituted 6- member aryl or heteroaryl.

[0294] In certain embodiments, the invention relates to any compounds of Formula (I), Formula

[0295] (Ila) or Formula (lib), wherein R2 is <R5)n . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2 is <Rs^ . In certain embodiments,

[0296] Foley HoagUS13043895.1 MTX-03225 the invention relates to any one of the aforementioned compounds, wherein R2 is In certain embodiments, the invention relates to any one of the aforementioned comp ounds, wherein R2 is (R5)m. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R2 is In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein

[0297] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R2 is 6- member aryl or heteroaryl substituted with R4 and one or more R5 selected from R5a, R5b, R5cand Rsa, wherein R4 is defined above, and each of R5a, R5b, Rso and Rsa, is independently selected from H, CN, halide, alkyl, cycloalkyl, alkoxy, - aryl, heterocyclyl, hydroxyl, and alkoxy, wherein the alkyl in each of R5a, R5b, R5cand Rsa, is optionally substituted with halide (e.g., CF3, C(H)F2, C(F)H2), alkoxy, aryl, cycloalkyl or heterocyclyl.

[0298] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R2 is

[0299] 43

[0300] Foley HoagUS13043895.1 MTX-03225

[0301] Ri is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-heterocycloalkyl,-O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl , -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and -alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each Rib is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; and each Rsa, R5b, R5cand Rsa, is independently selected from H, CN, halide, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy, wherein the alkyl in each of Rs a, R5b, R5cand Rsa, is optionally substituted with halide (e.g., CF3, C(H)F2, C(F)H2), alkoxy, aryl, cycloalkyl or heterocyclyl.

[0302] In certain embodiments, R5ais H. In certain embodiments, R5bis H, halide, CN, cycloalkyl, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2). In certain embodiments, R5cis H, or alkyl, wherein the alkyl in R5cis optionally substituted with halide (e.g., CF3, C(H)F2, C(F)H2), aryl, or heterocyclyl. In certain embodiments, R5ais H, halide, alkoxy, alkoxy-alkyl, heterocycyl or -O-heterocycyl. In certain embodiments, Rsa is H and R5bis H, halide or alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2). In certain embodiments, R5ais H and R5bis H, halide, CN, cycloalkyl (e.g., cyclopropyl) or

[0303] 44

[0304] Foley HoagUS13043895.1 MTX-03225 lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2), and R5cis H, or alkyl, wherein the alkyl in R5cis optionally substituted with halide (e.g., CF3, C(H)F2, C(F)H2), aryl, or heterocyclyl. In certain embodiments, R5aand R5care each H.

[0305] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R2 is , and R4 is cycloalkyl, -O-cycloalkyl, or heterocycloalkyl optionally substituted with one or more R4b; each Rib is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; R5ais H; R5bis H, CN, halide, cycloalkyl or lower alkyl optionally substituted with one or more halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with cycloalkyl, heterocyclyl, or halide, wherein the heterocyclyl in R5cis optionally further substituted with lower alkyl or cycloalkyl; and R5d is H, halide, alkoxy, -O-alkyl, heterocyclyl or -O-heterocyclyl.

[0306] In certain embodiments, R2 is cyclopropyl), 5-6 member heterocycloalkyl comprising at least one O heteroatom and optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl or spirocyclobutyl) optionally substituted with halide, hetoerocycloalkyl or lower alkyl optionally substituted with one or more halide; R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl), or 5-6 member heteroaryl, the 5-6 membered heteroaryl in R5cbeing optionally substituted with halide, lower alkyl or cycloalkyl (e.g., cyclopropyl); and R5ais H, halide,

[0307] Foley HoagUS13043895.1 MTX-03225 alkoxy, -O-alkyl, 5-6 member heterocycloalkyl comprising at least one O heteroatom or -O- heterocycloalkyl.. In certain embodiments, R4 is -O-lower alkyl, cyclopropyl, or a 5- or 6- member hetoerocyclolkyl ring containing one oxygen atom, wherein the heterocycloalkyl ring is optionally substituted with halide, lower alkyl, or spirocyclic cycloaklyl or spirocyclic heterocycloalkyl each optionally substituted with halide or alkyl; R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl), or 5-6 member heteroaryl, the 5-6 membered heteroaryl in R5cbeing optionally substituted with halide, lower alkyl or cycloalkyl (e.g., cyclopropyl); and R5d is H, halide, alkoxy, -O-alkyl, 5-6 member heterocycloalkyl comprising at least one O heteroatom or -O-heterocycloalkyl..

[0308] In certain embodiments, R2 is , and R4 is cycloalkyl (e.g., cyclopropyl), optionally substituted with one or more R4b as described above; R5bis H, halide (e.g., F) or lower alkyl (e.g., methyl); and R5band R5d are both H. In some embodiments, R2 is , and R4 is substituted or unsubstituted cycloalkyl (e.g., cyclopropyl); and R5bis halide (e.g., F).

[0309] In certain embodiments, R2 is

[0310] Foley HoagUS13043895.1 MTX-03225 wherein R4 is - cycloalkyl (e.g., C3-C6 cycloalkyl), or 5-6 member heterocycloalkyl comprising at least one O heteroatom, optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl); R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5CIS H; and R5dis H.

[0311] In certain embodiments, R2is , wherein R4 is - cycloalkyl (e.g., C3-C6 cycloalkyl), or 5-6 member heterocycloalkyl comprising at least one O heteroatom, optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl); R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H; and R5d is H.

[0312] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R2is a 6-membered heteroaryl substituted with R4 and one or more R5 selected from R5a, R5b, R5c, R5d. In some embodiments, R2is wherein R4 is cycloalkyl or heterocycloalkyl optionally substituted with cycloalkyl (e.g., spirocyclic cyclopropyl or cyclopropyl); and R5bis H, halide, lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl) or CN.

[0313] 47

[0314] Foley HoagUS13043895.1 MTX-03225

[0315] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R2 is

[0316] R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-heterocycloalkyl,-O-alkyl, - alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl , -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and -alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more R4b; each Rib is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; and each Rsa, R5b, R5cand R5ais independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene- cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl- cycloalkyl, -alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy;

[0317] In certain embodiments, the invention relates to any compounds of Formula (I), wherein a is 0. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein a is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein a is 2.

[0318] Foley HoagUS13043895.1 MTX-03225

[0319] In certain embodiments, the invention relates to any compounds of Formula (I), wherein b is 0. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein b is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein b is 2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein b is 3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein b is 4.

[0320] In certain embodiments, the invention relates to any compounds of Formula (I), wherein one instance of b’ is 0. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein one instance of b’ is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein one instance of b’ is 2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein one instance of b’ is 3.

[0321] In certain embodiments, the invention relates to any compounds of Formula (I), wherein both instances of b’ are 0.

[0322] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein n is 0. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein n is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein n is 2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein n is 3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein n is 4.

[0323] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein m is 0. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein m is 3.

[0324] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R3 isH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is 49

[0325] Foley HoagUS13043895.1 MTX-03225

[0326] C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is alkyl. In some embodiments, alkyl is methyl, ethyl, iso-propyl, or tert-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cylcopentyl, or cyclohexyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is -alkylene-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is aryl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3 is H, halide, Me, OMe, or Ph.

[0327] In certain embodiments, In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R4 is alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -C(F2)CH3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is heterocycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene- cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -O-alkylene-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -O-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is - O-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-O-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is -alkylene-O-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is - alkylene-O-alkylene-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is selected from -alkylene-cycloalkyl, -O-alkylene- cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl. In some embodiments, alkylene R4 is methylene or ethylene.

[0328] 50

[0329] Foley HoagUS13043895.1 MTX-03225

[0330] In certain embodiments, the invention relates to any compounds of Formula (I), Formula

[0331] In certain embodiments, the invention relates to any one of the aforementioned compounds, R4 is selected from optionally substituted certain embodiments, the invention relates to any one of the aforementioned compounds, R4 is In certain embodiments, the invention relates to any one of the aforementioned compounds, R4 is In certain embodiments, the invention relates to any one of the aforementioned compounds, R4 is In certain embodiments, the invention relates to any one of the aforementioned compounds, R4 is In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R4 is selected from

[0332] Foley HoagUS13043895.1 MTX-03225

[0333] In certain embodiments, the invention relates to any one of the aforementioned

[0334] In certain embodiments, In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R5 isH. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is CF3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is C(H)F2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is C(F)H2. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is alkyl. In some embodiments, alkyl is methyl, ethyl, iso-propyl, or tert-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is cycloalkyl. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cylcopentyl, or cyclohexyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is -alkylene-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is aryl. In certain embodiments, the invention 52

[0335] Foley HoagUS13043895.1 MTX-03225 relates to any one of the aforementioned compounds, wherein R5 is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5 is H, halide, Me, OMe, or Ph.

[0336] In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein each R5 independently is

[0337] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein each R5 independently is

[0338] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein R5 is F, Cl, cyclopropyl or cyclobutyl.

[0339] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein Ra is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, Ra is (Ci-C6)alkyl. In some embodiments, (Ci-C6)alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, Ra is -(Ci-C6)alkylene-O-(Ci- Ce)alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, Ra is -(Ci-C6)alkylene-O-C(O)O(Ci-C6)alkyl;

[0340] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (lib), wherein the absolute configuration at any stereocenter is R. In certain

[0341] 53

[0342] Foley HoagUS13043895.1 MTX-03225 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.

[0343] In certain embodiments, the invention relates to any compounds of Formula (I), Formula (Ila) or Formula (nb), wherein the compound is a pharmaceutically acceptable salt.

[0344] EXEMPLARY PHARMACEUTICAL COMPOSITIONS

[0345] In certain embodiments, the invention relates to a pharmaceutical composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable carrier.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 54

[0350] Foley HoagUS13043895.1 MTX-03225

[0351] 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.

[0352] 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.

[0353] 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.

[0354] If administered intravenously, carriers include physiological saline and phosphate buffered saline (PBS).

[0355] 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, polygly colic acid, collagen, poly orthoesters and polylactic acid. For example, enterically coated compounds

[0356] 55

[0357] Foley HoagUS13043895.1 MTX-03225 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.

[0358] 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.

[0359] METHODS

[0360] In some embodiments, compounds of Formula (I) are useful for inhibiting integrin avP8 by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).

[0361] Integrin av08 mediates cell type specific and tissue localized activation of TGF01 / 3 to regulate the immune system. For example, avP8 expressed on resident dendritic cells (DC) in the intestine has been shown to be a key mediator of tolerance, maintaining gut immunologic homeostasis. In some embodiments, a compound of Formula (I) is useful in the treatment of a patient diagnosed with certain forms of cancer having mechanisms related to the integrin avP8.

[0362] In some embodiments, a compound of Formula (I) is useful in the treatment of medical conditions characterized by or associated with the expression of avP8 integrin(s). In general, integrins are adhesion molecules and mediate the attachment of cells to extracellular matrix proteins. Integrin avP8 binds to the LAP of TGF-P and mediates the activation of TGF-pi and 3. In addition, integrin avP8 can serve as a gatekeeper of TGF- P through an avP8-mediated activation of TGF-P for in vivo activation of TGF-P and release of the mature TGF-P polypeptide. Integrin avP8 is expressed in a variety of tissue types and avP8 integrin mediated activation of TGF-P can result in COPD, pulmonary fibrosis, inflammatory bowel disease, hepatic and renal fibrosis, kidney disease, and certain forms of cancer. Recent reports described

[0363] 56

[0364] Foley HoagUS13043895.1 MTX-03225 below have reviewed expression of the gene for integrin beta-8 (itgb8) in a variety of human tissue obtained from patients.

[0365] In some embodiments, compounds of Formula (I) are useful for the development of treatments for idiopathic pulmonary fibrosis (IPF), a progressive lung disease. For example, high Itgb8 expression is reported in aberrant basaloid cell population of (a) IPF patients (Adams T.S. et. al., Sci Adv. 2020 Jul; PMID: 32832599 "Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis”); (b) ILD patients (Habermann, C.A. et. al., Sci Adv. 2020 Jul; PMID: 32832598, "Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis"); (c) ILD and IPF patients (Reyfman P. A. Am J Respir Crit Care Med. 2019 Jun 15, PMID: 30554520, “Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis”); and (d) IPF patients (Morse C et. al., European Respiratory Journal 2019, PMID: 31221805, "Proliferating SPPl / MERTK-expressing macrophages in idiopathic pulmonary fibrosis").

[0366] In some embodiments, compounds that inhibit avP8 can be useful for evaluation for the treatment of patients with forms of fibrosis, such as myelofibrosis, chronic obstructive pulmonary disease (COPD), liver cirrhosis, and myelofibrosis. For example, high itgb8 expression is reported in aberrant basaloid cell population of COPD patients (Adams T.S. et. al. Sci Adv. 2020 Jul; PMID: 32832599, "Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis"). Itgb8 expression is also reported in patients with liver cirrhosis. For example, differential expression of Itgb8 is reported in hepatocytes and mesothelial cells in liver cirrhosis sample compare to uninjured samples (Ramachandran P., Nature 2019, PMID: 31597160, "Resolving the fibrotic niche of human liver cirrhosis at singlecell level"). Itgb8 expression is also reported in patients with myelofibrosis. For example, differential expression of Itgb8 is reporeted in Megakaryocytes progenitor cells in myelofibrosis patients compare to healthy individual (Psaila B et. al. Molecular Cell, 2020, PMID: 32386542, "Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets). In certain embodiments, the subject is a mammal, e.g., a human.

[0367] 57

[0368] Foley HoagUS13043895.1 MTX-03225

[0369] EXEMPLIFICATION

[0370] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0371] General schemes and procedures for the preparation of compounds of the invention

[0372] The moiety Ri and R2 represents 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 pyrrolidine. represents an appropriate optionally substituted tetrahydronaphthyridine. represents an appropriate optionally substituted naphthyridine.

[0373] General Schemes for the synthesis of avp8 inhibitors

[0374] General Scheme 1

[0375] General Scheme 2

[0376] 58

[0377] Foley HoagUS13043895.1 MTX-03225

[0378] General Procedures

[0379] Cross-Coupling

[0380] Alkene intermediates may be cross-coupled to 2,3-dihalo pyridines by the following procedure.

[0381] To a solution of alkene (1 eq.) in DMF at ambient temperature was added 2-chloro-3 -iodopyridine (1.1 eq), Pd(OAc)2 (10 mol%), TBAC (10 mol%) and NaHCCb (10 mol%). The mixture was heated to 75 °C and stirred for 16 h. The reaction mixture was cooled to 0 °C, diluted with H2O (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography to give the cross coupled product.

[0382] Reductive Amination

[0383] The product of the cross-coupling reaction may be reduced by the following procedure. To a solution of the cross-coupling product (1 eq) in MeOH was added NLLOAc (1.5 eq) and the mixture was stirred at ambient temperature for 16 h. NaBFLCN (4 eq) was added, the mixture was stirred for 2 h then concentrated under reduced pressure to give the reductive amination product as an oil.

[0384] Boc Protection

[0385] Foley HoagUS13043895.1 MTX-03225

[0386] The reductive amination product may be protected as the corresponding / c / v-butyl carbamate by the following procedure. A mixture of the reductive amination product (1 eq, 68.18 mmol) TEA (3.5 eq) and BOC2O (4 eq) in THF (220 mL) and H2O (220 mL) and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H2O (100 mL), extracted with EtOAc (2 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (S1O2, EtOAc in petroleum ether) to give the / crz-butyl carbamate,

[0387] Ring Annulation

[0388] Ring annulation may be carried out according to the following procedure,

[0389] To a solution of the / c / v-butyl carbamate product from the Boc Protection step (1 eq) in toluene (100 mL) was added Z-BuOK (2 eq), Pd2(dba)s (5 mol%) and X-Phos (10 mol%) at 20 °C. The mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C, diluted with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the ring annulation product.

[0390] 60

[0391] Foley HoagUS13043895.1 MTX-03225

[0392] As an alternative to the Ring Annulation approach, a Hydroboration / Suzuki reaction may be carried out between a chloro tetrhydronapthyridine and an olefin, as in the following procedure.

[0393] To a solution of olefin (1 eq) in THF (50 mL) was added 9-BBN (2 eq) and the resulting mixture was stirred at 25 °C for 5 h. A suspension of tert-butyl 7-chloro-3,4-dihydro-l,8-naphthyridine- 1(2H) -carboxy late (1 eq), Pd(dppf C12'DCM (10 mol%) and CS2CO3 (2 eq) in dioxane (60 mL) and DMF (20 mL) were added and the reaction was heated at 100 °C for 12 h. The mixture was allowed to cool to ambient temperature, poured into H2O (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic extracts were concentrated under reduced pressure and purified via flash chromatography ( S 1O2, EtOAc in petroleum ether) to give the Suzuki product.

[0394] Boc Deprotection

[0395] Boc-protected amine (1 equiv.) was treated with HC1 (4-100 equiv.) in 1,4-dioxane (1-50 mL / mmol amine) at room temperature to 50 °C for 1-4 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 NaHCCh.

[0396] Amine alkylation:

[0397] The amine obtained from deprotection of the Boc derivative may be alkylated using the following procedure. DIEA (4 eq) was added to a solution of amine (1.2 eq) in CH3CN (3 mL) at 25°C. A solution of alkylating agent (1-1.5 eq) in CH3CN (3 mL) was then added and the mixture was stirred at 50°C for 0.5 hrs. The reaction mixture was cooled to 0°C, diluted with water (100 mL)

[0398] 61

[0399] Foley HoagUS13043895.1 MTX-03225 and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the desired amino acetic acid ester. The amine used may be the free base or a salt, such as hydrochloride or dihydrochloride. If the reaction is done with a salt of the amine, additional equivalents of base may be needed.

[0400] Saponification:

[0401] For certain esters such as R2 = Me or ethyl, the ester may be saponified under basic conditions. The ester (1 equiv.) was treated with LiOH-FFO (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.

[0402] For certain esters such as R2 = tert- butyl, the ester may be saponified under acidic conditions. The ester (1 equiv.) was treated with 4 N HC1 (4-100 equiv.) in 1,4-di oxane (1-25 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.

[0403] Petasis reaction:

[0404] 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 equiv.) aryl boronic acid or aryl boronate ester (1-1.5 equiv.) and 2-oxoacetic acid (1.5-2 equiv.) 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.

[0405] 62

[0406] Foley HoagUS13043895.1 MTX-03225

[0407] Analytical Methods

[0408] Prep-HPLC Methods

[0409] Crude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm:

[0410] Prep HPLC A: column: XB ridge Cl 8, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.

[0411] Prep HPLC B: column: XBridge C18, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM formic acid), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.

[0412] Prep HPLC C: column: XBridge OBD Cl 8, 19 * 100 mm, 5 pm; mobile phase: A water, B CH3CN; gradient elution as in text; flow rate: 20 mL / min.

[0413] Prep Chiral SFC Methods

[0414] Racemic products were separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:

[0415] Prep chiral SFC A: column: (R,R)-Whelk-Ol, 20*250mm, 5 pm (Decial), column temperature: 35 °C, mobile phase: CCL / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0416] Prep chiral SFC B: column: AD 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CCL / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0417] Prep chiral SFC C: column: AS 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CCL / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0418] Prep chiral SFC D: column: OD 20*250mm, 10 pm (Daicel), column temperature: 35 °C,

[0419] 63

[0420] Foley HoagUS13043895.1 MTX-03225 mobile phase: CCh / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0421] Prep chiral SFC E: column: Cellulose-SC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0422] Prep chiral SFC F: column: OZ 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0423] Prep chiral SFC G: column: IC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0424] Prep chiral SFC H: column: (S,S)-Whelk-01, 20*250mm, 5 pm (Decial), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0425] Analytical Chiral SFC Methods

[0426] Chiral products were analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:

[0427] Chiral SFC A: column: (R,R)-Whelk-Ol, 4.6* 100mm, 5 pm (Decial), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0428] Chiral SFC B: column: AD 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0429] Chiral SFC C: column: AS 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C,

[0430] 64

[0431] Foley HoagUS13043895.1 MTX-03225 mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0432] Chiral SFC D: column: OD 4.6*100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0433] Chiral SFC E: column: Cellulose-SC 4.6* 100mm, 5 pm (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.

[0434] Chiral SFC F: column: OZ 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0435] Chiral SFC G: column: IC 4.6*100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0436] Chiral SFC H: column: (S,S)-Whelk-01, 4.6*100mm, 5 pm (Decial), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0437] Chiral SFC I: column: IC 4.6*250mm, 5 pm (SF0MADZU), column temperature: 40 °C, mobile phase: n-Hexane(0.1%DEA):EtOH(0.1%DEA), isocratic elution as in text, flow rate: 1 mL / min.

[0438] Chiral SFC J: column: (S,S)-Whelk-01 4.6*250mm, 5 pm (SF0MADZU), column temperature: 40 °C, mobile phase: n-Hexane(0.1%DEA):EtOH(0.1%DEA), isocratic elution as in text, flow rate: 1 mL / min.

[0439] 65

[0440] Foley HoagUS13043895.1 MTX-03225

[0441] Chiral SFC K: column: OZ-H 4.6*250mm, 5 pm (SHIMADZU), column temperature: 40 °C, mobile phase: n-Hexane(0.1%DEA):EtOH(0.1%DEA), isocratic elution as in text, flow rate: 1 mL / min.

[0442] Chiral SFC L: column: chiral PAK IG 4.6*250mm, 5 pm (SHIMADZU), column temperature: 35 °C, mobile phase: n-Hexane(0.1%DEA):EtOH(0.1%DEA), isocratic elution as in text, flow rate: 1 mL / min.

[0443] Chiral SFC M: column: EnantioPak OJ 4.6*250mm, 5 pm (Decial), column temperature: 40 °C, mobile phase: n-Hexane(0.1%DEA):EtOH(0.1%DEA), isocratic elution as in text, flow rate: 1 mL / min.

[0444] Synthesis of Intermediates

[0445] The following intermediates were prepared according to the Methods below for use in synthesizing Examples 1-17:

[0446] Method LI: Preparation of trans-N-methyl--(4-((S)-l ,2,3,4-tetrahydro-l ,8-naphthyridin-2- yl)butoxy)cyclobutan-l -amine (Stereoisomer A) and cA-N-methyl-3-(4-((R)-l,2,3,4-tetrahydro- 1 , 8-naphthyridin-2-yl)butoxy)cyclobutan- 1 -amine (Stereoisomer B) :

[0447] Step 1 : c7.s-3-(methylamino)cyclobutan- l -ol

[0448] To a solution of tert-butyl (cis-3-hydroxycyclobutyl)carbamate (8 g, 42.73 mmol) in THF (80 mL) was added LAH (3.24 g, 85.45 mmol) at 0 °C, then the mixture was stirred at 60 °C for 2 h, judged to be complete by TLC and cooled to 0 °C. The reaction mixture was quenched by the addition of saturated aqueous ISfeSCL (3 mL), diluted with EtOAc (500 mL) and MeOH (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6 g, crude) as an oil. This material was used directly in the next step without further purification.

[0449] Step 2: tert-butyl (cis-3-hydroxycyclobutyl)(methyl)carbamate

[0450] 66

[0451] Foley HoagUS13043895.1 MTX-03225 oc

[0452] To a solution of cA-3-(methylamino)cyclobutan-l-ol (6 g, 59.32 mmol) in THF (55 mL) and MeOH (l l mL) was added TEA (12.01 g, 118.64 mmol, 16.51 mL) and Boc2O (19.42 g, 88.98 mmol, 20.44 mL) at 20 °C. The solution was stirred at 20 °C for 4 h, judged to be complete by TLC and concentrated under reduced pressure. The residue was purified via flash chromatography (SiCh, 0% to 100% EtOAc in petroleum ether) to give the title compound (3.8 g, 18.9 mmol, 31.8% yield) as a solid. 'H NMR (400 MHz, CDCh) 84.00 (t, J= l.Q Hz, 2H), 2.81 (s, 3H), 2.57 (dtd, J= 2.9, 6.8, 9.3 Hz, 2H), 2.08 - 1.98 (m, 2H), 1.45 (s, 9H).

[0453] Step 3: ((hex-5-en-l-yloxy)methyl)benzene

[0454] 1 eq. 50% aq. NaOH, TBAB n-heptane, 25-80°C, 16 hrs

[0455] Six parallel reactions were carried out together. To a solution of benzyl alcohol (99.5 g, 919.93 mmol, 95.65 mL), TBAB (9.89 g, 30.66 mmol) and 6-bromohex-l-ene (100 g, 613.29 mmol, 81.97 mL) in / ?-heptane (1.2 L) was added NaOH (36.80 g, 919.93 mmol) in H2O (37 mL) at 25 °C. The mixture was stirred at 80 °C for 16 h, judged to be complete by TLC and allowed to cool to ambient temperature. The reaction mixture was diluted with H2O (2.0 L) and extracted with MTBE (3 x 1.0 L). The combined organic layers were washed with brine (2 x 1.0 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (SiO2, 0% to 91% EtOAc in petroleum ether) to give the title compound (560 g, 2.94 mol, 80.0% yield) as an oil. ' H NMR (400 MHz, CDCh) 8 7.31 - 7.18 (m, 4H), 5.74 (tdd, J = 6.6, 10.3, 17.0 Hz, 1H), 4.99 - 4.84 (m, 2H), 4.44 (s, 2H), 3.44 - 3.39 (m, 2H), 2.06 - 1.96 (m, 2H), 1.62 - 1.53 (m, 2H), 1.46 - 1.36 (m, 2H).

[0456] Step 4: 5-(benzyloxy)pentanal

[0457] 67

[0458] Foley HoagUS13043895.1 MTX-03225

[0459] THF / H2O, 0-20°C, 2 hrs

[0460] 59%

[0461] Two reactions were carried out in parallel. To a solution of ((hex-5-en-l-yloxy)methyl)benzene (200 g, 1.05 mol, 1 eq) in THE (3 L) and H2O (LO L) was added OsO4(1 g, 3.93 mmol, 204.08 uL, 0.004 eq) and NaIO4(449.63 g, 2.10 mol, 116.49 mL, 2.0 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h, judged to be complete by TLC, diluted with H2O (LO L) and extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (2 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (240 g, 1.25 mol, 59.4% yield) as an oil.1H NMR (400 MHz, CDCh) 8 9.69 (t, J= 1.7 Hz, 1H), 7.31 - 7.19 (m, 4H), 4.45 - 4.41 (m, 2H), 3.42 (t, J= 6.1 Hz, 2H), 2.39 (dt, J= 1.7, 7.2 Hz, 1H), 1.74 - 1.54 (m, 4H).

[0462] Step 5: 7-(benzyloxy)hept-l-en-3-ol , , 33%

[0463] Two identical reactions were carried out in parallel. To a solution of 5-(benzyloxy)pentanal (120 g, 624.18 mmol) in THF (1.2 L) was added vinyl magnesium bromide (1 M, 686.59 mL, 1.1 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 2 h, judged to be complete by TLC, diluted with aqueous NH4CI (1.0 L) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 600 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiC>2, EtOAc in petroleum ether) to give the title compound (91 g, 413.06 mmol, 33.1% yield) as an oil. 'H NMR (400 MHz, CDCL) 8 7.32 - 7.19 (m, 4H), 5.80 (ddd, J= 6.3, 10.5, 17.1 Hz, 1H), 5.15 (td, J= 1.4, 17.2 Hz, 1H), 5.04 (td, J= 1.3, 10.4 Hz, 1H), 4.45 - 4.42 (m, 2H), 4.09 - 3.99 (m, 1H), 3.44 - 3.39 (m, 2H), 1.60 (br d, J= 6.4 Hz, 2H), 1.53 - 1.45 (m, 2H), 1.44 - 1.29 (m, 2H).

[0464] Foley HoagUS13043895.1 MTX-03225

[0465] Step 6: 7-(benzyloxy)-l-(2-chloropyridin-3-yl)heptan-3-one

[0466] Two identical reactions were carried out in parallel. To a solution of 7-(benzyloxy)hept-l-en-3- ol (21 g, 95.32 mmol) and 2-chl oro-3 -iodopyridine (22.82 g, 95.32 mmol) in DMF (200 mL) was added TBAC (2.65 g, 9.53 mmol, 2.67 mL) and NaHCCh (20.02 g, 238.30 mmol, 9.27 mL) at 25 °C under N2. The mixture was treated with Pd(OAc)2 (2.14 g, 9.53 mmol), heated to 70 °C and stirred for 16 h. The reaction mixture was allowed to cool to ambient temperature, diluted with H2O (400 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (2 x 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiCL, EtOAc in petroleum ether) to give the title compound (41 g, 123.56 mmol, 64.8% yield) as an oil.JH NMR (400 MHz, CDCh) 8 8.19 (dd, J= 1.8, 4.6 Hz, 1H), 7.54 (dd, J= 1.8, 7.5 Hz, 1H), 7.34 - 7.19 (m, 5H), 7.10 (dd, J= 4.9, 7.5 Hz, 1H), 4.46 - 4.40 (m, 2H), 3.44 - 3.38 (m, 2H), 2.98 - 2.85 (m, 2H), 2.76 - 2.67 (m, 2H), 2.37 (t, J= 7.2 Hz, 2H), 1.72 - 1.50 (m, 4H).

[0467] Step 7: 7-(benzyloxy)-l-(2-chloropyridin-3-yl)heptan-3-amine

[0468] Two identical reactions were carried out in parallel. A mixture of 7-(benzyloxy)-l-(2- chloropyridin-3-yl)heptan-3-one (30 g, 90.41 mmol) and NH4OAC (104.53 g, 1.36 mol) in MeOH (600 mL) was stirred at 25 °C for 4 h. NaBHsCN (22.72 g, 361.62 mmol) was added and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and concentrated under reduced pressure to give the title compound (60 g, crude) as an oil. This

[0469] 69

[0470] Foley HoagUS13043895.1 MTX-03225 material was used directly in the next step without further purification. LCMS (ESI): m / z 331 [M+H]+).

[0471] Step 8: tert-butyl (7-(benzyloxy)-l-(2-chloropyridin-3-yl)heptan-3-yl)carbamate

[0472] Two identical reactions were carried out in parallel. To a solution of 7-(benzyloxy)-l-(2- chloropyridin-3-yl)heptan-3 -amine (30 g, 52.27 mmol), BOC2O (45.63 g, 209.09 mmol, 48.04 mL) in THF (1.2 L) was added TEA (21.16 g, 209.09 mmol, 29.10 mL) at 25 °C, The mixture was stirred at 25 °C for 2 h, diluted with H2O (1.0 L) and extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (2 x 600 mL), dried over IS^SCL, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiCE, EtOAc in petroleum ether) to give the title compound (40 g, 92.4 mmol, 88.4% yield) as an oil. 'H NMR (400 MHz, CDCh) 8 8.18 (dd, J= 1.5, 4.6 Hz, 1H), 7.51 (br d, J = 7.7 Hz, 1H), 7.30 - 7.19 (m, 5H), 7.10 (dd, J= 4.7, 7.4 Hz, 1H), 4.56 (br d, J = 4.0 Hz, 4H), 4.45 - 4.40 (m, 2H), 4.34 (br d, J= 9.3 Hz, 1H), 3.62 - 3.50 (m, 1H), 3.40 (t, J= 6.3 Hz, 2H), 2.80 - 2.71 (m, 1H), 2.69 - 2.59 (m, 1H), 2.00 (s, 1H), 1.80 - 1.69 (m, 1H), 1.63 - 1.48 (m, 4H), 1.47 - 1.41 (m, 2H), 1.39 (s, 9H). LCMS (ESI): m / z 433 [M+H]+.

[0473] Step 9: tert-butyl 2-(4-(benzyloxy)butyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate

[0474] Three identical reactions were carried out in parallel. A mixture of tert-butyl (7-(benzyloxy)-l- (2-chloropyridin-3-yl)heptan-3-yl)carbamate (30.0 g, 69.29 mmol), t-BuOK (15.55 g, 138.57 mmol), X-phos (3.30 g, 6.93 mmol) and Pd2(dba)s (3.17 g, 3.46 mmol) in toluene (1.2 L) was degassed and purged with N2 three times then heated to 100 °C and stirred for 4 h. The reaction mixture was allowed to cool to ambient temperature, filtered and concentrated under reduced

[0475] 70

[0476] Foley HoagUS13043895.1 MTX-03225 pressure to give a residue that was purified via flash chromatography (SiCh, EtOAc in petroleum ether) to give the title compound (45 g, 113.4 mmol, 54.6% yield) as an oil.JH NMR (400 MHz, CDC13) 8 8.35 (dd, J= 1.7, 4.5 Hz, 1H), 7.39 (dd, J= 1.1, 7.5 Hz, 2H), 7.36 - 7.31 (m, 4H), 7.00 - 6.91 (m, 1H), 4.58 - 4.44 (m, 4H), 3.44 (t, J= 6.5 Hz, 3H), 2.79 - 2.62 (m, 3H), 2.25 - 2.11 (m, 1H), 1.72 - 1.66 (m, 2H), 1.63 - 1.60 (m, 2H), 1.52 (s, 9H). LCMS (ESI): m / z 431 [M+H]+.

[0477] Step 10: tert-butyl 2-(4-hydroxybutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate

[0478] Boc Boc i

[0479] Six identical reactions were carried out in parallel. A solution of tert-butyl 2-(4- (benzyloxy)butyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate (5.0 g, 12.61 mmol) in MeOH (1.0 L) charged with Pd / C (10 g) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 70 °C for 72 h, allowed to cool to ambient temperature, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (9.3 g, 30.35 mmol, 40.12% yield) as a solid.1H NMR (400 MHz, CDCh) 8 8.33 (br d, J= 3.1 Hz, 1H), 7.43 - 7.37 (m, 1H), 6.97 (dd, J= 4.9, 7.3 Hz, 1H), 4.68 - 4.43 (m, 1H), 3.59 (br s, 2H), 2.71 (br t, J= 6.7 Hz, 2H), 2.33 - 2.07 (m, 1H), 1.75 - 1.60 (m, 3H), 1.59 - 1.54 (m, 1H), 1.51 (s, 9H), 1.48 - 1.26 (m, 4H).

[0480] Step 11: tert-butyl 2-(4-((methylsulfonyl)oxy)butyl)-3,4-dihydro-l,8-naphthyridine-l(2H)- carboxylate

[0481] To a solution of tert-butyl 2-(4-hydroxybutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate (9.3 g, 30.35 mmol) and TEA (6.14 g, 60.71 mmol, 8.45 mL) in DCM (100 mL) was added dropwise MsCl (6.95 g, 60.71 mmol, 4.70 mL) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by the addition of saturated aqueous NaHCCb (50 mL) at 71

[0482] Foley HoagUS13043895.1 MTX-03225

[0483] 20 °C, and then extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (11.6 g, 30.17 mmol, 99.4% yield) as an oil.JH NMR (400 MHz, CDCL) 8 8.46 - 8.26 (m, 1H), 7.45 (br d, J= 7.1 Hz, 1H), 7.02 (dd, J= 5.0, 7.4 Hz, 1H), 4.69 - 4.50 (m, 1H), 4.19 (t, J = 6.5 Hz, 2H), 2.98 (s, 3H), 2.74 (br t, J= 6.7 Hz, 2H), 2.25 - 2.12 (m, 1H), 1.83 - 1.65 (m, 4H), 1.58 - 1.55 (m, 1H), 1.52 (s, 9H), 1.50 - 1.45 (m, 2H).

[0484] Step 12: / c / 7-butyl 2-(4-iodobutyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate

[0485] Two identical reactions were carried out in parallel. To a solution of / crz-butyl 2-(4- ((methylsulfonyl)oxy)butyl)-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate (15 g, 39 mmol) in acetone (200 mL) was added Lil (15.67 g, 117 mmol, 4.5 mL). The mixture was stirred at 28 °C for 48 h. The reaction mixture was quenched by the addition of saturated aqueous IS^SCh (200 mL) at 20 °C, and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over IS^SCL, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (SiCL, EtOAc in petroleum ether) to give the title compound (12.5 g, 30.03 mmol, 38.5% yield) as an oil. 'H NMR (400 MHz, CDCl2) 8 8.42 - 8.24 (m, 1H), 7.40 (br d, J= 7.5 Hz, 1H), 6.98 (dd, J= 4.7, 7.4 Hz, 1H), 4.53 (quin, J= 6.2 Hz, 1H), 3.21 - 3.10 (m, 2H), 2.71 (t, J= 6.8 Hz, 2H), 2.27 - 2.12 (m, 1H), 1.89 - 1.76 (m, 2H), 1.73 - 1.66 (m, 1H), 1.61 - 1.54 (m, 2H), 1.52 (s, 9H), 1.50 - 1.42 (m, 2H).

[0486] Step 13: / crz-butyl 2-(4-cis-3 -((tert-butoxycarbonyl )(methyl)amino)cyclobutoxy)butyl)-3, 4- dihydro-l,8-naphthyridine-l(2H)-carboxylate Stereoisomer A and Stereoisomer B carboxylate

[0487] Foley HoagUS13043895.1 MTX-03225

[0488] To a solution of tert-butyl cis-3 -hydroxy cyclobutyl(methyl)carbamate (1.2 g, 6.0 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 288.45 mg, 7.21 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and tert-butyl 2-(4-iodobutyl)-3,4-dihydro-l,8- naphthyridine-l(2H)-carboxylate (2.5 g, 6.01 mmol) in DMF (10 mL) was added. The mixture was stirred at 20 °C for 2 h, cooled to 0 °C, quenched by the addition of H2O (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over IS^SCL, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (SiCL, EtOAc in petroleum ether) and separated by SFC (Condition A: Column: Phenomenex Cellulose-2 (250 mm * 30 mm, 10 pm); Eluent A: CO2, Eluent B: 0.1% NH3 in IPA; Isocratic method: 50% B, 5 min) to give two peaks (Peak 1 and Peak 2).

[0489] Peak 1 was obtained as a yellow oil (700 mg, 1.43 mmol, 23.8% yield) and randomly assigned as Stereoisomer A. LCMS (ESI): m / z 490.2 [M+H]+.

[0490] Peak 2 was obtained as a yellow oil (700 mg, 1.43 mmol, 23.8% yield) and randomly assigned as Stereoisomer B. LCMS (ESI): m / z 490.2 [M+H]+.

[0491] Step 14: cA-N-methyl-3-(4-((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutan-l- amine (Stereoisomer A)

[0492] Stereoisomer A

[0493] TFA (616.00 mg, 5.40 mmol, 0.4 mL) was added to a stirred solution of / crz-butyl (S)-2-(4-(cA- 3-(( / / 7-butoxycarbonyl)(methyl)amino)cyclobutoxy)butyl)-3,4-dihydro-l ,8-naphthyridine- 1(2H) -carboxy late Stereoisomer A (200 mg, 408.46 pmol) in DCM (2 mL) at 20 °C. The mixture was heated to 50 °C and stirred for 3 h, judged to be complete by LCMS and allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure, neutralized with basic resin, filtered and concentrated to give the title compound (Inter L12, 200 mg) as an oil. LCMS (ESI): m / z 290.2 [M+H]+.

[0494] 73

[0495] Foley HoagUS13043895.1 MTX-03225

[0496] The following intermediates were prepared by the procedure of Method LI, Step 14 using the appropriate starting materials: trans-N-methyl--(4-((R)-l ,2, 3, 4-tetrahydro-l ,8-naphthyridin-2-yl)butoxy)cyclobutan- l -amine Stereoisomer B

[0497] Stereoisomer B

[0498] LCMS (ESI): m / z 290.2 [M+H]+.

[0499] Method L2: trans-N-methyl-3-(4-((S)-l , 2, 3, 4-tetrahydro- l , 8-naphthyridin-2- yl)butoxy)cyclobutan-l -amine (Stereoisomer A, Inter L14) and tra«s-N-methyl-3-(4-((R)- 1,2, 3, 4-tetrahydro-l, 8-naphthyridin-2-yl)butoxy)cyclobutan-l -amine (Stereoisomer B, Inter

[0500] L15)

[0501] Stereoisomer A Stereoisomer B

[0502] Stereoisomer A: LCMS (ESI): m / z 290.2 [M+H]+.

[0503] Stereoisomer B: LCMS (ESI): m / z 290.2 [M+H]+.

[0504] Method L3: Preparation of trans-N-methyl--((5-((l , 2, 3, 4-tetrahydro-l , 8-naphthyridin-2- yl)pentyl)oxy)cyclobutan-l -amine Stereoisomer A and Stereoisomer B

[0505] Step 1 : tert-butyl (cis-3-(hept-6-en-l -yloxy)cyclobutyl)(methyl)carbamate

[0506] Foley HoagUS13043895.1 MTX-03225

[0507] Two identical reactions were carried out in parallel. To a solution of tert-butyl cis-3- hydroxycyclobutyl)(methyl)carbamate (35 g, 173.90 mmol) in toluene (360 mL) was added TBAB (5.61 g, 17.39 mmol), NaOH (34.78 g, 869.51 mmol) in H2O (360 mL) and 7-bromohept- 1-ene (76.99 g, 434.76 mmol) at 25 °C and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to 0 °C, diluted with H2O (100 mL) and extracted with MTBE (2 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiCL, EtOAc in petroleum ether) to give the title compound (67 g, 225.26 mmol, 64.8% yield) as an oil. 'H NMR (400 MHz, CDC13) 8 5.87 - 5.76 (m, 1H), 5.06 - 4.89 (m, 2H), 3.63 (t, J= 7.0 Hz, 1H), 3.33 (t, J= 6.7 Hz, 2H), 2.81 (s, 3H), 2.55 - 2.45 (m, 2H), 2.09 - 2.05 (m, 2H), 2.03 - 1.93 (m, 2H), 1.59 - 1.51 (m, 2H), 1.46 (s, 9H), 1.43 - 1.32 (m, 4H), 1.32 - 1.21 (m, 1H).

[0508] Step 2: tert-butyl methyl(cis-3-((6-oxohexyl)oxy)cyclobutyl)carbamate

[0509] Two identical reactions were carried out in parallel. To a solution of / er / -butyl (c7.s-3-(hept-6-en- l-yloxy)cyclobutyl)(methyl)carbamate (35 g, 117.67 mmol) in THF (400 mL) and H2O (400 mL) was added OsO4(1.35 g, 5.30 mmol, 274.74 uL) and NaIO4(50.34 g, 235.35 mmol, 13.04 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered, extracted with EtOAc (2 x 500 mL), washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (40 g, 133.60 mmol, 56.8% yield) as an oil. 'H NMR (400 MHz, CDCh) 8 9.78 (t, J= 1.7 Hz, 1H), 3.66 - 3.58 (m, 1H), 3.33 (t, J= 6.5 Hz, 2H), 2.80 (s, 3H), 2.54 - 2.42 (m, 4H), 2.03 - 1.93 (m, 2H), 1.70 - 1.52 (m, 5H), 1.50 - 1.38 (m, 12H).

[0510] Step 3: tert-butyl (cis-3-((6-hydroxyoct-7-en-l-yl)oxy)cyclobutyl)(methyl)carbamate

[0511] 75

[0512] Foley HoagUS13043895.1 MTX-03225

[0513] Two identical reactions were carried out in parallel. Vinylmagnesium bromide (1 M in THF, 73.48 mL) was added dropwise to a stirred solution of tert-butyl methyl(cis-3-((6- oxohexyl)oxy)cyclobutyl)carbamate (20 g, 66.80 mmol) in THF (200 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, quenched with saturated aqueous NH4CI (500 mL), extracted with EtOAc (2 x 200 mL), washed with brine (200 mL), dried over IS^SCL, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography ( S 102, EtOAc in petroleum ether) to give the title compound (27 g, 82.45 mmol, 61.7% yield) as an oil. ' H NMR (400 MHz, CDCh) 8 5.87 (ddd, J = 6.2, 10.5, 17.0 Hz, 1H), 5.22 (d, J= 17.1 Hz, 1H), 5.11 (d, J= 10.4 Hz, 1H), 4.13 - 4.08 (m, 1H), 3.62 (t, J = 6.8 Hz, 1H), 3.33 (t, 7 = 6.7 Hz, 2H), 2.80 (s, 3H), 2.54 - 2.44 (m, 2H), 2.02 - 1.94 (m, 2H), 1.61 - 1.50 (m, 5H), 1.45 (s, 9H), 1.43 - 1.33 (m, 4H), 0.89 - 0.84 (m, 1H).

[0514] Step 4: tert-butyl (cis-3-((8-(2-chloropyridin-3-yl)-6- oxooctyl)oxy)cyclobutyl)(methyl)carbamate Boc

[0515] Two identical reactions were carried out in parallel. To a solution of tert-butyl (cis-3-((6- hydroxyoct-7-en-l-yl)oxy)cyclobutyl)(methyl)carbamate (12 g, 36.65 mmol) in DMF (120 mL) at 20 °C was added 2-chl oro-3 -iodopyridine (9.65 g, 40.31 mmol), Pd(OAc)2 (822.73 mg, 3.66 mmol), TBAC (1.02 g, 3.66 mmol, 1.02 mL) and NaHCCh (7.70 g, 91.61 mmol, 3.56 mL). The mixture was heated to 75 °C and stirred for 16 h. The reaction mixture was cooled to at 0 °C, diluted with H2O (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (22 g, 50.12 mmol, 68.4% yield) as an oil. 'H NMR

[0516] Foley HoagUS13043895.1 MTX-03225

[0517] (400 MHz, CDCh) 8 8.33 - 8.24 (m, 1H), 7.62 (dd, J= 1.8, 7.5 Hz, 1H), 7.17 (dd, J= 4.8, 7.5 Hz, 1H), 3.61 (t, J= 6.6 Hz, 1H), 3.31 (t, J= 6.6 Hz, 2H), 3.06 - 2.93 (m, 2H), 2.89 - 2.73 (m, 5H), 2.54 - 2.38 (m, 4H), 2.02 - 1.92 (m, 2H), 1.65 - 1.48 (m, 5H), 1.46 (s, 9H), 1.35 - 1.29 (m, 2H).

[0518] Step 5: tert-butyl (cA-3-((6-amino-8-(2-chloropyridin-3- yl)octyl)oxy)cyclobutyl)(methyl)carbamate

[0519] Boc Boc

[0520] To a solution of tert-butyl (cis-3-((8-(2-chloropyridin-3-yl)-6- oxooctyl)oxy)cyclobutyl)(methyl)carbamate (22 g, 50.12 mmol) in MeOH (220 mL) was added NH4OAC (57.95 g, 751.73 mmol) at 20 °C and the mixture was stirred for 16 h. NaBHsCN (12.60 g, 200.46 mmol) was added, the mixture was stirred for 2 h then concentrated under reduced pressure to give the title compound (30 g, crude) as an oil. LCMS (ESI): m / z 440.2 [M+H]+.

[0521] Step 6: tert-butyl (cis-3-((6-((tert-butoxycarbonyl)amino)-8-(2-chloropyridin-3- yl)octyl)oxy)cyclobutyl)(methyl)carbamate

[0522] To a solution of tert-butyl (cA-3-((6-amino-8-(2-chloropyridin-3- yl)octyl)oxy)cyclobutyl)(methyl)carbamate (30 g, 68.18 mmol) in THF (220 mL) and H2O (220 mL) was added TEA (27.60 g, 272.72 mmol, 37.96 mL) and BOC2O (59.52 g, 272.72 mmol, 62.65 mL) at 20 °C and the mixture was stirred for 16 h. The reaction mixture was diluted with H2O (100 mL), extracted with EtOAc (2 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (SiCh, EtOAc in 77

[0523] Foley HoagUS13043895.1 MTX-03225 petroleum ether) to give the title compound (22 g, 40.73 mmol, 59.7% yield) as an oil.JH NMR (400 MHz, CDC13) 8 8.25 (dd, J= 1.6, 4.6 Hz, 1H), 7.59 (br d, J= 7.0 Hz, 1H), 7.18 (dd, J= 4.8, 7.5 Hz, 1H), 4.33 (br d, J= 9.2 Hz, 1H), 3.62 (br t, J= 6.7 Hz, 2H), 3.31 (t, J= 6.6 Hz, 2H), 2.87 - 2.77 (m, 4H), 2.77 - 2.63 (m, 1H), 2.55 - 2.43 (m, 2H), 2.03 - 1.92 (m, 2H), 1.92 - 1.74 (m, 1H), 1.46 (d, J= 3.7 Hz, 24H).

[0524] Step 7: tert-butyl methyl(cis-3-((5-(l,2,3,4-tetrahydro-l,8-naphthyridin-2- yl)pentyl)oxy)cyclobutyl)carbamate

[0525] To a solution of tert-butyl (cis-3-((6-((tert-butoxycarbonyl)amino)-8-(2-chloropyridin-3- yl)octyl)oxy)cyclobutyl)(methyl)carbamate (11 g, 20.37 mmol) in toluene (100 mL) was added t- BuOK (4.57 g, 40.73 mmol), Pd2(dba)3(932.45 mg, 1.02 mmol) and X-Phos (970.86 mg, 2.04 mmol) at 20 °C. The mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C, diluted with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (12 g, 27.80 mmol, 68.3% yield) as an oil. LCMS (ESI): m / z 404.2 [M+H]+.

[0526] Step 8: trans-N-methyl--((5-( l ,2,3,4-tetrahydro- l ,8-naphthyridin-2-yl)pentyl)oxy)cyclobutan-l - amine Stereoisomer A and Stereoisomer B.

[0527] Foley HoagUS13043895.1 MTX-03225

[0528] To a solution of tert-butyl methyl(c7.s-3-((5-( l ,2,3,4-tetrahydro- l ,8-naphthyridin-2- yl)pentyl)oxy)cyclobutyl)carbamate (12 g, 29.74 mmol, 1 eq) in DCM (100 mL) was added TFA (30.80 g, 270.13 mmol, 20.00 mL) at 20 °C. The mixture was heated to 30 °C and stirred for 16 h. The reaction mixture was allowed to cool to ambient temperature, concentrated under reduced pressure and the residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 (250 mm * 100 mm, 15 pm); Eluent A: 0.1% TFA in H2O, Eluent B: MeCN; Gradient method: 0% - 28% B, 20 min. HPLC: ET24671-539-P1A1, Rt = 2.000 min) to give a product. The product was then separated by SFC (Column: DAI CEL CHIRALPAK AD (250 mm * 50 mm, 10 pm); Eluent A: 0.1% NH3 in H2O, Eluent B: MeOH; Isocratic method: 35% B, min) to give two peaks.

[0529] Peak 1 was obtained as an oil and randomly assigned as Stereoisomer A (Inter L28, 2.6 g, 8.14 mmol, 27.4% yield, 95.0% purity). ' H NMR (400 MHz, CDCh) 8 7.85 (br s, 1H), 7.15 (br d, J = 6.6 Hz, 1H), 6.52 - 6.43 (m, 1H), 4.81 (br s, 1H), 3.74 - 3.58 (m, 1H), 3.50 (d, J= 2.1 Hz, 1H), 3.40 (br s, 1H), 3.37 - 3.30 (m, 2H), 2.84 - 2.68 (m, 3H), 2.68 - 2.60 (m, 2H), 2.36 (d, J= 2.1 Hz, 3H), 1.94 (br s, 1H), 1.60 - 1.53 (m, 5H), 1.42 (br s, 4H), 1.27 (br s, 1H). LCMS (ESI): m / z 304.1 [M+H]+.

[0530] Peak 2 was obtained as an oil and randomly assigned as Stereoisomer B (Inter L29, 3.0 g, 9.70 mmol, 32.6% yield, 98.1% purity).XH NMR (400 MHz, CDCh) 8 9.22 (br s, 1H), 7.69 - 7.60 (m, 1H), 7.40 (d, J= l.Q Hz, 1H), 6.59 - 6.55 (m, 1H), 3.80 - 3.72 (m, 1H), 3.63 - 3.56 (m, 1H), 3.33 (t, J = 6.1 Hz, 2H), 3.24 - 3.14 (m, 1H), 2.86 - 2.74 (m, 2H), 2.71 - 2.63 (m, 2H), 2.58 (s, 3H), 2.21 - 2.12 (m, 2H), 1.74 - 1.64 (m, 2H), 1.60 - 1.51 (m, 3H), 1.49 - 1.39 (m, 4H), 1.26 (s, 1H). LCMS (ESI): m / z 304.1 [M+H]+.

[0531] Method L4: cA-N-methyl-3-((5-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)pentyl)oxy)cyclobutan-l -amine (Inter L30)

[0532] Step 1 : tert-butyl methyl(cis-3-(pent-4-en-l -yloxy)cyclobutyl)carbamate

[0533] 25-100°C, 12 hrs

[0534] 79

[0535] Foley HoagUS13043895.1 MTX-03225

[0536] To a solution of tert-butyl (cis-3-hydroxycyclobutyl)(methyl)carbamate (9 g, 44.72 mmol) in toluene (70 mL) was added TBAB (1.44 g, 4.47 mmol), NaOH (8.94 g, 223.59 mmol) in H2O (70 mL) and 5-bromopent-l-ene (16.66 g, 111.79 mmol) at 25 °C. The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was allowed to cool to ambient temperature, diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over IS^SCL, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography ( S 102, 0% to 17% EtOAc in petroleum ether) to afford the title compound (9 g, 33.41 mmol, 74.7% yield) as an oil. 'H NMR (400 MHz, CDCh) 8 5.81 (tdd, J= 6.7, 10.3, 17.0 Hz, 1H), 5.08 - 4.91 (m, 2H), 3.63 (quin, J= 6.9 Hz, 1H), 3.34 (t, J= 6.6 Hz, 2H), 2.81 (s, 3H), 2.55 - 2.44 (m, 2H), 2.12 (q, J= l.Q Hz, 2H), 2.04 - 1.92 (m, 2H), 1.66 (quin, J= l.Q Hz, 2H), 1.45 (s, 9H).

[0537] Step 2: tert-butyl 7-(5-(cA-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)pentyl)-3,4- dihydro-1 ,8-naphthyridine-l (2H)-carboxylate

[0538] Boc b. Cs2CO3, Pd(dppf)CI2, DMF / dioxane, 20-100°C, 4 h

[0539] To a solution of tert-butyl methyl(c7.s-3-(pent-4-en- l -yloxy)cyclobutyl)carbamate (8.06 g, 29.92 mmol) in THF (20 mL) was added 9-BBN (0.5 M, 124.66 mL) at 0 °C and the mixture was stirred at 20 °C for 2 h. The mixture was added to a solution of tert-butyl 7-chloro-3,4-dihydro- l,8-naphthyridine-l(2H)-carboxylate (6.7 g, 24.93 mmol), CS2CO3 (24.37 g, 74.79 mmol) and Pd(dppf)Ch (912.12 mg, 1.25 mmol) in DMF (150 mL) and dioxane (50 mL) at 20 °C. The mixture was stirred at 100 °C for 4 h, judged to be complete by TLC, allowed to cool to ambient temperature and diluted with H2O (300 mL). The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (SiO2, 0% to 25% EtOAc in petroleum ether) to afford the title compound (10 g,

[0540] 80

[0541] Foley HoagUS13043895.1 MTX-03225

[0542] 13.90 mmol, 55.7% yield) as an oil. 'H NMR (400 MHz, CDCh) 8 7.22 (br d, J= 7.7 Hz, 1H), 6.73 (d, J= 7.6 Hz, 1H), 3.73 - 3.67 (m, 2H), 3.59 - 3.50 (m, 1H), 3.26 (t, J= 6.7 Hz, 2H), 2.73 (s, 3H), 2.68 - 2.61 (m, 4H), 2.47 - 2.37 (m, 2H), 1.95 - 1.88 (m, 2H), 1.87 - 1.83 (m, 2H), 1.68 (td, J= 7.8, 15.5 Hz, 2H), 1.56 - 1.51 (m, 2H), 1.44 (s, 9H), 1.38 (s, 9H).

[0543] Step 3: trans-N-methyl--((5-(5,6,7,8-tetrahydro- l ,8-naphthyridin-2-yl)pentyl)oxy)cyclobutan-l - amine

[0544] To a solution of / cr / -butyl 7-(5-(c7.s-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)pentyl(- 3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate (790 mg, 1.57 mmol) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL) at 25 °C. The mixture was heated at 50 °C and kept at this temperature for 12 h, judged to be complete by LCMS, neutralized, filtered and concentrated under reduced pressure to give the title compound as an oil (800 mg, crude). This material was used without further purification. LCMS (ESI): m / z 304.1 [M+H]+.

[0545] Method L5: trans-N-methyl--(4-(5,6,7,8-tetrahydro- l ,8-naphthyridin-2-yl)butoxy)cyclobutan-l- amine (Inter ZL01)

[0546] Step 1 : tert-butyl (cis-3-(but-3-en- l -yloxy)cyclobutyl)(methyl)carbamate ,

[0547] To a mixture of tert-butyl (c7.s-3 -hydroxycyclobuty l)(methyl (carbamate (5 g, 24.84 mmol) in toluene (50 mL) and H2O (50 mb) at ambient temperature was added TBAB (800.86 mg, 2.48 mmol), NaOH (4.97 g, 124.22 mmol) and 4-bromobut-l-ene (16.77 g, 124.22 mmol, 12.61 mL). The mixture was heated at 100 °C for 8 h, allowed to cool to ambient temperature and the phases were separated. The aqueous phase was extracted with DCM (3 x 30 mL) and the combined extracts were washed with brine (3 x 30 mL), dried over Na2SC>4, filtered and concentrated under

[0548] Foley HoagUS13043895.1 MTX-03225 reduced pressure. The residue was purified via flash chromatography (SiCh, 0% to 9% EtOAc in petroleum ether) to give the title compound (1.9 g, 7.44 mmol, 29.95% yield) as an oil.JH NMR (400 MHz, CDC13) 8 5.81 (tdd, J= 6.7, 10.3, 17.1 Hz, 1H), 5.10 (dd, J= 1.6, 17.2 Hz, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.29 - 3.96 (m, 1H), 3.64 (quin, J = 7.0 Hz, 1H), 3.39 (t, J = 6.8 Hz, 2H), 2.80 (s, 3H), 2.55 - 2.45 (m, 2H), 2.32 (q, J= 6.9 Hz, 2H), 2.04 - 1.92 (m, 2H), 1.74 - 1.59 (m, 1H), 1.45 (s, 9H).

[0549] Step 2: tert-butyl 7-(4-(cA-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)butyl)-3,4- dihydro-1 ,8-naphthyridine-l (2H)-carboxylate

[0550] Boc

[0551] To a solution of tert-butyl methyl(cis-3-(pent-4-en-l -yloxy)cyclobutyl)carbamate (1.2 g, 4.70 mmol) in THF (20 mb) was added 9-BBN (0.5 M, 18.80 mL) dropwise at 0 °C and the mixture was stirred at 50 °C for 5 h. The mixture was added to a solution of tert-butyl 7-chloro-3,4-dihydro- l,8-naphthyridine-l(2H)-carboxylate (1.26 g, 4.7 mmol), CS2CO3 (3.06 g, 9.4 mmol) and Pd(PPh3)4 (543 mg, 470 mmol) in DMF (12 mL) at ambient temperature. The mixture was stirred at 100 °C for 15 h, judged to be complete by LCMS, allowed to cool to ambient temperature and diluted with H2O (30 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (SiO2, EtOAc in petroleum ether) to afford the title compound (920 mg, 2.36 mmol, 50.26% yield) as an oil. 'H NMR (400 MHz, CDCI3) 8 7.29 (d, J= 7.7 Hz, 1H), 6.81 (d, J= 7.7 Hz, 1H), 3.75 - 3.75 (m, 1H), 3.75 - 3.75 (m, 1H), 3.75 - 3.75 (m, 1H), 3.79 - 3.72 (m, 2H), 3.62 (quin, J = 7.0 Hz, 1H), 3.36 (t, J= 6.7 Hz, 2H), 2.80 (s, 3H), 2.76 - 2.68 (m, 4H), 2.53 - 2.43 (m, 2H), 2.03 - 1.94 (m, 2H), 1.93 - 1.87 (m, 2H), 1.84 - 1.74 (m, 2H), 1.68 - 1.59 (m, 2H), 1.57 - 1.49 (m, 9H), 1.45 (s, 9H). LCMS (ESI): m / z 490.3 [M+H]+.

[0552] Foley HoagUS13043895.1 MTX-03225

[0553] Method L6: czs-N-methyl-3-(3-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)propoxy)cyclobutan-l - amine (Inter ZL02)

[0554] Step 1 : tert-butyl (cis-3-(allyloxy)cyclobutyl)(methyl (carbamate ,

[0555] To a solution of tert-butyl (cis-3-hydroxycyclobutyl)(methyl)carbamate (2.5 g, 12.42 mmol) in DMF (30 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 993.63 mg, 24.84 mmol) and the resulting mixture was stirred at 25 °C for 1 h. Allyl bromide (7.51 g, 62.11 mmol) was added and stirring was continued for 1 h. The mixture was extracted with EtOAc (2x 50 mL), concentrated under reduced pressure and purified via flash chromatography (SiO2, EtOAc in petroleum ether) to give the title compound (2.5 g, 10.36 mmol, 83.40% yield) as an oil. 'H NMR (400 MHz, CDC13) 5 7.21 (s, 1H), 5.76 - 5.91 (m, 1H), 5.17 - 5.22 (m, 1H), 5.11 (dd, J = 10.35, 1.19 Hz, 1H), 3.83 (d, J= 5.77 Hz, 2H), 3.62 (quin, J = 7.00 Hz, 1H), 2.73 (s, 3H), 2.38 - 2.50 (m, 2H), 1.91 - 1.99 (m, 2H), 1.38 (s, 9H).

[0556] Step 2: tert-butyl 7-(3-(cis-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)propyl)-3,4- dihydro-1 ,8-naphthyridine-l (2H)-carboxylate

[0557] Boc b) Pd(dppf)2Cl2.CH2Cl2, Cs2CO3dioxane, DMF, 100°C, 12hrs

[0558] To a solution of tert-butyl (cis-3-(allyloxy)cyclobutyl)(methyl)carbamate (2 g, 8.29 mmol) in THF (50 mL) was added 9-BBN (0.5 M, 33.16 mL) and the resulting mixture was stirred at 25 °C for 5 h. A suspension of tert-butyl 7-chloro-3,4-dihydro-l,8-naphthyridine-l(2H)-carboxylate (2.23 g, 8.29 mmol), Pd(dppf)Cl2DCM (676.79 mg, 829.00 umol) and Cs2CO3(5.40 g, 16.58

[0559] 83

[0560] Foley HoagUS13043895.1 MTX-03225 mmol) in dioxane (60 mL) and DMF (20 mL) were added and the reaction was heated at 100 °C for 12 h. The mixture was allowed to cool to ambient temperature, poured into H2O (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic extracts were concentrated under reduced pressure and purified via flash chromatography (SiCL, EtOAc in petroleum ether) to give the title compound (1.7 g, 3.57 mmol, 43.12% yield) as an oil.JH NMR (400 MHz, CDCh) 8 7.23 (s, 1 H), 7.20 (s, 1H), 6.75 (d, J= 7.65 Hz, 1H), 3.66 - 3.72 (m, 2H), 3.57 (quin, J= 6.96 Hz, 1H), 3.32 (t, J= 6.46 Hz, 2H), 2.70 - 2.77 (m, 1H) 2.62 - 2.76 (m, 7H), 1.88 - 1.96 (m, 5H), 1.81 - 1.88 (m, 1H), 1.84 (quin, J= 6.34 Hz, 1H), 1.44 (s, 9H), 1.38 (s, 9H).

[0561] Step 3 : trans-N-methyl--(3-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)propoxy)cyclobutan-l - amine

[0562] To a solution of tert-butyl 7-(3-(cA-3-((tert- butoxycarbonyl)(methyl)amino)cyclobutoxy)propyl)-3 ,4-dihydro- 1 , 8-naphthyridine- 1 (2H)- carboxylate (1.7 g, 3.57 mmol) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL). The mixture was stirred at 25 °C for 16 h, concentrated under reduced pressure, diluted with EtOH (20 mL) and treated with basic resin. The mixture was filtered and concentrated under reduced pressure to give the title compound (1 g, crude) as an oil. LCMS (ESI): m / z 276.2 [M+H]+.

[0563] The following methods were used to prepare compounds 1-64:

[0564] Method Rl: ethyl 2-(2-cyclopropylpyridin-3-yl)-2-(methylsulfonyloxy)acetate (used in the synthesis of Examples 1-4, 18, 27, 30, 40, 41, 48)

[0565] Step 1: 3-bromo-2-cyclopropylpyridine

[0566] Foley HoagUS13043895.1 MTX-03225

[0567] To a solution of 2,3-dibromopyridine (3g,12.8mmol) and cyclopropylzinc(II) bromide (76 mb, 0.5 M in THF) in THF (30mL) was added Pd(PPh3)4 (740 mg, 0.64mmol). The mixture was stirred at 70 °C under N2 for 4 hours, then diluted with water (50ml) and extracted with EtOAc (3x 50mL). The combined organic layers 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 3- bromo-2-cyclopropylpyridine as a yellow oil (1.2g). Yield 48% (ESI 198(M+H) +).

[0568] Step 2: ethyl 2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate

[0569] To a solution of EtMgBr (IM, 3.65m, 3.65mmol) in THF (20 mL) at 0°C under N2, was added n- BuLi (2.9mL, 7.3mmol). The solution was stirred at 0 °C for 30 min, then a solution of 3-bromo- 2-cyclopropylpyridine (1.2g, 6. Immol) in THF (5 mL) was added at -10 °C. The mixture was stirred at that temperature for 30 min, and ethyl 2-oxoacetate (50% in toluene, 5g, 24.4mmol) was added. The reaction was stirred at 0 °C for 2 hours, then quenched with saturated K2CO3 solution (20 mL) and extracted with EtOAc (3x 50mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (pet ether: EtOAc 2: 1) to give the desired product ethyl 2-(2-cyclopropylpyridin-3- yl)-2-hydroxyacetate as a yellow oil (700 mg). Yield 52% (ESI 222 (M+H) +).

[0570] Step 3: ethyl 2-(2-cyclopropylpyridin-3-yl)-2-(methylsulfonyloxy)acetate

[0571] To a solution of ethyl 2-(2-cyclopropylpyridin-3-yl)-2-hydroxyacetate(300 mg, 1.36mmol) and triethylamine (411mg, 4. Immol) in DCM (5mL) at 0°C was added MsCl(232mg, 2mmol). The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and purified by silica gel column (pet ether: EtOAc 4: 1) to get the desired product ethyl 2-(2-cyclopropylpyridin- 3-yl)-2-(methylsulfonyloxy)acetate as a yellow oil (190 mg). Yield 47% (ESI 300 (M+H) +).

[0572] 85

[0573] Foley HoagUS13043895.1 MTX-03225

[0574] Method R2: methyl 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (used in the synthesis of Examples 7, 10, 26, 28, 43)

[0575] Step 1: methyl 2-(2-bromo-5-fluorophenyl)acetate

[0576] To a solution of 2-(2-bromo-5-fluorophenyl) acetic acid (10g, 43 mmol) in 60 mL MeOH was added 0.5 mL H2SO4. The mixture was refluxed for 4 hours, allowed to cool to room temperature and concentrated under reduced pressure. The resulting pale yellow oil (10 g, 94.3%) was used without any further purification. (ESI 246.1 (M+H)+)

[0577] Step 2: methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fhiorophenyl)acetate

[0578] 60°C

[0579] To solution of methyl 2-(2-bromo-5-fluorophenyl)acetate (6.3 g, 25.6 mmol) in DMF (60 mL) was added 3,4-dihydro-27 / -pyran-6-boronic acid pinacol ester (5 g, 23.8 mmol), tris(dibenzylideneacetone) dipalladium (0) (468 mg, 0.52 mmol), X-Phos (238 mg, 0.52 mmol), and potassium phosphate (2.1g, 25.6 mmol). The mixture was stirred at 60 °C for 12 hours under N2. The mixture was allowed to cool to room temperature an partitioned between ethyl acetate (120 mL) and water (120 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (60 mL X 3). The combined organic phases were washed with brine and dried over anhydrous ISfeSCL. After filtration and concentration, the residue was chromatographed (Combiflash), using 0-20% EtOAc / petroleum ether as eluent, to give methyl 2- (2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (5.2g, 87.4%). (ESI 251.1(M+H)+)

[0580] Foley HoagUS13043895.1 MTX-03225

[0581] Step 3: methyl 2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0582] To a solution of methyl 2-(2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (500 mg, 2 mmol) in 25ml anhydrous MeOH was added diisopropylethylamine ( 0.5ml ) and Pd / C (100 mg). The mixture was stirred for 3 hours at 40 °C under H2 (balloon). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (Combiflash), using 0-20% EtOAc / petroleum ether as eluent, to give methyl 2- (2-(3,4-dihydro-2H-pyran-6-yl)-5-fluorophenyl)acetate (260 mg, 52%) as an oil. (ESI 253.1(M+H)+)

[0583] Step 4: methyl 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate

[0584] LDA (1.25ml, 2.5mmol, 2M in THF) was added to a solution of methyl 2-(5-fluoro-2-(tetrahydro- 2H-pyran-2-yl)phenyl)acetate (260 mg, 1.03 mmol) in 10 mL THF at -78°C under N2. The reaction was stirred for 0.5 h and TMSC1 (324 mg, 3 mmol) was added. After an additional 0.25 h a solution of NBS (534 mg, 3 mmol) in 10 mL THF was added and reaction was stirred for 0.5 h at -78°C. The mixture was allowed to warm to room temperature and diluted with water (10 mL). The mixture was extracted with ethyl acetate (30 mL X3) and the combined organic phases were washed with brine and dried over anhydrous Na2S O4. After filtration and concentration, the residue was chromatographed (Combiflash), using 0-20% EtOAc / petroleum ether as eluent, to give methyl

[0585] 87

[0586] Foley HoagUS13043895.1 MTX-03225

[0587] 2-bromo-2-(5-fluoro-2-(tetrahydro-2H-pyran-2-yl)phenyl)acetate (280 mg, 84.8%). (ESI 333.1(M+H)+)

[0588] Method R4: tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate (used in the synthesis of Example 9)

[0589] Step 1: l-(2-bromo-4-fluorophenyl)cyclopropanol

[0590] To a solution of l-(2-bromo-4-fluorophenyl)ethanone (5.0 g, 23.1 mmol) and Et3N (3.51 g, 34.7 mmol) in DCM (50 mL) at 0°C under nitrogen, was added TMSOTf (6.17 g, 27.8 mmol) dropwise via syringe over a period of 10 min. The reaction mixture was stirred at RT overnight, then quenched with saturated NaHCO3 aqueous (20 mL), extracted the aqueous with DCM (2 x 30 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrate in vacuo to obtain crude ether. The crude ether was dissolved in anhydrous DCM (50 mL), added diiodomethane (25.0 g, 92.4 mmol), cooled to 0°C, then added diethyl zinc (IM in THE, 93 mL, 93 mmol) dropwise. The reaction was stirred at RT for 16 hours, then quenched with a saturated solution of NH4C1 (30 mL), extracted with DCM (2*50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrate in vacuo to obtain crude material. The crude material was dissolved in MeOH (20 mL), followed by addition of K2CO3 (3.2 g, 23.1 mmol), then stirred at RT for 30 min. Solven was removed under vacuum, added H2O (20 mL), extracted with EtOAc (2*40 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 5: 1) to afford the desired product l-(2-bromo-4-fluorophenyl)cyclopropanol as a colorless oil (3.1 g). Yield 86% (ESI 213 / 215 [M+H]+).

[0591] Step 2: ethyl 5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate

[0592] Foley HoagUS13043895.1 MTX-03225

[0593] A mixture of l-(2-bromo-4-fluorophenyl)cyclopropanol (100 mg, 0.44 mmol), ethyl 2-bromo-2,2- difluoroacetate (351 mg, 1.74 mmol), Cui (8.2 mg, 0.044 mmol), Phenanthroline (17.2 mg, 0.088 mmol) and K2CO3 (120 mg, 0.88 mmol) in MeCN (5 mb) was stirred at 90°C for 17 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (3*10 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 5: 1) to afford the desired product ethyl 5-(2- bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate as a colorless oil (81 mg). Yield 53% (ESI 353 / 355 [M+H]+).

[0594] Step 3: 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran

[0595] To a solution of ethyl 5-(2-bromo-4-fluorophenyl)-2,2-difluoro-5-oxopentanoate (100 mg, 0.28 mmol) in MeOH (5 mL) at 0°C was added NaBH4 (44 mg, 1.12 mmol). The reaction solution was stirred at RT for 15 hours. Solven was removed under vacuum, added H2O (10 mL), extracted with DCM (3*10 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in DCM (3 mL) and triflic acid (100 mg, 0.32 mmol) was added. The reaction was stirred at RT for 15 hours, then quenched by sat. aq. NaHCO3 (5 mL), extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10: 1) to give the desired product 2-(2-bromo-4-fluorophenyl)-5,5- difhiorotetrahydro-2H-pyran a colorless oil (40 mg). Yield 47% (ESI 297 / 299 [M+H]+).

[0596] Step 4: tert-butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate

[0597] A mixture of 2-(2-bromo-4-fluorophenyl)-5,5-difluorotetrahydro-2H-pyran (800 mg, 2.93 mmol),

[0598] 89

[0599] Foley HoagUS13043895.1 MTX-03225

[0600] (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (0.5 M in THF, 30 mL, 15 mmol), Pd2(dba)3 (152 mg, 0.15 mmol) and Q-phos ( 105 mg, 0.15 mmol) in THF (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was poured into sat. NaHCO3 solution (20 mL) and EtOAc (30 mL). The mixture was filtered, the organic layer was washed with brine, dried over Na2SO4, 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-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5- fluorophenyl)acetate as a red oil (703 mg). Yield 78% (ESI 275 [M+H-tBu]+).

[0601] Step 5: tert-butyl 2-bromo-2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-

[0602] To a solution of tert- butyl 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)acetate (703 mg, 2.12 mmol) in THF (5 mL) at -78°C, was added lithium diisopropylamide solution (2M, 2.65 mL, 5.3 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then a solution of chlorotrimethylsilane (573 mg, 5.3 mmol) in THF (ImL) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (944 mg, 5.3 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), solvent was removed 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-(5,5-difluorotetrahydro-2H- pyran-2-yl)-5-fluorophenyl)acetate as a red oil (816 mg). Yield 66% (ESI 352 / 354 [M+H-tBu]+).

[0603] Method R5: ethyl 2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate (Example 13, 49)

[0604] Step 1: 3-bromo-2-cyclobutylpyridine

[0605] Amixture of magnesium turnings (612 mg, 25.5 mmol) and cyclobutyl bromide (3.4g, 25.5 mmol) in anhydrous THF(50mL) was heated for 3 hours at 60 °C until complete dissolution of the

[0606] 90

[0607] Foley HoagUS13043895.1 MTX-03225 magnesium. The solution was cooled to -78 °C and treated with ZnC12 (3.48g, 25.5 mmol) in THF (50mL). The resulting white suspension was warmed gradually to room temperature and stirred for 1 hour. Then a solution of 2,3-dibromopyridine (4g, 17 mmol) and Pd(PPh3)4 (983 mg, 0.85 mmol) in THF (30mL) was added to the reaction. The mixture was stirred at 60 °C for 1 hour under N2, then diluted with water (lOOmL) and extracted with EtOAc (3x 50mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc=10: l) to give the desired product 3-bromo-2- cyclopropylpyridine as a yellow oil (2.3g). Yield 94% (ESI 212(M+H) +).

[0608] Step 2: ethyl 2-(2-cyclobutylpyridin-3-yl)-2-hydroxyacetate

[0609] To a solution of EtMgBr (IM, 6.54mL, 6.54 mmol) in THF (20mL) at 0° C under N2 was added n-BuLi (2.5M, 5.2mL,13.08 mmol). The solution was stirred at 0°C for 30 min, then a solution of 3-bromo-2-cyclobutylpyridine (2.3 g, 10.9 mmol) in THF (5mL) was added at -10°C. The mixture was stirred at that temperature for 30 min. Then ethyl 2-oxoacetate (50% in toluene, 8.9 g, 43.6 mmol) was added, and the reaction was stirred at 0 °C for 2 hours, then poured into 20 mL of a saturated K2CO3 solution and extracted with EtOAc (3x 50mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc=2: l) to give the desired product ethyl 2-(2-cyclopropylpyridin-3- yl)-2-hydroxyacetate as a yellow oil (1.1g). Yield 43% (ESI 236(M+H) +).

[0610] Step 3: ethyl 2-chloro-2-(2-cyclobutylpyridin-3-yl)acetate

[0611] Foley HoagUS13043895.1 MTX-03225

[0612] A solution of ethyl 2-(2-cyclobutylpyridin-3-yl)-2-hydroxyacetate (480 mg, 2 mmol) in SOC12 (5mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo, adjusted to pH=8 with aq NaHCO3 and extracted with EtOAc (3x 20mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc=10:l) to give the desired product ethyl 2-chloro-2-(2- cyclobutylpyridin-3-yl)acetate as a yellow oil (310 mg). Yield 47% (ESI 254(M+H) +).

[0613] Method R7: tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate (used in the synthesis of Examples 15, 29)

[0614] Step 1: cyanomethyl 2-bromo-4-fluorobenzoate

[0615] To a solution of 2-bromo-4-fluorobenzoic acid (5.0 g, 0.23 mol) in dry DCM (20 mL) at 0°C was added triethylamine (9.2 g, 0.69 mol) and chloroacetonitrile (3.5 g, 0.46 mol). The reaction was then heated to reflux and stirred overnight. After cooling to room temperature, the reaction mixture was washed successively with aqueous HC1 (2M, 20 mL) and sat. NaHCO3 solution (20 mL). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the desired product cyanomethyl 2-bromo-4-fluorobenzoate as a pale yellow oil (4.0 g). Yield 68% (ESI 258 / 260 [M+H]+).

[0616] Step 2: l-(2-bromo-4-fluorophenyl)-5-hydroxypentane-l, 4-dione

[0617] To a solution of cyanomethyl 2-bromo-4-fluorobenzoate (3.4 g, 13.2 mmol) and Ti(OiPr)4 (4.15g , 14.6 mmol) inEt2O (70 mL) at 0°C under argon, was added EtMgBr (28ml, 28 mmol, IM in THF) dropwise. After the addition of the Grignard reagent, the mixture was warmed to RT and stirred for 1 hour. The turbid yellow mixture was quenched with water (10 mL), then IM HC1 (30 mL) were added, extracted with EtOAc (3*50 mL). The combined organic phases were washed with 92

[0618] Foley HoagUS13043895.1 MTX-03225 saturated aqueous NaHC03 and dried (MgSO4). After evaporation of the solvents, the residue was purified by silica gel column (pet ether: EtOAc 3:1) to afford the desired product l-(2-bromo-4- fluorophenyl)-5-hydroxypentane- 1,4-dione (901 mg) as a colorless oil. Yield 25% (ESI 289 / 271 [M+H]+).

[0619] Step 3: 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol

[0620] To a solution of l-(2-bromo-4-fluorophenyl)-5-hydroxypentane- 1,4-dione (900 mg, 3.13 mmol) in DCM (40 mL) at 0°C was added Boron trifluroide (diethyl ether complex, 1110 mg, 7.8 mmol) dropwise. After the addition, tri ethylsilane (910 mg, 7.8 mmol) was added and the reaction was stirred at 0°C for 1 hour. The reaction mixture was quenched with sat. NaHCO3 (20 mL), extracted with DCM (2*50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 3: 1) to give the desired product 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol as a colorless oil (650 mg). Yield 80% (ESI 275 / 277 [M+H]+).

[0621] Step 4: 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one

[0622] To a solution of 6-(2-bromo-4-fluorophenyl)tetrahydro-2H-pyran-3-ol (100 mg, 0.37 mmol) in DCM (5 mL) was added Dess-Martin Periodonane (150 mg, 0.50 mmol) in several portions. After the addition, the reaction mixture was stirred RT for 2 hours, then quenched with a solution of saturated NaHCO3 (5 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to afford the desired product 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one as a colorless oil (20 mg). Yield 20% (ESI 273 / 275 [M+H]+).

[0623] Step 5: 2-(2-bromo-4-fluorophenyl)-5-methylenetetrahydro-2H-pyran

[0624] 93

[0625] Foley HoagUS13043895.1 MTX-03225

[0626] To a solution of methyltriphenylphosphonium bromide (134 mg, 0.52 mmol) in THF (3 mL) at 0°C, n-BuLi (2.5M in hexane, 0.21 mL, 0.52 mmol) was added and the reaction was stirred at 0°C for 30 minutes, then added a solution of 6-(2-bromo-4-fluorophenyl)dihydro-2H-pyran-3(4H)-one (70 mg, 0.26 mmol) in THF (2 mL). The reaction was stirred at room temperature for 12 hours, quenched with sat. aq. NH4C1 and extracted with DCM (2*10 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10: 1) to afford the desired product 2-(2-bromo-4- fhrorophenyl)-5-methylenetetrahydro-2H-pyran as a colorless oil (51 mg, 70% yield). 1H NMR

[0627] (400 MHz, CDC13) 8 7.52 - 7.50 (m, 1H), 7.27-7.25 (m, 1H), 7.05-7.01 (m, 1H), 4.89-4.88 (m, 2H), 4.75-4.73 (m, 1H), 4.37-4.34 (m, 1H), 4.20- 4.17 (m, 1H), 2.50- 2.46 (m, 2H), 2.15-2.10 (m, 1H), 1.52-1.50 (m, 1H).

[0628] Step 6: 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5] octane

[0629] To a solution of ZnEt2 (IM in THF, 6mL, 6.0 mmol) in DCM (20 mL) at 0°C was added TFA(690 mg, 6.0 mmol). The reaction was stirred at 0°C for 0.5 hour, then CH2I2 (1.7 g, 6.0 mmol) was added dropwise. The reaction was stirred at 0°C for 0.5 hour, then 2-(2-bromo-4-fluorophenyl)-5- methylenetetrahydro-2H-pyran(280 mg, 1.0 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at rt for 2 hours, quenched with sat. NaHCO3 solution (20 mL), and the DCM layer was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 50:1) to give the desired product 6-(2-bromo-4-fluorophenyl)- 5-oxaspiro[2.5] octane as a yellow oil (250 mg). Yield 80% (ESI 267 / 269 [M+H-H2OJ+).

[0630] Step 7: tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate

[0631] 94

[0632] Foley HoagUS13043895.1 MTX-03225

[0633] A mixture of 6-(2-bromo-4-fluorophenyl)-5-oxaspiro[2.5]octane (250 mg, 0.88 mmol), (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution 0.5 M in THF (10 mL, 5 mmol), Pd2(dba)3 (40 mg, 0.05mmol) and Q-phos ( 31 mg, 0.05mmol) in THF (2 mL) was stirred at 80°C for 2 hours. Then the mixture was poured into sat. NaHC03 solution (50 mL) and EtOAc (60 mL). The mixture was filtered, the organic layer was washed with brine, dried over Na2SO4, 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-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate as a red oil (160 mg). Yield 53% (ESI 343 [M+Na]+).

[0634] Step 8: tert-butyl 2-bromo-2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate

[0635] To a solution of tert-butyl 2-(5-fluoro-2-(5-oxaspiro[2.5]octan-6-yl)phenyl)acetate (160 mg, 0.5 mmol) in THF (5 mL) at -78°C, was added lithium diisopropylamide solution 2.0 M in THF / hexanes (0.62 mL, 1.25 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then a solution of chlorotrimethylsilane (135 mg, 1.25 mmol) in THF (ImL) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (221 mg, 1.25 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), solvent was removed 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-(5-fluoro-2-(5- oxaspiro[2.5]octan-6-yl)phenyl)acetate as a colorless oil (130 mg). Yield 60% (ESI 419 / 421 [M+Na]+).

[0636] Method R8: tert-butyl 2-bromo-2-(5-fluoro-2-((S)-2,9-dioxaspiro[5.5]undecan-3- yl)phenyl)acetate stereoisomer A (used in the synthesis of Example 16)

[0637] 95

[0638] Foley HoagUS13043895.1 MTX-03225

[0639] Step 1: ethyl 4-(biit-3-en-l-yl)tetrahydro-2 / / -pyran-4-carboxylate

[0640] To a solution of diisopropylamine (3.19 mL, 22.8 mmol) in dry tetrahydrofuran (20 mL) under nitrogen atmosphere at -78 °C was added n- butyllithium in hexanes (2.5 M, 7.28 mL, 18.2 mmol). This mixture was stirred for 45 minutes at -78 °C, then ethyl tetrahydropyran-4-carboxylate (2.87 mL, 19.0 mmol) was added dropwise, and the mixture was stirred for 30 minutes at -78 °C. A mixture of 4-bromo-l -butene (2.5 mL, 24.6 mmol) and HMPA (1.85 mL, 10.6 mmol) in dry tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred for five minutes at -78 °C, taken out of the acetone / dry ice bath and stirred in an ice / water bath at 0 °C for 20 minutes, then stirred for 25 minutes at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 3% to 15% diethyl ether in pentane) afforded the desired ethyl 4-(but-3-en-l-yl)tetrahydro-277-pyran-4-carboxylate (3.19 g). Yield 79%.JH NMR (400 MHz, Chloroform- ) 8 5.82 - 5.69 (m, 1H), 5.04 - 4.91 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.53 - 3.39 (m, 2H), 2.14 - 2.05 (m, 2H), 2.02 - 1.92 (m, 2H), 1.66 - 1.59 (m, 2H), 1.55 - 1.45 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0641] Step 2: (4-( but-3-en- 1 -yl)tetrahydro-2 / / -pyran-4-yl (methanol

[0642] To a solution of ethyl 4-(but-3-en-l-yl)tetrahydro-2H-pyran-4-carboxylate (3.17 g, 14.9 mmol) in dry tetrahydrofuran (30 mL) under argon atmosphere at 0 °C was added lithium aluminium hydride in tetrahydrofuran (2,4 M, 6.22 mL, 14.9 mmol). The mixture was stirred at room temperature for 1 hour and quenched by slow addition of ethyl acetate (20 mL). The mixture was washed with IM

[0643] 96

[0644] Foley HoagUS13043895.1 MTX-03225 hydrochloric acid, the layers were separated and the water layer was extracted with ethyl acetate. The combined organic layers were washed with IM hydrochloric acid and brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 15% to 50% ethyl acetate in heptane afforded the desired product (4-(but-3-en- l -yl)tetrahydro-2 / 7-pyran-4- yl)methanol (2.21 g). Yield 87%. *H NMR (400 MHz, Chloroform- ) 8 5.91 - 5.78 (m, 1H), 5.10 - 4.92 (m, 2H), 3.76 - 3.60 (m, 4H), 3.53 (s, 2H), 2.09 - 1.98 (m, 2H), 1.59 - 1.48 (m, 4H), 1.48 - 1.40 (m, 2H), 1.36 (br. s, 1H).

[0645] Step 3: (4-(but-3-en-l-yl)tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate

[0646] To a solution of (4-(but-3-en-l-yl)tetrahydro-277-pyran-4-yl)methanol (1.75 g, 10.3 mmol) in di chloromethane (39 mb) at 0 °C was added pyridine (2.5 mL, 30.9 mmol) and p-toluenesulfonyl chloride (3.14 g, 16.5 mmol). The reaction mixture was stirred at room temperature for 4 days, concentrated in vacuo, diluted saturated aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 10 to 30% ethyl acetate in heptane) afforded the desired product (4-(but-3-en-l-yl)tetrahydro-2H-pyran-4- yl)methyl 4-methylbenzenesulfonate (3.15 g). Yield 94%. 'H NMR (400 MHz, Chloroform-<7) 8 7.84 - 7.75 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.78 - 5.64 (m, 1H), 5.00 - 4.89 (m, 2H), 3.88 (s, 2H), 3.67 - 3.47 (m, 4H), 2.46 (s, 3H), 1.90 - 1.79 (m, 2H), 1.56 - 1.47 (m, 2H), 1.44 (t, J = 5.6 Hz, 4H).

[0647] Step 4: (4-(3-oxopropyl)tetrahydro-2Tf-pyran-4-yl)methyl 4-methylbenzenesulfonate

[0648] Foley HoagUS13043895.1 MTX-03225

[0649] To a solution of (4-(but-3-en-l-yl)tetrahydro-277-pyran-4-yl)methyl 4-methylbenzenesulfonate (3.15 g, 9.70 mmol) in tetrahydrofuran (74 mL) and water (24 mL) was added sodium periodate (5.19 g, 24.3 mmol) and osmium tetroxide solution (4 wt% in water, 9.9 mg, 0.04 mmol). The mixture was stirred at room temperature for 1.5 hours, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. This afforded the desired product (4-(3-oxopropyl)tetrahydro-2 / 7- pyran-4-yl)methyl 4-methylbenzenesulfonate (3.17 g). Yield 100%.JH NMR (400 MHz, Chloroform- ) 8 9.73 (d, J = 1.7 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.87 (s, 2H), 3.70 - 3.57 (m, 2H), 3.57 - 3.46 (m, 2H), 2.47 (s, 3H), 2.36 - 2.25 (m, 2H), 1.84 - 1.72 (m, 2H), 1.50 - 1.36 (m, 4H).

[0650] Step 5: (4-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate

[0651] To a solution of 2-bromo-4-fluoroiodobenzene (1.66 mL, 12.8 mmol) in dry toluene (80 mL) at - 18 °C under argon atmosphere was added isopropylmagnesium chloride (2M in THF, 6.37 mL, 12.7 mmol). After stirring for 20 minutes, a solution of (4-(3-oxopropyl)tetrahydro-2 / 7-pyran-4- yl)methyl 4-methylbenzenesulfonate (3.2 g, 9.8 mmol) in dry tetrahydrofuran (50 mL) was added. The mixture was allowed to come to room temperature overnight, then quenched by pouring it into

[0652] 98

[0653] Foley HoagUS13043895.1 MTX-03225 saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 15% to 55% ethyl acetate in heptane) afforded the desired product (4-(3-(2-bromo-4-fluorophenyl)-3 -hydroxypropy l)tetrahydro-2 / 7-pyran-4-y l)methyl 4- methylbenzenesulf onate (3.1 g). Yield 63%.JH NMR (400 MHz, Chloroform-<7) 87.78 (d, J = 8.0 Hz, 2H), 7.54 - 7.46 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.31 - 7.23 (m, 1H), 7.11 - 7.01 (m, 1H), 4.98 - 4.89 (m, 1H), 3.86 (s, 2H), 3.65 - 3.47 (m, 4H), 2.45 (s, 3H), 2.10 (d, J = 4.0 Hz, 1H), 1.80 - 1.36 (m, 8H).

[0654] Step 6: 3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane

[0655] To a solution of (4-(3-(2-bromo-4-fluorophenyl)-3-hydroxypropyl)tetrahydro-27 / -pyran-4- yl)methyl 4-methylbenzenesulfonate (3.1 g, 6.2 mmol) in dry tetrahydrofuran (250 mb) under argon atmosphere at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.37 g, 9.3 mmol). The mixture was stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 2% to 12% ethyl acetate in heptane) afforded the desired product 3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane (844 mg). Yield 42%. 'H NMR (400 MHz, Chloroform- ) 8 7.54 - 7.47 (m, 1H), 7.29 - 7.22 (m, 1H), 7.09 - 7.00 (m, 1H), 4.64 - 4.50 (m, 1H), 4.10 - 4.02 (m, 1H), 3.80 - 3.57 (m, 4H), 3.36 (d, J = 11.5 Hz, 1H), 2.02 - 1.83 (m, 3H), 1.77 - 1.67 (m, 1H), 1.60 - 1.44 (m, 2H), 1.43 - 1.31 (m, 2H).

[0656] Aracemic mixture of 3-(2-bromo-4-fluorophenyl)-2,9-dioxaspiro[5.5]undecane (1.165 gram) was separated by chiral preparative SFC. Apparatus: Waters Prep 100 SFC UV / MS directed system;

[0657] 99

[0658] Foley HoagUS13043895.1 MTX-03225

[0659] Waters 2998 Photodiode Array (PDA) Detector; Waters Acquity QDa MS detector; Waters 2767 Sample Manager; Column: Phenomenex Lux Amylose- 1 (250x21mm, 5pm), column temp: 35°C; flow: 100 mL / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Isopropanol; Isocratic method: 5% B for 4 min; Loading: 25 mg; Detection: PDA (210-400 nm); fraction collection based on PDA TIC.

[0660] The first eluting fraction (stereoisomer A, 0.43 g) was isolated as a white solid, yield 37%. RT: 1.44 min, 100% ee. Apparatus: Waters Acquity UPC2System; Column: Phenomenex Amylose- 1 (100x4.6mm, 5pm), column temp: 35°C; flow: 2.5 mL / min; BPR: 170 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Isopropanol; Gradient method: t=0 min 5% B, t=5 min 15% B, t=6 min 15% B. Detection: PDA (210-320 nm). The second eluting fraction (stereoisomer B, 0.43 g) was isolated as a white solid, yield 37%. RT: 1.96 min, 96% ee. Apparatus: Waters Acquity UPC2System; Column: Phenomenex Amylose-1 (100x4.6mm, 5pm), column temp: 35°C; flow: 2.5 mL / min; BPR: 170 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Isopropanol; Gradient method: t=0 min 5% B, t=5 min 15% B, t=6 min 15% B. Detection: PDA (210-320 nm).

[0661] Step 7: (-)-tert-butyl 2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate stereoisomer A

[0662] An oven dried flask was charged with zinc dust (0.342 g, 5.22 mmol) and heated with a heat gun under an argon flow. After cooling to room temperature, dry tetrahydrofuran (6 mL) was added followed by 1,2- dibromoethane (0.011 mL, 0.13 mmol). The mixture was heated to reflux and cooled to room temperature 3 times. Then, trimethylsilyl chloride (0.017 mL, 0.13 mmol) was added which caused the mixture to reflux spontaneously and the zinc to change morphology. After

[0663] 100

[0664] Foley HoagUS13043895.1 MTX-03225 stirring for 20 minutes, tert-butyl bromoacetate (0.38 mb, 2.61 mmol) was added drop wise, resulting in an exotherm. The mixture was kept at an elevated temperature (45 °C) for 30 minutes and then allowed to cool to room temperature. A separate flask was charged with 3-(2-bromo-4- fluorophenyl)-2,9-dioxaspiro[5.5]undecane stereoisomer A (0.43 g, 1.31 mmol), tri-tert- butylphosphine tetrafluoroborate (0.038 g, 0.13 mmol) and bis-(dibenzylideneacetone)palladium (0.075 g, 0.13 mmol). The reaction vessel was flushed with argon, dry tetrahydrofuran (6 mb) was added and argon was bubbled through for five minutes. The zincate solution was added by syringe, and the reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature overnight, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 0% to 15% ethyl acetate in heptane) afforded the desired product (-) -tert-butyl 2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3- yl)phenyl)acetate stereoisomer A (251 mg). Yield 53%.JH NMR (400 MHz, Chloroform-<7) 87.45 - 7.38 (m, 1H), 7.01 - 6.91 (m, 2H), 4.42 (dd, J = 11.3, 2.4 Hz, 1H), 4.03 (dd, J = 11.4, 2.7 Hz, 1H), 3.78 - 3.49 (m, 6H), 3.32 (d, J = 11.4 Hz, 1H), 2.04 - 1.58 (m, 5H), 1.53 - 1.23 (m, 12H). Specific Optical Rotation: -41.2°, c=0.3, CHCh, 20.3 °C, 589 nm.

[0665] Step 8: tert-butyl 2-bromo-2-(5-fluoro-2-((S)-2,9-dioxaspiro[5.5]undecan-3- yl)phenyl)acetate stereoisomer A

[0666] To a solution of tert-butyl 2-(5-fluoro-2-(2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)acetate stereoisomer A (110 mg, 0.32 mmol) in THF (3 mb) at -78 °C, was added lithium diisopropylamide solution 2.0 M in THF / hexanes (0.32 mb, 0.64 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (70 mg, 0.64 mmol) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (114 mg, 0.64 mmol) in THF (2 mb) was added and the reaction was stirred at -78°C for 1 hour. The reaction was quenched with MeOH (2 mb), solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: 101

[0667] Foley HoagUS13043895.1 MTX-03225

[0668] EtOAc 10: 1) to give the desired product tert-butyl 2-bromo-2-(5-fluoro-2-(2,9- dioxaspiro[5.5]undecan-3-yl)phenyl)acetate stereoisomer A as a yellow oil (120 mg). Yield 85% ( ESI 465.0 (M+Na) +).

[0669] Method R9: tert-butyl 2-bromo-2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4- yloxy)phenyl)acetate (Example 52)

[0670] Step 1: 2-cyclopropyl-3-nitrophenol

[0671] 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-cy cl opropyl-3 -nitrophenol as a colorless oil (6.4 g). Yield 77% (ESI 180.0 (M+H) +).

[0672] Step 2: 4-(2-cyclopropyl-3-nitrophenoxy)tetrahydro-2H-pyran

[0673] To a mixture of 2-cy cl opropyl-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) +).

[0674] Step 3: 2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)aniline

[0675] 102

[0676] Foley HoagUS13043895.1 MTX-03225

[0677] To a mixture of 2-cyclopropyl-l-isopropoxy-3-nitrobenzene (3.7 g, 14.1 mmol) and NH4CI (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 Na2SC>4, 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) +).

[0678] Step 4: 4-(3-bromo-2-cyclopropylphenoxy)tetrahydro-2H-pyran

[0679] 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) +).

[0680] Step 5: tert-butyl 2-(2,4-dicyclopropylpyrimidin-5-yl)acetate

[0681] 103

[0682] Foley HoagUS13043895.1 MTX-03225

[0683] I. A mixture of l-bromo-2-cyclopropyl-3-isopropoxybenzene (480 mg, 1.62 mmol), (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution (13 mb, 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) +).

[0684] Step 6: tert-butyl 2-bromo-2-(2-cyclopropyl-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)acetate

[0685] IL 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) +).

[0686] Method R10: methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate

[0687] Step 1: methyl 2-(2-(furan-2-yl)phenyl) acetate

[0688] 104

[0689] Foley HoagUS13043895.1 MTX-03225

[0690] To a solution of methyl 2-(2-iodophenyl)acetate (552 mg, 2 mmol) in 5 mL dry DMF was added furan-2-ylboronic acid (224 mg, 2 mmol), tris(dibenzylideneacetone) dipalladium (0) (91.5 mg, 0.1 mmol), X-Phos (47.6 mg, 0.1 mmol), and potassium phosphate (424 mg, 2 mmol). The mixture was stirred at 60 °C for 1 hour under N2. The reaction was allowed to cool and diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times (20 mL X 2). The combined organic layer was washed with brine and dried over anhydrous Na2SO-i. After filtration and concentration, the residue was chromatographed (Combiflash), using 5-20% EtOAc / petroleum ether as eluent, to give methyl 2- (2-(furan-2-yl)phenyl) acetate 340 mg (78.3 %); (ESI 217 (M+H)+).

[0691] Step 2: methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate

[0692] To a solution of methyl 2-(2-(furan-2-yl) phenyl) acetate (340 mg, 1.57 mmol) in 10ml anhydrous MeOH was added Pd / C (30 mg). The mixture was stirred for 3 hours at 40°C under H2 atmosphere (balloon). After the reaction was over, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (Combiflash), using 5- 20% EtOAc / petroleum ether as eluent, to give methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (290 mg, 84 %) as an oil. (ESI 221(M+H)+)

[0693] Step 3: methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate

[0694] 105

[0695] Foley HoagUS13043895.1 MTX-03225

[0696] A solution of methyl 2-(2-(tetrahydrofuran-2-yl)phenyl)acetate (220 mg, 1 mmol) in 10 mb THF under N2 was cooled to -78°C and treated with LDA (1.25 mb, 2.5 mmol, 2M in THF). The reaction was stirred for 0.5 h, treated with TMSCI (324 mg, 3 mmol) and, after 0.25 h, NBS (534 mg, 3 mmol) as a solution in 10 mb dry THF. The mixture was stirred for 0.5 h at -78°C and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mb X 2). The combined organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration and concentration, the residue was chromatographed (Combiflash), using 0-20% EtOAc / petroleum ether as eluent, to give methyl 2-bromo-2-(2-(tetrahydrofuran-2-yl)phenyl) acetate (210 mg, 70.5%); (ESI 299 (M+H)+)

[0697] Method Rll: 2-cyclopropyl-5-fluorophenylboronic acid (synthesis of Examples 21, 32)

[0698] Step 1: 2-cyclopropyl-5-fluoroaniline r K3PO4, toluene

[0699] A mixture of 2-bromo- 5 -fluoroaniline (3.0 g, 15.8 mmol), cyclopropylboronic acid (2.7 g, 31.4 mmol), PCy3 (440 mg, 1.57 mmol), Pd(OAc)2 (352 mg, 1.57 mmol) andK3PO4 (20 g, 94.3 mmol) in toluene (50mL) and H2O (10 mb) was stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with H2O (lOmL) and extracted with EtOAc (3 x 100 mb). The combined organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 2: 1) to afford the desired product as a colorless oil (1.8 g). Yield 75% (ESI: 152[M+H]+ ).

[0700] Step 2: l-cyclopropyl-4-fluoro-2-iodobenzene

[0701] 106

[0702] Foley HoagUS13043895.1 MTX-03225

[0703] 2-cyclopropyl-5-fluoroaniline (1.8 g, 11.9 mmol) was added to a solution of para-toluene sulfonic acid monohydrate (6.8 g, 35.8 mmol) in acetonitrile (60mL). The reaction was stirred for 10 minutes at room temperature and then cooled to 10 °C. A solution of sodium nitrite (2.0 g, 29.0 mmol) and potassium iodide (4.0 g, 24.1 mmol) in water (20mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 4 hours, then basified to pH 9- 10 with aqueous sodium bicarbonate, then diluted with EtOAc (100 mL) and 10% aqueous sodium metabisulphite (20mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). Organics were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10: 1) to afford the desired product as a colorless oil (1.3g). Yield 42% (ESI: N / A).

[0704] Step 3: 2-cyclopropyl-5-fluorophenylboronic acid

[0705] To a solution of l-cyclopropyl-4-fluoro-2-iodobenzene (1.3g, 4.96 mmol) in THF (50 mL) was added n-BuLi (2.5M, 2.2mL, 5.5 mmol) dropwise. The reaction was stirred for 1 h at -78 °C under Ar. A solution of trimethyl borate (1.0g, 9.62 mmol) in THF (10 mL) was added dropwise, and the reaction was stirred for another 1 hour at -78 °C, then slowly warmed to room temperature and stirred overnight. Aqueous HC1 (IN, 20 mL) was added, and the mixture was stirred at room temperature for 30 min, then extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc =1 : 1) to give the desired product as a white solid (500 mg). Yield: 56% (ESI: 179[M-H]-).

[0706] Method R12: tert-butyl 2-bromo-2-(2-cyclopropyl-3-methoxyphenyl)acetate (Examples 35,

[0707] 107

[0708] Foley HoagUS13043895.1 MTX-03225

[0709] 36, 37, 46)

[0710] Step 1: 2-cyclopropyl-3-methoxyaniline

[0711] 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) +).

[0712] Step 2: 2-cyclopropyl-l-iodo-3-methoxybenzene

[0713] 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 (IM). 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-l-iodo-3- methoxybenzene as a pale yellow oil (500 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) 87.41 (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).

[0714] Step 3: tert-butyl 2-(2-cyclopropyl-3-methoxyphenyl)acetate

[0715] 108

[0716] Foley HoagUS13043895.1 MTX-03225

[0717] " O °^

[0718] \ / Q-phos,Pd2B(duba)3

[0719] A mixture of 2-cyclopropyl-l-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) +).

[0720] Step 4: tert-butyl 2-bromo-2-(2-cyclopropyl-3-methoxyphenyl)acetate

[0721] 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) +).

[0722] Method R13: tert-butyl 2-bromo-2-(3-chloro-2-cyclopropylphenyl)acetate (used in the synthesis of Example 51)

[0723] Step 1: l-bromo-3-chloro-2-cyclopropylbenzene

[0724] 109

[0725] Foley HoagUS13043895.1 MTX-03225 — B(OH)2

[0726] To a mixture of l-bromo-3-chloro-2-iodobenzene (20 g, 63.02 mmol, 1 eq) and cyclopropylboronic acid (7.04 g, 81.93 mmol, 1.3 eq) in dioxane (200 mL) and H2O (20 mL) was added Cs2CO2(61.60 g, 189.07 mmol, 3 eq) and Pd(dppf)Cl2(2.31 g, 3.15 mmol, 0.05 eq) in one portion at 25°C under N2. The mixture was stirred at 80°C for 12 hrs. The mixture was filtered and H2O (55 mL) was added into the filtrate. The layers were separated and the aqueous phase was extracted with ethyl acetate (55 mL x 3). The combined organic phase was washed with brine (50 mL x 1), dried with anhydrous Na2SO-i, filtered and concentrated under reduced pressure. The residue was purified by preparative- TLC (SiO2, Petroleum ether / Ethyl acetate = 10 / 1, Rfpi = 0.70) to give the title compound (900 mg, 3.89 mmol, 40.1% yield) as an oil. ' H NMR (400 MHz, chloroform-d) 8 ppm 0.79 (q, J=5.62 Hz, 2 H) 1.16 - 1.24 (m, 2 H) 1.73 - 1.83 (m, 1 H) 7.00 (t, .7=8.01 Hz, 1 H) 7.31 (d, 7=7.95 Hz, 1 H) 7.47 (d, 7=8.07 Hz, 1 H)

[0727] Step 2: tert-butyl 2-(3-chloro-2-cyclopropylphenyl)acetate

[0728] To a solution of Zn (2.4 g, 36.7 mmol, 1.7 eq) in THF (44 mL) was added TMSCI (0.23 g, 2.16 mmol, 0.1 eq) at 20°C, and then the mixture was stirred at 20°C for 0.5 hrs. Tert-butyl 2- bromoacetate (4.21 g, 21.59 mmol, 1 eq) was added to the mixture at 20°C and the mixture was stirred at 20°C for 16 hrs. To the above solution, l-bromo-3-chloro-2-cyclopropylbenzene (1 g, 4.32 mmol, 1 eq) and Pd(t-Bu2P)2(220.74 mg, 431.93 umol, 0.1 eq) in THF (10 mL) was added at 10°C. The mixture was stirred at 60°C for 4 hrs. The mixture was filtered and H2O (50 mL) was added into the filtrate. The layers were separated and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50mL x 1), dried with anhydrous NazSCL, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiCL, Petroleum ether / Ethyl acetate = 1 / 1) to give the title compound (400 mg, 1.50 mmol,

[0729] 110

[0730] Foley HoagUS13043895.1 MTX-03225

[0731] 34.72% yield) as an oil. ' H NMR (400 MHz, chloroform-d) 8 ppm 0.78 - 0.88 (m, 2 H) 1.22 - 1.31 (m, 2 H) 1.62 (s, 9 H) 1.83 - 1.97 (m, 1 H) 3.98 (s, 2 H) 7.26 (br s, 1 H) 7.28 - 7.32 (m, 1 H) 7.40 - 7.46 (m, 1 H)

[0732] Step 3: tert-butyl 2-bromo-2-(3-chloro-2-cyclopropylphenyl)acetate

[0733] To a mixture of tert-butyl 2-(3-chloro-2-cyclopropylphenyl)acetate in THF (5 mL) was added LDA (2 M, 674.76 uL, 1.2 eq) at -78°C for 0.5 hrs. To the mixture was added TMSC1 (183.26 mg, 1.69 mmol, 214.09 uL, 1.5 eq) at -78°C for 0.5 hrs. To the mixture was added NBS (400.32 mg, 2.25 mmol, 2 eq) in THF (5 mL) at -78°C for 0.5 hrs. The mixture was quenched with saturated aqueous NH4CI (10 mL) at 0°C. Ethyl acetate (10 mL) was added into the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous IS^SCL, filtered and concentrated in vacuum. The residue was purified by prep-TLC (S1O2, Petroleum ether / Ethyl acetate = 5 / 1) to give the title compound (300 mg, 867.91 umol) as a solid. LCMS; m / z 279 (MH+). ' H NMR (400 MHz, chloroform-d) 8 ppm 0.63 - 0.77 (m, 1 H) 0.79 - 0.96 (m, 1 H) 1.07 - 1.34 (m, 4 H) 1.46 (s, 9 H) 1.74 - 1.85 (m, 1 H) 3.79 - 3.84 (m, 1 H) 3.82 (s, 1 H) 6.25 (s, 1 H) 7.18 - 7.24 (m, 1 H) 7.30 - 7.35 (m, 1 H) 7.62 (d, 7=7.94 Hz, 1 H)

[0734] Method R14: tert-butyl 2-bromo-2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (synthesis of Examples 61 and 63)

[0735] Step 1 : 4-(2-bromo-4,6-difluorophenyl)-3,6-dihydro-2H-pyran

[0736] To a solution of l-bromo-3,5-difluoro-2-iodobenzene (15 g, 47.0 mmol, 1 eq) and 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.81 g, 37.6 mmol, 0.8 eq) in dioxane (150 mL) and H2O (20 mL) was added K2CO3 (13.0 g, 94.1 mmol, 2 eq) and Pd(dppf)C12 (3.44 g,

[0737] 111

[0738] Foley HoagUS13043895.1 MTX-03225

[0739] 4.70 mmol, 0.1 eq). The reaction was stirred at 80°C for 12 h, filtered and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, concentrated under reduced pressure and chromatographed on silica (Petroleum ether: Ethyl acetate = 1 :0 to 50: 1) to give the title compound (3.7 g, 13.5 mmol, 28.6% yield) as an oil. ' H NMR (400 MHz, chloroform-d) 8 = 7.10-7.07 (m, 1H), 6.76-6.67 (m, 1H), 5.64-5.63 (m, 1H), 4.23 (q, J = 2.68 Hz, 2H), 3.86 (t, J= 5.40 Hz, 2H), 2.25-2.21 (m, 2H).

[0740] Step 2: tert-butyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)-3,5-difluorophenyl)acetate

[0741] Two parallel reactions were carried out together. To a suspension of Zn (4.52 g, 69.1 mmol, 10 eq) in THF (30 mL) was added TMSC1 (1.50 g, 13.8 mmol, 2 eq). After the addition, the reaction mixture was stirred at 50°C for 10 min, then tert-butyl 2-bromoacetate (13.5 g, 69.1 mmol, 10 eq) was added at 20°C, and the reaction was stirred at 50°C for 2 hrs, followed by 4-(2-bromo-4,6- difluorophenyl)-3,6-dihydro-2H-pyran (1.9 g, 6.91 mmol, 1 eq) and Pd(t-BusP)2 (353 mg, 691 umol, 0.1 eq) was added, then the reaction was stirred at 60°C for 12 h. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by reversed-phase chromatography to give the title compound (0.9 g, 2.90 mmol, 17.9% yield) as an oil.JH NMR (400 MHz, chloroform-d) 8 = 6.68 (d, J = 9.17 Hz, 1H), 6.60-6.55 (m, 1H), 5.51 (s, 1H), 4.13 (m, 2H), 3.38 (s, 2H), 1.28 (s, 9H).

[0742] Step 3: tert- butyl 2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate

[0743] To a solution of tert-butyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)-3,5-difluorophenyl)acetate (0.9 g, 2.90 mmol, 1 eq) in MeOH (15 mL) was added Pd(OH)2 / C (10%, 1.5 g, 10.7 mmol, 3.68 eq), the reaction was stirred at 80°C for 3 hrs under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to give the title compound (0.7 g, 2.24 mmol, 77.2% yield) as an oil. LCMS: m / z = 257.3 [MH+], 'H NMR (400 MHz, chloroform-d) 8 = 6.72-6.67 (m, 2H), 4.07-4.04 (m, 2H), 3.58 (s, 2H), 3.47-3.41 (m, 2H), 2.67-2.83 (m, 1H), 2.29-2.18 (m, 2H), 1.53 (dd, J= 12.72, 1.75 112

[0744] Foley HoagUS13043895.1 MTX-03225

[0745] Hz, 2H), 1.43 (s, 9H).

[0746] Step 4: tert-butyl 2-bromo-2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate

[0747] To a solution of tert-butyl 2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)acetate (0.7 g, 2.24 mmol, 1 eq) in THF (15 mb) was added LDA (2 M, 1.68 mL, 1.5 eq) at -70°C, after stirred at - 70°C for 30 min, TMSCI (365 mg, 3.36 mmol, 1.5 eq) was added and stirred for another 30min, then a solution of NBS (1.20 g, 6.72 mmol, 3 eq) in THF (15 mL) was addded at -70°C. The resulting reaction mixture was stirred at 25°C for 12 hrs. H2O (10 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 2). The separated organic layer was concentrated and purified by column (Petroleum ether : Ethyl acetate = 10: 1) to give the title compound (0.62 g, 1.58 mmol, 71.9% yield) as colorless-oil.

[0748] Examples for Group 2

[0749] The following intermediates were prepared by the procedure of Example 40, Step 1 or Example 16, Step 1 using the appropriate starting materials:

[0750] The following intermediates were prepared by the procedure of Example 42, Step 1

[0751] Method M43: methyl 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl((lR,3R)- 3-(4-((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (used in the synthesis of Example 43).

[0752] LCMS (ESI); m / z 490 (MH+).

[0753] Method M44: methyl (S)-2-(5-fhroro-2-((R)-tetrahydrofuran-3-yl)phenyl)-2-(methyl((lR,3R)-3- (4-((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (as used in the synthesis of Example 44)).

[0754] 113

[0755] Foley HoagUS13043895.1 MTX-03225

[0756] LCMS (ESI); m / z 512 (MH+).

[0757] Method M45: methyl 2-(5-fluoro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-

[0758] (methyl((lR,3R)-3-(4-((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2- yl)butoxy)cyclobutyl)amino)acetate (as used in the synthesis of Example 45).

[0759] Method M46: methyl 2-(2-cyclopropyl-3-methoxyphenyl)-2-(methyl(czs-3-(4-((S)-l,2,3,4- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (as used in the synthesis of

[0760] Example 46).

[0761] Method M47: methyl 2-(2-cyclopropyl-3-ethoxyphenyl)-2-(methyl(czs-3-(4-((S)-l,2,3,4- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (as used in the synthesis of Example 47).

[0762] Method M48: methyl 2-(2-cyclopropylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro- l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (as used in the synthesis of Example 48).

[0763] 114

[0764] Foley HoagUS13043895.1 MTX-03225

[0765] Table 1.

[0766] 115

[0767] Foley HoagUS13043895.1 MTX-03225

[0768] 116

[0769] Foley HoagUS13043895.1 MTX-03225

[0770] 117

[0771] Foley HoagUS13043895.1 MTX-03225

[0772] 118

[0773] Foley HoagUS13043895.1 MTX-03225

[0774] 119

[0775] Foley HoagUS13043895.1 MTX-03225

[0776] 120

[0777] Foley HoagUS13043895.1 MTX-03225

[0778] 121

[0779] Foley HoagUS13043895.1 MTX-03225

[0780] 122

[0781] Foley HoagUS13043895.1 MTX-03225

[0782] 123

[0783] Foley HoagUS13043895.1 MTX-03225

[0784] Example 1: 2-(2-cyclopropylpyridin-3-yl)-2-(methyl(trans-3-(3-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)propoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0785] Compound 1ALCMS (ESI): m / z 451.2 (MH+); lHNMR (400 MHz, MeOD) 88.38 (s, 1H), 8.00- 7.90 (m, 1H), 7.20-7.10 (m, 2H), 6.34 (d, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.00-3.80 (m, 2H), 3.40- 3.30 (m, 2H), 3.28-3.18 (m, 2H), 2.75-2.65 (m, 2H), 2.63-2.50 (m, 5H), 2.48-2.38 (m, 2H), 2.30- 2.00 (m, 2H), 1.90-1.70 (m, 4H), 1.65-1.50 (m, 1H), 1.30-1.10 (m, 1H), 1.05-0.80 (m, 3H). Chiral SFC J (35% MeOH): ee 100%, Rt = 3.31 mm.

[0786] Compound IB; LCMS (ESI): m / z 451.2 (MH+), 1H NMR (400 MHz, MeOD) 8 8.38-8.36 (m, 1H), 7.96-7.94 (m, 1H), 7.18-7.14 (m, 2H), 6.35 (d, J = 7.2 Hz, 1H), 4.93 (s, 1H), 4.00-3.80 (m, 2H), 3.40-3.30 (m, 2H), 3.28-3.20 (m, 2H), 2.75-2.65 (m, 2H), 2.63-2.50 (m, 5H), 2.48-2.38 (m, 2H), 2.30-2.00 (m, 2H), 1.90-1.70 (m, 4H), 1.65-1.55 (m, 1H), 1.38-1.22 (m, 1H), 1.21-1.18 (m, 1H), 1.10-0.85 (m, 3H). Chiral SFC J (35% MeOH): ee 100%, Rt = 4.42 mm.

[0787] Example 3: 2-(2-cyclopropylpyridin-3-yl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0788] Compound 3A; LCMS (ESI): m / z 465.3 (MH+), 1H NMR (400 MHz, MeOD) 8 8.40-8.38 (m, 1H), 8.05-7.95 (m, 1H), 7.30-7.10 (m, 2H), 6.40 (d, J = 7.2 Hz, 1H), 4.94 (s, 2H), 3.62-3.58 (m, 124

[0789] Foley HoagUS13043895.1 MTX-03225

[0790] 1H), 3.43-3.38 (m, 2H), 2.80-2.70 (m, 2H), 2.62 (s, 4H), 2.58-2.40 (m, 3H), 2.25-2.15 (m, 1H), 2.10-1.80 (m, 5H), 1.75-1.50 (m, 4H), 1.30-0.90 (m, 5H). Chiral SFC B (25% EtOH): ee 100%, Rt = 1.96 min.

[0791] Compound 3B; LCMS (ESI): m / z 465.3 (MH+), 1H NMR (400 MHz, MeOD) 8 8.27-8.22 (m, 1H), 7.95-7.82 (m, 1H), 7.20-7.00 (m, 2H), 6.28 (d, J = 7.6 Hz, 1H), 4.88 (s, 2H), 3.55-3.45 (m, 1H), 3.35-3.25 (m, 2H), 2.65-2.58 (m, 2H), 2.55-2.30 (m, 7H), 2.18-2.00 (m, 1H), 1.98-1.62 (m, 5H), 1.61-1.38 (m, 4H), 1.20-0.80 (m, 5H). Chiral SFC B (25% EtOH): ee 90%, Rt = 2.84 min.

[0792] Example 4: 2-(3-chlorophenyl)-2-(methyl(trans-3-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0793] Compound 4A; LCMS (ESI): m z 444 (MH+), 1H NMR (400 MHz, MeOD) 87.64 (s, 1H), 7.51- 7.38 (m, 3H), 7.23- 7.18 (m, 1H), 6.38 (d, J = 7.2 Hz, 1H), 4.41 - 4.31 (m, 1H), 3.98 - 3.79 (m, 2H), 3.48 - 3.36 (m, 2H), 3.30 - 3.24 (m, 2H), 2.77 - 2.69 (m, 2H), 2.65 - 2.42 (m, 6H), 2.30 - 2.18 (m, 2H), 1.97 - 1.68 (m, 5H). Chiral SFC A (45% MeOH): ee 100%, Rt = 1.47 mm.

[0794] Compound 4B; LCMS (ESI): m / z 444 (MH+), 1H NMR (400 MHz, MeOD) 87.64 (s, 1H), 7.52- 7.38 (m, 3H), 7.19 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 4.39 (s, 1H), 3.88 - 3.79 (m, 2H), 3.47 - 3.37 (m, 2H), 3.30 - 3.24 (m, 2H), 2.78 - 2.70 (m, 2H), 2.63 - 2.41 (m, 6H), 2.37 - 2.20 (m, 2H), 1.94 - 1.70 (m, 5H). Chiral SFC A (45% MeOH): ee 100%, Rt = 2.04 mm.

[0795] Example 5: 2-(2-cyclobutyl-5-fluoropyridin-3-yl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0796] Compound 5A; LCMS (ESI): m / z 497 (MH+). 1H NMR (400 MHz, MeOD) 8 8.31 (d, J = 2.8

[0797] Hz, 1H), 7.35 (d, J = 10.0 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.36 (s,

[0798] 125

[0799] Foley HoagUS13043895.1 MTX-03225

[0800] 1H), 4.03 - 3.99 (m, 1H), 3.51 - 3.30 (m, 5H), 3.02 - 2.99 (m, 1H), 2.66 - 2.48 (m, 4H), 2.36 -

[0801] 2.25 (m, 8H), 1.98 - 1.61 (m, 6H), 1.59 - 1.44 (m, 6H). Chiral SFC F (40% MeOH): ee 100%, Rt

[0802] = 2.69 min.

[0803] Compound 5B; LCMS (ESI): m / z 497 (MH+). 1H NMR (400 MHz, MeOD) 8 8.40 (d, J = 2.8 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H), 4.43 (s, 1H), 4.14 - 4.12 (m, 1H), 3.62 - 3.35 (m, 5H), 3.11 - 3.04 (m, 1H), 2.77 - 2.59 (m, 4H), 2.32 - 2.14 (m, 8H), 2.14 - 1.71 (m, 6H), 1.60 - 1.39 (m, 6H). Chiral SFC F (40% MeOH): ee 100%, Rt = 3.44 min.

[0804] Example 6: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cis-3-(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0805] Compound 6A; LCMS (ESI): m / z 526 (MH+), 1H NMR (400 MHz, MeOD) 87.59-7.50 (m, 2H), 7.22 (d, 7=7.6 Hz, 1H), 7.17-7.15 (m, 1H), 6.40 (d, 7= 7.2 Hz, 1H), 4.80 (d, 7= 9.6 Hz, 1H), 4.66 (s, 1H), 4.12-4.10 (m, 1H), 3.80-3.32 (m, 8H), 2.74-2.50 (m, 8H), 2.03-1.58 (m, 16H).

[0806] Compound 6B; LCMS (ESI): m / z 526 (MH+), 1H NMR (400 MHz, MeOD) 87.45-7.38 (m, 2H), 7.20 (d, 7 =7.2 Hz, 1H), 7.12-7.11 (m, 1H), 6.40 (d, 7= 7.6 Hz, 1H), 5.24 (bs, 1H), 4.68-4.66 (s, 1H), 4.21-4.19 (m, 1H), 3.70-3.32 (m, 8H), 2.74-2.50 (m, 8H), 2.03-1.58 (m, 16H).

[0807] Example 7: 2-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(cis-3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0808] Compound 7A; LCMS (ESI): m / z 526 (MH+), 1H NMR (400 MHz, MeOD) 87.58-7.40 (m, 2H),

[0809] 126

[0810] Foley HoagUS13043895.1 MTX-03225

[0811] 7.25 (d, J = 7.6 Hz, 1H), 7.20-7.10 (m, 1H), 6.42 (d, J = 7.2 Hz, 1H), 4.74 (s, 1H), 4.15-3.98 (m, 2H), 3.78-3.58 (m, 3H), 3.50-3.38 (m, 2H), 3.35-3.25 (m, 3H), 2.74 (t, J = 6.4 Hz, 2H), 2.70-2.50 (m, 6H), 2.30-1.45 (m, 14H).

[0812] Compound 7B; LCMS (ESI): m / z 526 (MH+), 1H NMR (400 MHz, MeOD) 87.55-7.40 (m, 2H), 7.30-7.20 (m, 1H), 7.19-7.10 (m, 1H), 6.45-6.38 (m, 1H), 4.78 (s, 1H), 4.18-4.00 (m, 2H), 3.80- 3.58 (m, 3H), 3.50-3.38 (m, 3H), 3.25-3.10 (m, 2H), 2.80-2.70 (m, 2H), 2.68-2.50 (m, 6H), 2.35- 1.45 (m, 14H).

[0813] Example 8: 2-(2-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-(methyl(cis-3-(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0814] Compound 8A; LCMS (ESI): m / z 562 (MH+), 1H NMR (400 MHz, MeOD) 8 7.60 - 7.55 (m, 2H), 7.21 - 7.12 (m, 2H), 6.39 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 8.8 Hz, 1H), 4.51 (s, 1H), 4.11 - 3.99 (m, 1H), 3.97 - 3.78 (m, 1H), 3.62 - 3.51 (m, 1H), 3.41 - 3.37 (m, 2H), 3.25 - 3.12 (m, 1H), 3.09 - 3.0 (m, 2H), 2.76 - 2.65 (m, 2H), 2.62 - 2.25 (m, 9H), 2.24 - 1.51 (m, 10H). Chiral SFC H (35% i-PrOH): ee 75%, Rt = 1.80 mm.

[0815] Compound 8B; LCMS (ESI): m / z 562 (MH+), 1H NMR (400 MHz, MeOD) 8 7.60 - 7.51 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.38 (d, J = 7.6 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 4.38 (s, 1H), 4.08 - 3.78 (m, 2H), 3.62 - 3.50 (m, 1H), 3.41 - 3.25 (m, 4H), 3.10 - 2.99 (m, 1H), 2.76 - 2.70 (m, 2H), 2.58 - 2.20 (m, 9H), 2.18 - 1.41 (m, 10H). Chiral SFC H (35% i-PrOH): ee 82%, Rt = 2.14 min.

[0816] Example 9: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cis-3-(3-(5, 6,7,8- tetrahydro- 1 , 8-naphthyridin-2-yl)propoxy)cyclobutyl)amino)acetic acid

[0817] 127

[0818] Foley HoagUS13043895.1 MTX-03225

[0819] Compound 9; LCMS (ESI): m / z 512 (MH+), 1H NMR (400 MHz, MeOD) 87.61 - 7.50 (m, 2H), 7.20 - 7.16 (m, 2H), 6.39 (d, J = 7.2 Hz, 1H), 4.80 - 4.71 (m, 2H), 4.12 - 4.09 (m, 1H), 3.79 - 3.60 (m, 2H), 3.30 - 3.32 (m, 5H), 2.74 - 2.56 (m, 8H), 2.30 - 1.72 (m, 13H).

[0820] Example 10: 2-(3-chlorophenyl)-2-(methyl(cis-3-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0821] Compound 10A; LCMS (ESI): m / z 444 (MH+), 1H NMR (400 MHz, MeOD) 87.64 (s, 1H), 7.51

[0822] - 7.42 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.38 (s, 1H), 3.65 - 3.60 (m, 1H), 3.45 - 3.28 (m, 5H), 2.74 - 2.56 (m, 8H), 2.30 - 1.75 (m, 7H). Chiral SFC C (20% MeOH): ee 100%, Rt = 1.96 min.

[0823] Compound 10B; LCMS (ESI): m / z 444 (MH+), 1H NMR (400 MHz, MeOD) 87.63 (s, 1H), 7.51

[0824] - 7.42 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 4.30 (s, 1H), 3.61 - 3.57 (m, 1H), 3.41 - 3.18 (m, 5H), 2.78 - 2.51 (m, 8H), 2.20 - 1.75 (m, 7H). Chiral SFC C (20% MeOH): ee 100%, Rt = 3.10 min.

[0825] Example 11: 2-(2-cyclopropyl-5-fluoropyridin-3-yl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0826] Compound 11A; LC / MS ESI 483 (M+H) +. 1H NMR (400 MHz, MeOD) 8 8.20 (d, J = 10.4 Hz, 1H), 7.70 (d, J = 12.4 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.73 (s, 1H), 128

[0827] Foley HoagUS13043895.1 MTX-03225

[0828] 3.54 - 3.30 (m, 5H), 2.65 - 2.24 (m, 10H), 2.09 - 1.43 (m, 10H), 1.30 - 1.03 (m, 6H).

[0829] Compound 11B; LC / MS ESI 483 (M+H) +.1H NMR (400 MHz, MeOD) 8 8.26 (d, J = 10.4 Hz, 1H), 7.75 (d, J = 12.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 3.42 - 3.31 (m, 5H), 2.75 - 2.51 (m, 10H), 2.12 - 1.54 (m, 10H), 1.13 - 1.00 (m, 5H).

[0830] Example 12: 2-(2-cyclobutylpyridin-3-yl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0831] Compound 12A; LC / MS ESI 479 (M+H) +. 1H NMR (400 MHz, MeOD) 8 8.20 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.56 (s, 1H), 4.22 - 4.18 (m, 1H), 3.60 - 3.40 (m, 6H), 2.74 - 2.40 (m, 12H), 2.16 - 1.90 (m, 8H), 1.66 - 1.53 (m, 4H).

[0832] Compound 12B; LC / MS ESI 479 (M+H) +.1H NMR (400 MHz, MeOD) 8 8.38 (d, J = 10.4 Hz, 1H), 7.94 (d, J = 12.4 Hz, 1H), 7.14 - 7.11 (m, 1H), 6.26 (d, J = 7.6 Hz, 1H), 4.40 (s, 1H), 3.48- 3.10 (m, 5H), 3.04- 3.00 (m, 1H), 2.70 - 2.35 (m, 12H), 2.00 - 1.44 (m, 12H).

[0833] Example 13: 2-(2-((S)-5,5-dimethyltetrahydro-2H-pyran-2-yl)-5-fluorophenyl)-2-(methyl(cis-3- (4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer

[0834] A and Stereoisomer B)

[0835] Compound 13A; LC / MS ESI 554 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.63 - 7.50 (m, 2H), 7.19 - 7.14 (m, 2H), 6.39 (d, J = 7.2 Hz, 1H), 4.90 - 4.73 (m, 1H), 4.64 (s, 1H), 3.63 - 3.33 (m, 8H), 2.74 - 2.54 (m, 8H), 2.25 - 2.15 (m, 2H), 1.97 - 1.58 (m, 11H), 1.15 (s, 3H), 0.95 (s, 3H).

[0836] Compound 13B; LC / MS ESI 554 (M+H) +.1H NMR (400 MHz, MeOD) 8 7.53 - 7.37 (m, 2H), 7.13 - 7.04 (m, 2H), 6.30 (d, J = 7.2 Hz, 1H), 4.60 - 4.59 (m, 2H), 3.52 - 3.20 (m, 8H), 2.63 - 129

[0837] Foley HoagUS13043895.1 MTX-03225

[0838] 2.43 (m, 8H), 2.18 - 2.05 (m, 2H), 1.86 - 1.76 (m, 5H), 1.61 - 1.42 (m, 7H), 1.02 (s, 3H), 0.85 (s, 3H).

[0839] Example 14: 2-(5-fluoro-2-((S)-5-oxaspiro[2.5]octan-6-yl)phenyl)-2-(methyl-cis-3-(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid

[0840] Compound 14; LC / MS ESI 552 (M+H)+, 'H NMR (400 MHz, MeOD) 8 7.64 (dd, J = 8.8, 5.8 Hz, 1H), 7.51 (dd, J= 10.0, 2.7 Hz, 1H), 7.40 (d, J= 7.4 Hz, 1H), 7.21 (td, J = 8.5, 2.7 Hz, 1H), 6.52 (d, J = 7.3 Hz, 1H), 4.85-4.83 (m, 1H), 4.76 (s, 1H), 4.17 (dd, J= 11.2, 1.6 Hz, 1H), 3.69 - 3.62 (m, 1H), 3.51 - 3.42 (m, 3H), 3.38 (t, J= 6.1 Hz, 2H), 3.17 (d, J= 11.2 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.73 - 2.58 (m, 6H), 2.30 (m, 3H), 2.13 - 1.90 (m, 5H), 1.72 (m, 2H), 1.64 - 1.55 (m, 2H), 1.25 (m, 1H), 0.62 - 0.38 (m, 4H).

[0841] Example 15: 2-(5-fluoro-2-((S)-2,9-dioxaspiro[5.5]undecan-3-yl)phenyl)-2-(methyl(cis-3-(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid

[0842] Compound 15; LC / MS ESI 596 (M+H)+, 1H NMR (400 MHz, MeOD) 8 7.61 (dd, J = 8.9, 6.0 Hz, 1H), 7.52 (dd, J = 10.0, 2.8 Hz, 1H), 7.22-7.17 (m, 2H), 6.41 (d, J = 7.4 Hz, 1H), 4.77-4.76 (m, 1H), 4.68 (s, 1H), 4.04 (d, J = 9.5 Hz, 1H), 3.80 - 3.39 (m, 10H), 2.78 - 2.52 (m, 8H), 2.33 - 1.50 (m, 16H), 1.40 (t, J = 5.3 Hz, 2H).

[0843] Example 16: 2-(2-((S)-2,2-difluoro-6-oxaspiro[3.5]nonan-7-yl)-5-fluorophenyl)-2-(methyl(cis-3- (4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0844] Foley HoagUS13043895.1 MTX-03225

[0845] Compound 16A; LC / MS ESI 602.2 (M+H)+, 1H NMR (400 MHz, MeOD) 8 7.40-7.25 (m, 2H),

[0846] 7.15-6.93 (m, 2H), 6.27 (d, J = 7.2 Hz, 1H), 4.70-4.50 (m, 2H), 3.85-3.75 (m, 1H), 3.60-3.40 (m, 2H), 3.35-3.21 (m, 5H), 2.65-2.20 (m, 10H), 2.18-1.20 (m, 15H). Chiral SFC D (25% MeOH): ee 90%, Rt = 1.10 min.

[0847] Compound 16B; LC / MS ESI 602.2 (M+H)+, 1H NMR (400 MHz, MeOD) 8 7.55-7.40 (m, 2H),

[0848] 7.15-7.00 (m, 2H), 6.27 (d, J = 7.6 Hz, 1H), 4.75-4.65 (m, 1H), 4.51 (s, 1H), 3.82-3.70 (m, 1H), 3.65-3.60 (m, 1H), 3.58-3.42 (m, 1H), 3.35-3.25 (m, 5H), 2.62-2.30 (m, 10H), 2.25-1.30 (m, 15H). Chiral SFC D (25% MeOH): ee 95%, Rt = 1.44 min.

[0849] Example 17: 2-(2-cyclopropylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)-7-methyl-5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0850] Compound 17A; LC / MS ESI 479.3 (M+H)+ 1HNMR (400 MHz, MeOD) 8 8.40 - 8.38 (m, 1H), 8.01 - 7.99 (m, 1H), 7.25 - 7.17 (m, 2H), 6.41 (d, J = 7.2 Hz, 1H), 4.93 - 4.91 (m, 1H), 3.63-3.59 (m, 2H), 3.36 - 3.32 (m, 3H), 2.76 - 2.73 (m, 2H), 2.62 - 2.51 (m, 7H), 2.21 - 2.18 (m, 1H), 2.06

[0851] - 1.96 (m, 2H), 1.90 - 1.83 (m, 1H), 1.70 - 1.64 (m, 2H), 1.58 - 1.52 (m, 2H), 1.27 - 1.21 (m, 3H), 1.20 - 0.93 (m, 4H).

[0852] Compound 17B; LC / MS ESI 479.3 (M+H)+1H NMR (400 MHz, MeOD) 8 8.40 - 8.38 (m, 1H), 8.01 - 7.99 (m, 1H), 7.25 - 7.17 (m, 2H), 6.41 (d, J = 7.2 Hz, 1H), 4.92 - 4.88 (m, 1H), 3.62-3.58 (m, 2H), 3.39 - 3.32 (m, 3H), 2.76 - 2.73 (m, 2H), 2.64 - 2.49 (m, 7H), 2.17 - 1.91 (m, 3H), 1.90

[0853] - 1.83 (m, 1H), 1.70 - 1.64 (m, 2H), 1.58 - 1.52 (m, 2H), 1.27 - 1.21 (m, 3H), 1.20 - 0.93 (m, 4H).

[0854] 131

[0855] Foley HoagUS13043895.1 MTX-03225

[0856] Example 18: 2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-(methyl(cis-3-(4-((S)-7-methyl- 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0857] Compound 18A; LC / MS ESI 526.3 (M+H)+'H NMR (400 MHz, MeOD) 8 7.60 - 7.48 (m, 2H), 7.21 - 7.13 (m, 2H), 6.40 (d, J = 7.2 Hz, 1H), 5.30 (t, J = 6.8 Hz, 1H), 4.72 (s, 1H), 4.17- 4.12 (m, 1H), 4.01 - 3.96 (m, 1H), 3.61-3.50 (m, 2H), 3.41 - 3.32 (m, 3H), 2.76 - 2.73 (m, 2H), 2.61 - 2.47 (m, 7H), 2.18 - 2.05 (m, 4H), 2.01 - 1.86 (m, 3H), 1.70 - 1.63 (m, 2H), 1.60 - 1.44 (m, 3H), 1.26 (d, J = 8.0 Hz, 1H).

[0858] Compound 18B; LC / MS ESI 526.3 (M+H)+ 1HNMR (400 MHz, MeOD) 87.60 - 7.48 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.13 - 7.10 (m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.13 (t, J = 6.4 Hz, 1H), 4.76 (s, 1H), 4.20- 4.17 (m, 1H), 3.96 - 3.86 (m, 1H), 3.67-3.50 (m, 2H), 3.41 - 3.32 (m, 3H), 2.76 - 2.73 (m, 2H), 2.60 - 2.50 (m, 3H), 2.46 - 2.40 (m, 4H), 2.18 - 2.05 (m, 4H), 2.01 - 1.86 (m, 3H), 1.70 - 1.63 (m, 2H), 1.60 - 1.44 (m, 3H), 1.26 (d, J = 8.0 Hz, 1H).

[0859] Example 19: 2-(3,5-difluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cis-3-(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0860] Compound 19A; LC / MS ESI 544 (M+H)+, 'H NMR (400 MHz, MeOD) 8 7.43 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 9.8 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.52 (d, J= 7.3 Hz, 1H), 4.10 (d, J= 9.0 Hz, 1H), 3.74 - 3.61 (m, 2H), 3.48 - 3.38 (m, 5H), 2.79 (t, J= 6.2 Hz, 2H), 2.64-2.55 (m, 6H), 2.22 - 1.55 (m, 15H).

[0861] Compound 19B; LC / MS ESI 544 (M+H)+, 'H NMR (400 MHz, MeOD) 8 7.39 (d, J = 7.3 Hz, 1H), 7.34 (d, J= 9.4 Hz, 1H), 7.10-7.08 (m, 1H), 6.51 (d, J= 7.3 Hz, 1H), 5.60 (s, 1H), 5.00 (d, J 132

[0862] Foley HoagUS13043895.1 MTX-03225

[0863] = 10.6 Hz, 1H), 4.25 (d, J= 10.7 Hz, 1H), 3.79 - 3.61 (m, 3H), 3.43-3.35 (m, 4H), 2.78 - 2.28 (m, 10H), 2.24 - 1.54 (m, 13H).

[0864] Example 20: 2-(2-cyclopropyl-5-fluorophenyl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0865] Compound 20A; LC / MS ESI 482 (M+H)+, ' H NMR (400 MHz, MeOD) 8 7.41 (dd, J= 10.0, 2.7 Hz, 1H), 7.19 -6.98 (m, 3H), 6.33 (d, J= 7.3 Hz, 1H), 5.01 (s, 1H), 3.62-3.58 (m, 1H), 3.40-3.35 (m, 5H), 2.80 - 2.61 (m, 6H), 2.54 (t, J= 7.6 Hz, 2H), 2.33 - 2.05 - 1.87 (m, 6H), 1.74 - 1.65 (m, 2H), 1.57 - 1.50 (m, 2H), 1.07 (dd, J= 8.4, 1.7 Hz, 2H), 0.92 - 0.84 (m, 1H), 0.65-0.63 (m, 1H). Compound 20B; LC / MS ESI 482 (M+H)+, ' H NMR (400 MHz, MeOD) 87.45 (dd, J= 10.0, 2.7 Hz, 1H), 7.20 -7.03 (m, 3H), 6.38 (d, J= 7.3 Hz, 1H), 5.07 (s, 1H), 3.62-3.58 (m, 1H), 3.40-3.35 (m, 5H), 2.80 - 2.61 (m, 6H), 2.54 (t, J= 7.6 Hz, 2H), 2.33 - 2.05 - 1.87 (m, 6H), 1.74 - 1.65 (m, 2H), 1.57 - 1.50 (m, 2H), 1.07 (dd, J= 8.4, 1.7 Hz, 2H), 0.92 - 0.84 (m, 1H), 0.65-0.63 (m, 1H).

[0866] Example 21: 2-(2,4-dicyclopropylpyrimidin-5-yl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0867] Compound 21A; LC / MS ESI 506 (M+H)+, ' H NMR (400 MHz, MeOD) 8 8.57 (s, 1H), 7.28 (d, J=7.6Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H), 3.71-3.67 (m, 1H), 3.40-3.25 (m, 6H), 2.78 - 2.41 (m, 9H), 2.15 - 2.04 (m, 3H), 1.98-1.92 (m, 3H), 1.74 - 1.65 (m, 2H), 1.57 - 1.50 (m, 2H), 1.22 - 0.94 (m, 8H). Chiral SFC C (20% MeOH): ee 100%, Rt = 1.20 mm.

[0868] Compound 21B; LC / MS ESI 506 (M+H)+, ' H NMR (400 MHz, MeOD) 8 8.57 (s, 1H), 7.28 (d, J=7.6Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 4.70 (s, 1H), 3.71-3.67 (m, 1H), 3.40-3.25 (m, 6H), 2.78 - 133

[0869] Foley HoagUS13043895.1 MTX-03225

[0870] 2.41 (m, 9H), 2.15 - 2.04 (m, 3H), 1.98-1.92 (m, 3H), 1.74 - 1.65 (m, 2H), 1.57 - 1.50 (m, 2H), 1.22 - 0.94 (m, 8H). Chiral SFC C (20% MeOH): ee 100%, Rt = 1.84 min.

[0871] Example 22: 2-(methyl(cis-3-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)propoxy)cyclobutyl)amino)-2-(4-(trifluoromethyl)phenyl)acetic acid (Stereoisomer A and Stereoisomer B)

[0872] Compound 22A; LC / MS ESI 478 (M+H)+, ' H NMR (400 MHz, MeOD) 8 7.75-7.67 (m, 4H), 7.17 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 7.2 Hz, 1H), 4.30 (s, 1H), 3.61-3.55 (m, 1H), 3.40-3.05 (m, 4H), 2.70 - 2.51 (m, 5H), 2.45 (s, 3H), 2.18-1.82 (m, 7H).

[0873] Compound 22B; LC / MS ESI 478 (M+H)+, 'H NMR (400 MHz, MeOD) 8 7.75-7.65 (m, 4H), 7.16 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 4.23 (s, 1H), 3.61-3.55 (m, 1H), 3.40-3.35 (m, 3H), 3.02-2.98 (m, 1H), 2.70 - 2.51 (m, 5H), 2.39 (s, 3H), 2.18-1.82 (m, 7H).

[0874] Example 23: 2-(3-chlorophenyl)-2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0875] Compound 23A; LC / MS ESI 458 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.63 (s, 1H), 7.52 - 7.38 (m, 3H), 7.27 - 7.20 (m, 1H), 6.41 (d, J = 7.6 Hz, 1H), 4.94 - 4.92 (m, 1H), 4.33 (s, 1H), 3.66 - 3.57 (m, 1H), 3.44 - 3.38 (m, 2H), 3.28 - 3.13 (m, 1H), 2.77 - 2.68 (m, 2H), 2.68 - 2.49 (m, 6H), 2.26 - 1.49 (m, 10H). Chiral SFC H (40% MeOH): ee 100%, Rt = 2.18 mm.

[0876] Compound 23B; LC / MS ESI 458 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.51 (s, 1H), 7.43 - 7.25 (m, 3H), 7.10 (d, J = 7.2 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 4.83 - 4.79 (m, 1H), 4.22 (s, 1H),

[0877] 134

[0878] Foley HoagUS13043895.1 MTX-03225

[0879] 3.54 - 3.44 (m, 1H), 3.44 - 3.26 (m, 2H), 3.16 - 3.01 (m, 1H), 2.66 - 2.57 (m, 2H), 2.55 - 2.37 (m, 6H), 2.15 - 1.36 (m, 10H). Chiral SFC H (40% MeOH): ee 100%, Rt = 3.04 min.

[0880] Example 24: 2-(methyl(cis-3-(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butoxy)cyclobutyl)amino)-2-(4-(trifluoromethyl)phenyl)acetic acid (Stereoisomer A and Stereoisomer B)

[0881] Compound 24A; LC / MS ESI 492 (M+H)+, ' H NMR (400 MHz, MeOD) 8 7.77-7.71 (m, 4H), 7.24 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.45 (s, 1H), 3.63-3.59 (m, 1H), 3.40-3.25 (m, 5H), 2.75 - 2.51 (m, 8H), 2.22-1.85 (m, 5H), 1.74-1.50 (m, 4H). Chiral SFC B (40% EtOH): ee 100%, Rt = 1.23 mm.

[0882] Compound 24B; LC / MS ESI 492 (M+H)+, 'H NMR (400 MHz, MeOD) 8 7.77-7.71 (m, 4H), 7.21 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.41 (s, 1H), 3.63-3.59 (m, 1H), 3.40-3.25 (m, 5H), 2.75 - 2.51 (m, 8H), 2.22-1.85 (m, 5H), 1.74-1.50 (m, 4H). Chiral SFC B (40% EtOH): ee 98%, Rt = 2.08 mm.

[0883] Example 25: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cis-3-((5-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0884] Compound 25A; LC / MS ESI 540 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.62 - 7.49 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.20 - 7.11 (m, 1H), 6.41 (d, J = 7.2 Hz, 1H), 4.84 - 4.78 (m, 1H), 4.64 (s, 1H), 4.14 - 4.07 (m, 1H), 3.83 - 3.74 (m, 1H), 3.68 - 3.60 (m, 1H), 3.43 - 3.35 (m, 3H), 2.76 - 2.46 (m, 9H), 2.34 - 2.15 (m, 2H), 2.09 - 1.35 (m, 16H).

[0885] 135

[0886] Foley HoagUS13043895.1 MTX-03225

[0887] Compound 25B; LC / MS ESI 540 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.48 - 7.39 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.11 (s, 1H), 4.76 - 4.68 (m, 1H), 4.20 - 4.12 (m, 1H), 3.72 - 3.61 (m, 2H), 3.42 - 3.36 (m, 3H), 2.76 - 2.39 (m, 9H), 2.39 - 2.15 (m, 2H), 2.11 - 1.33 (m, 16H).

[0888] Example 26: 2-(2-cyclopropylpyridin-3-yl)-2-(methyl(cis-3-((5-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0889] Compound 26A; LC / MS ESI 479 (M+H)+, ' H NMR (400 MHz, MeOD) 8 8.38 (dd, J= 4.7, 1.6 Hz, 1H), 8.02 (dd, J= 7.9, 1.6 Hz, 1H), 7.27 (d, J= 7.3 Hz, 1H), 7.18 (dd, J = 7.9, 4.8 Hz, 1H), 6.42 (d, J = 7.3 Hz, 1H), 4.86 (s, 1H), 3.69 - 3.59 (m, 1H), 3.43 - 3.38 (m, 3H), 3.29 - 3.21 (m, 2H), 2.74 (t, J = 6.2 Hz, 2H), 2.67 - 2.48 (m, 7H), 2.18-2.15 (m, 2H), 1.98 - 1.85 (m, 3H), 1.68 - 1.36 (m, 6H), 1.26 - 1.16 (m, 1H), 1.11 - 0.96 (m, 3H). Chiral SFC H (35% MeOH): ee 100%, Rt = 2.71 min.

[0890] Compound 26B; LC / MS ESI 479 (M+H)+, ' H NMR (400 MHz, MeOD) 8 8.38 (dd, J= 4.7, 1.7 Hz, 1H), 8.02 (dd, J= 7.9, 1.7 Hz, 1H), 7.25 (d, J= 7.3 Hz, 1H), 7.19 (dd, J = 7.9, 4.8 Hz, 1H), 6.42 (d, J = 7.3 Hz, 1H), 4.87 (s, 1H), 3.69 - 3.59 (m, 1H), 3.45 - 3.37 (m, 3H), 3.30 - 3.19 (m, 2H), 2.77 - 2.47 (m, 9H), 2.30 - 1.84 (m, 5H), 1.71 - 0.95 (m, 10H). Chiral SFC H (35% MeOH): ee 97%, Rt = 4.15 min.

[0891] Example 27: 2-(5-fluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cis-3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0892] Compound 27A; LC / MS ESI 526.3 (M+H)+ 1HNMR (500 MHz, MeOD) 87.60 - 7.48 (m, 2H),

[0893] 136

[0894] Foley HoagUS13043895.1 MTX-03225

[0895] 7.21 - 7.17 (m, 2H), 6.40 (d, J = 7.0 Hz, 1H), 4.76 (d, J = 8.0 Hz, 1H), 4.68 (s, 1H), 4.06 - 4.02 (m, 2H), 3.94 - 3.90 (m, 1H), 3.79-3.70 (m, 1H), 3.41 - 3.32 (m, 2H), 3.30 - 3.28 (m, 1H), 2.74 - 2.73 (m, 2H), 2.62 - 2.54 (m, 6H), 2.30 - 2.20 (m, 2H), 2.06 - 1.96 (m, 2H), 1.90 - 1.83 (m, 3H), 1.80 - 1.56 (m, 9H).

[0896] Compound 27B; LC / MS ESI 526.3 (M+H)+ 1HNMR (500 MHz, MeOD) 87.60 - 7.48 (m, 2H), 7.21 (d, J = 7.0 Hz, 1H), 7.14 - 7.12 (m, 1H), 6.41 (d, J = 7.0 Hz, 1H), 5.25 (s, 1H), 4.96 - 4.92 (m, 1H), 4.61 (d, J = 11.5.0 Hz, 1H), 4.16- 4.12 (m, 2H), 3.96 (s, 1H), 3.61-3.59 (m, 1H), 3.41 - 3.36 (m, 3H), 2.75 - 2.73 (m, 2H), 2.57 - 2.54 (m, 6H), 2.31 - 2.21 (m, 2H), 1.96 - 1.78 (m, 4H), 1.74 - 1.58 (m, 9H).

[0897] Example 28: 2-(4-((4-cyclopropyl-lH-pyrazol-l-yl)methyl)phenyl)-2-(methyl(cis-3-(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid

[0898] Compound 28; LC / MS ESI 544 (M+H)+. ' H NMR (400 MHz, MeOD) 8 7.54-7.25 (m, 7H), 6.48 (d, J= 7.2 Hz, 1H), 5.23 (s, 2H), 4.50 (s, 1H), 3.55 - 3.52 (m, 1H), 3.46 - 3.30 (m, 5H), 2.76 - 2.52 (m, 9H), 2.28-2.24 (m, 1H), 2.13 - 1.88 (m, 4H), 1.69 -1.51 (m, 5H), 0.84 - 0.78 (m, 2H), 0.52 - 0.48 (m, 2H).

[0899] Example 29: 2-(2-cyclopropyl-5-fluorophenyl)-2-(methyl(cis-3-((5-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0900] Compound 29A; LC / MS ESI 496 (M+H) +.1H NMR (400 MHz, MeOD) 87.49-7.46 (m, 1H),

[0901] 137

[0902] Foley HoagUS13043895.1 MTX-03225

[0903] 7.22-7.14 (m, 2H), 7.05-6.39 (m, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.00 (s, 1H), 3.65-3.69 (m, 1H), 3.38-3.32 (m, 5H), 2.74-2.54 (m, 8H), 2.21-1.87 (m, 6H), 1.66-1.42 (m, 6H), 1.18-0.76 (m, 3H), 0.65-0.58 (m,lH).

[0904] Compound 29B; LC / MS ESI 496 (M+H) +.1H NMR (400 MHz, MeOD) 87.59-7.46 (m, 1H),

[0905] 7.41-7.34 (m, 2H), 7.21-6.69 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.01 (s, 1H), 3.75-3.61 (m, 1H),

[0906] 3.42-3.38 (m, 5H), 2.84-2.66 (m, 8H), 2.29-1.93 (m, 6H), 1.76-1.39 (m, 6H), 1.25-0.96 (m, 3H), 0.84-0.69 (m,lH).

[0907] Example 30: 2-(5-fluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(cis-3-((5-(5, 6,7,8- tetrahydro- 1 , 8-naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid (enantiomeric compounds 33A and 33B)

[0908] Compound 30A; LC / MS ESI 540 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.50 (d, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.14 - 7.06 (m, 1H), 6.42 (d, J = 7.2 Hz, 1H), 4.65 (s, 1H), 4.11 - 4.01 (m, 2H), 3.73 - 3.61 (m, 3H), 3.43 - 3.34 (m, 4H), 3.27 - 3.18 (m, 1H), 2.77 - 2.43 (m, 8H), 2.28 - 2.15 (m, 2H), 2.03 - 1.85 (m, 5H), 1.78 - 1.38 (m, 9H). Chiral SFC L (20% MeOH): ee 100%, Rt = 0.68 mm.

[0909] Compound 30B; LC / MS ESI 540 (M+H) +. 1H NMR (400 MHz, MeOD) 8 7.50 (d, J = 7.6 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 - 7.06 (m, 1H), 6.42 (d, J = 7.2 Hz, 1H), 4.6 (s, 1H), 4.11 - 4.0 (m, 2H), 3.72 - 3.60 (m, 3H), 3.43 - 3.34 (m, 4H), 3.27 - 3.18 (m, 1H), 2.77 - 2.43 (m, 8H), 2.29 - 2.14 (m, 2H), 2.02 - 1.85 (m, 5H), 1.78 - 1.35 (m, 9H). Chiral SFC L (20% MeOH): ee 100%, Rt = 1.04 mm.

[0910] Example 31: 2-(5-fluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-(methyl(cis-3-(5-(5, 6,7,8- tetrahydro- 1 , 8-naphthyridin-2-yl)pentyloxy)cyclobutyl)amino)acetic acid

[0911] 138

[0912] Foley HoagUS13043895.1 MTX-03225

[0913] Compound 31; LC / MS ESI 526 (M+H) +. 1H NMR (400 MHz, MeOD) 8 8.55 (bs, 1H), 7.60- 7.43 (m, 3H), 7.20-7.19 (m, 1H), 6.51 (d, J= 7.2 Hz, 1H), 5.26-5.24 (m, 1H), 425-3.90 (m, 2H), 3.60-3.32 (m, 5H), 2.75-2.50 (m, 9H), 2.49-1.56 (m, 16H).

[0914] Example 32: 2-(2-cyclopropyl-3 -methoxyphenyl)-2-(methyl(trans-3 -(4-(5, 6, 7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid (Stereoisomer A and Stereoisomer B)

[0915] Compound 32A; LC / MS ESI 494.3 (M+H)+ 1H NMR (400 MHz, MeOD) 8 7.26 - 7.13 (m, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 7.2 Hz, 1H), 5.27 (s, 1H), 3.91 - 3.81 (m, 5H), 3.42 - 3.39 (m, 2H), 3.32 - 3.28 (m, 2H), 2.72 - 2.70 (m, 2H), 2.56 - 2.48 (m, 6H), 2.25 - 2.23 (m, 2H), 1.92 - 1.87 (m, 2H), 1.71 - 1.50 (m, 6H), 1.09 - 1.01 (m, 3H), 0.61 - 0.60 (m, 1H).

[0916] Compound 32B; LC / MS ESI 494.3 (M+H)+ 1H NMR (400 MHz, MeOD) 8 7.56 (d, J = 7.2 Hz, 1H), 7.37 - 7.23 (m, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.46 (s, 1H), 4.17 - 3.91 (m, 2H), 3.85 (s, 3H) 3.48 - 3.42 (m, 2H), 3.39 - 3.32 (m, 2H), 2.84 - 2.81 (m, 2H), 2.73 - 2.68 (m, 6H), 2.37 - 2.34 (m, 2H), 1.99 - 1.93 (m, 2H), 1.77 - 1.56 (m, 6H), 1.09 - 1.01 (m, 3H), 0.61 - 0.60 (m, 1H).

[0917] Example 33: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(methyl((ls,3S)-3-(3-(5, 6, 7, 8-tetrahydro- l,8-naphthyridin-2-yl)propoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0918] Compound 33A; LC / MS ESI 480.2 (M+H) +. 'HNMR (400 MHz, MeOD) 87.30 - 7.24 (m, 2H),

[0919] 139

[0920] FoleyHoagUS13043895.1 MTX-03225

[0921] 7.16 (d, J = 7.3 Hz, 1H), 6.99-6.96 (m, 1H), 6.36 (d, J= 7.3 Hz, 1H), 5.40 (s, 1H), 3.84 (s, 3H), 3.63-3.59 (m, 1H), 3.44 - 3.35 (m, 3H), 3.32 - 3.26 (m, 2H), 2.72-2.70 (m, 2H), 2.65-2.63 (m, 4H), 2.60 - 2.52 (m, 2H), 2.30-2.28 (m, 1H), 2.11 - 1.93 (m, 2H), 1.91 - 1.77 (m, 4H), 1.73-1.71 (m, 1H), 1.14 - 1.04 (m, 3H), 0.67 - 0.59 (m, 1H)

[0922] Example 34: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(methyl(cis-3-((5-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid Stereoisomer A and

[0923] Stereoisomer B .

[0924] Compound 34A; LCMS (ESI); m / z 508.4 (MH+). 'H NMR (500 MHz, MeOD) 87.27 - 7.22 (m, 2H), 7.15 (d, J= 7.3 Hz, 1H), 6.99 (dd, J= 6.1, 3.3 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.39 (s, 1H), 3.85 (s, 3H), 3.66 - 3.59 (m, 1H), 3.43 - 3.37 (m, 3H), 3.34 (m, 2H), 3.32 - 3.27 (m, 2H), 2.72 (t, J= 6.3 Hz, 2H), 2.69 - 2.64 (m, 1H), 2.62 (s, 3H), 2.55 - 2.49 (m, 2H), 2.32 - 2.23 (m, 1H), 2.11 - 2.02 (m, 1H), 2.01 - 1.92 (m, 1H), 1.93 - 1.86 (m, 2H), 1.74 - 1.67 (m, 1H), 1.67 - 1.59 (m, 2H), 1.58 - 1.51 (m, 2H), 1.44 - 1.34 (m, 2H), 1.13 - 1.05 (m, 3H), 0.64 (t, J= 5.2 Hz, 1H).

[0925] Compound 34B; LCMS (ESI); m / z 508.4 (MH+). ' H NMR (500 MHz, MeOD) 8 7.53 (s, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 5.50 (s, 1H), 3.87 (s, 2H), 3.75 (s, 1H), 3.60 (s, 1H), 3.46 (s, 2H), 2.76 (m, 5H), 2.54 (s, 3H), 2.21 (m, 1H), 2.04 (s, 1H), 2.02 - 1.86 (m, 3H), 1.72 (m, 2H), 1.59 (m, 5H), 1.32 (s, 4H), 1.21 - 1.03 (m, 3H), 0.92 (t, J= 7.0 Hz, 1H), 0.65 (s, 1H).

[0926] Example 35: 2-(2-cyclopropyl-3-ethoxyphenyl)-2-(methyl(cis-3-((5-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0927] 140

[0928] Foley HoagUS13043895.1 MTX-03225

[0929] Compound 35A; LCMS (ESI); m / z 522.4 (MH+). ' H NMR (400 MHz, MeOD) 57.14 - 7.06 (m, 2H), 7.03 (d, J= 7.3 Hz, 1H), 6.25 (d, J= 7.3 Hz, 1H), 5.25 (s, 1H), 4.03 - 3.86 (m, 2H), 3.57 - 3.45 (m, 1H), 3.31 - 3.24 (m, 3H), 3.17-3.23 (m, 2H), 2.65 - 2.44 (m, 6H), 2.44 - 2.35 (m, 2H), 2.22 - 2.08 (m, 1H), 2.00 - 1.92 (m, 1H), 1.90 - 1.71 (m, 3H), 1.64 - 1.38 (m, 6H), 1.37 - 1.16 (m, 7H), 1.04 - 0.91 (m, 3H), 0.59 - 0.52 (m, 1H).

[0930] Compound 35B; LCMS (ESI); m / z 522.4 (MH+). 'H NMR (400 MHz, MeOD) 8 7.27 - 7.18 (m, 2H), 7.15 (d, J= 7.3 Hz, 1H), 6.96 (dd, J= 7.4, 1.8 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 5.39 (s, 1H), 4.06 (m, 2H), 3.69 - 3.58 (m, 1H), 3.45 - 3.36 (m, 3H), 3.30 (m, 3H), 2.69 -2.50 (m, 6H), 2.55 - 2.48 (m, 2H), 2.28-2.20 (m, 1H), 2.10-1.95 (m, 1H), 1.92-1.75 (m, 3H), 1.76 - 1.49 (m, 6H), 1.50 - 1.28 (m, 7H), 1.10 (t, J= 6.5 Hz, 3H), 0.71 - 0.64 (m, 1H).

[0931] Example 36: (S)-2-(2-cyclobutylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0932] Step 1 : methyl (S)-2-(2-cyclobutylpyridin-3-yl)-2-(methyl(cA-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate

[0933] DIEA (618.67 mg, 4.79 mmol, 833.78 uL, 4 eq) was added to a solution of cA-N-methyl-3-(4- ((S)- 1 ,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-2-yl)butoxy)cyclobutan- 1 -amine (Method L 1 , Stereoisomer A, 346.35 mg, 1.20 mmol, 1 eq) in CH3CN (3 mL) at 25°C. Asolution of methyl 2- chloro-2-(l-phenyl-lH-pyrazol-5-yl)acetate (300 mg, 1.20 mmol, 1 eq) and Nal (179.38 mg, 141

[0934] Foley HoagUS13043895.1 MTX-03225

[0935] 1.20 mmol, 1 eq) in CH3CN (3 mL) was then added and the mixture was stirred at 50°C for 0.5 hrs. The reaction mixture was quenched by water (100 mL) at 0°C and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (700 mg) as an oil. LCMS (ESI); m / z 504 (MH+).

[0936] Step 2: (S)-2-(2-cy cl obutylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)- 1,2,3, 4-tetrahydro- 1,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0937] To a solution of methyl (S)-2-(2-cyclobutylpyridin-3-yl)-2-(methyl(cA-3-(4-((S)-l,2,3,4- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (700 mg, 1.39 mmol, 1 eq) in THF (7 mL), MeOH (2 mL) and H2O (2 mL) was added L1OHH2O (116.65 mg, 2.78 mmol, 2 eq) and the mixture was stirred at 25°C for 16 h. The reaction mixture was quenched by water (100 mL) at 0°C, extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 250* 50mm* 10 um; mobile phase: [water (0.1%TFA)-ACN]; B%: 5%-35%, lOmin. HPLC: ET24671-404-P1 Al, Rt = 1.996 min) to give a product. The product was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [0.1% NH3H2O IPA]; B%: 40%-40%, min. Rtl = 1.72 min, Rt2 = 2.17 min) to give two peaks (peak 1 and peak 2). Peak 1 was purified by prep-HPLC (column: Nano-micro Cl 8 100*40mm 3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%, 8min).

[0938] Peak 1, was randomly assigned as Stereoisomer A (Compound 36A;, 44.2 mg, 89.92 umol, 12.9% yield). SFC Rt = 1.76 mm); LCMS (ESI); m / z 490 (MH+).

[0939] Peak 2, was randomly assigned as Stereoisomer B (Compound 36B;, 66.9 mg, 136.64 umol, 19.7% yield) SFC Rt = 2.23 mm); LCMS (ESI); m / z 490 (MH+).

[0940] 142

[0941] Foley HoagUS13043895.1 MTX-03225

[0942] Example 37: 2-(3-chloro-2-cyclopropylphenyl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0943] Compound 37A; ' H NMR (400 MHz, methanol-d4) 8= 7.74 -7.62 (m, 3H), 7.39 (dd, J= 2.6, 9.7 Hz, 1H), 7.30 -7.23 (m, 1H), 6.79 (t, J= 6.8 Hz, 1H), 5.08 (s, 1H), 4.73 (br d, J= 10.1 Hz, 1H), 4.10 (br s, 1H), 3.83 -3.75 (m, 1H), 3.69 -3.51 (m, 3H), 3.38 (br t, J= 5.8 Hz, 2H), 2.93 -2.82 (m, 2H),2.80 -2.66 (m, 4H), 2.36 -2.26 (m, 1H), 2.10 -1.97 (m, 4H), 1.82 -1.48 (m, 12H); LCMS (ESI); m / z 526 (MH+).

[0944] Compound 37B;XH NMR (400 MHz, METHANOL- d4) 8= 7.72 -7.64 (m, 2H), 7.46 -7.39 (m, 1H), 7.35 -7.30 (m, 1H), 7.25 -7.18 (m, 1H), 6.80 -6.75 (m, 1H), 5.90 -5.61 (m, 1H), 4.63 (br d, J= 10.4 Hz, 1H), 4.26 -4.20 (m, 1H), 3.76 -3.62 (m, 4H), 3.50 -3.44 (m, 1H), 3.40 (br d, J= 6.6 Hz, 1H), 2.93-2.84 (m, 2H), 2.81 -2.75 (m, 1H), 2.66 -2.30 (m, 4H), 2.12 -1.94 (m, 4H), 1.81 -1.55 (m, 12H); LCMS (ESI); m / z 526 (MH+).

[0945] Example 38: (S)-2-(5-fluoro-2-((R)-tetrahydrofuran-3-yl)phenyl)-2-(methyl(cis-3-(4-((S)- l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0946] Peak 1 was obtained from Method M44 using prep HPLC Condition Q followed by prep HPLC Condition R and randomly assigned as Stereoisomer A.

[0947] Compound 38A; 52.9 mg, 103.40 umol, 10.87% yield). LCMS; m / z 512.3 (M+, 98.8%).JH NMR (400 MHz, chlor oform-d) 8 ppm 1.45 - 1.73 (m, 7 H) 1.74 - 1.86 (m, 1 H) 1.87 - 2.06 (m, 3 H) 2.21 (s, 3 H) 2.30 - 2.45 (m, 2 H) 2.53 (br dd, J=10.03, 5.40 Hz, 1 H) 2.77 (br s, 2 H) 3.14 (br t, J=6.62 Hz, 1 H) 3.39 (br s, 2 H) 3.54 - 3.66 (m, 2 H) 3.71 (dd, J=8.05, 6.06 Hz, 1 H) 3.91 (q, J=7.42 Hz, 1 H) 3.95 - 4.01 (m, 1 H) 4.02 - 4.09 (m, 1 H) 4.10 - 4.16 (m, 1 H) 4.60 (s, 1 H) 6.45 (t, J=6.50 Hz, 1 H) 6.93 (td, J=8.16, 2.87 Hz, 1 H) 7.26 (br s, 1 H) 7.28 - 7.33 (m, 2 H) 7.46 (br d, 143

[0948] FoleyHoagUS13043895.1 MTX-03225

[0949] J=6.39 Hz, 1 H) 10.30 (br s, 1 H).

[0950] Peak 2 was obtained from Method M44 using using prep HPLC Condition Q followed by by prep HPLC Condition R and randomly assigned as Stereoisomer B.

[0951] Compound 38B; 49.2 mg, 92.32 umol, 9.71% yield) LCMS; m / z 512.3 (M+, 97.3%).JH NMR (400 MHz, chloroform-d) 8 ppm 0.08 (s, 1 H) 1.25 (br d, J=12.23 Hz, 2 H) 1.45 - 1.69 (m, 8 H) 2.02 (s, 1 H) 2.40 - 2.56 (m, 1 H) 2.59 - 2.70 (m, 1 H) 2.72 - 2.89 (m, 2 H) 3.21 - 3.33 (m, 1 H) 3.36 - 3.46 (m, 2 H) 3.46 - 3.62 (m, 4 H) 3.81 (s, 3 H) 4.03 (br s, 3 H) 4.28 - 4.39 (m, 1 H) 4.39 - 4.49 (m, 1 H) 4.68 (br s, 1 H) 5.19 (br s, 1 H) 6.52 - 6.63 (m, 2 H) 6.88 (br d, J=8.93 Hz, 1 H) 7.39 - 7.44 (m, 1 H) 7.52 (br d, J=6.11 Hz, 1 H) 9.85 (br s, 1 H).

[0952] Example 39: 2-(5-fluoro-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(cis-3-(4- ((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid.

[0953] Peak 1 was randomly assigned as Stereoisomer A.

[0954] Compound 39 A; 17.1 mg, 29.82 umol, 5.7% yield). LCMS; m / z 556.3 (M+, 96.9%).JH NMR (400 MHz, chloroform-d) 8 = 9.93 - 9.73 (m, 1H), 7.52 (br d, J= 5.3 Hz, 1H), 7.29 (br s, 1H), 6.96 (br d, J= 9.8 Hz, 1H), 6.55 - 6.51 (m, 1H), 6.49 - 6.43 (m, 1H), 4.61 (s, 1H), 4.08 - 4.00 (m, 2H), 3.79 (s, 3H), 3.65 - 3.48 (m, 4H), 3.44 - 3.32 (m, 3H), 3.14 (br s, 1H), 2.76 (br t, J= 5.8 Hz, 2H), 2.57 - 2.48 (m, 2H), 2.57 - 2.37 (m, 2H), 2.22 (s, 3H), 2.05 - 1.93 (m, 2H), 1.81 - 1.74 (m, 1H), 1.81 - 1.57 (m, 7H), 1.51 - 1.37 (m, 2H).

[0955] Peak 2 was randomly assigned as Stereoisomer B.

[0956] Compound 39B; 45.1 mg, 75.40 umol, 14.3% yield) LCMS; m / z 556.3 (M+, 92.9 %) H NMR (400 MHz, chloroform-d) 8 = 10.24 - 9.67 (m, 1H), 7.48 (br d, J= 5.9 Hz, 1H), 7.30 (br d, J= 7.2 Hz, 1H), 6.94 (br d, J= 10.8 Hz, 1H), 6.54 (br d, J= 10.6 Hz, 1H), 6.45 (t, J= 6.5 Hz, 1H), 4.63 (s, 1H), 4.10 - 3.99 (m, 2H), 3.79 (s, 3H), 3.70 - 3.64 (m, 1H), 3.63 - 3.58 (m, 1H), 3.56 - 3.46 (m, 2H), 3.41 (br s, 3H), 3.14 (br d, J= 7.1 Hz, 1H), 2.76 (br d, J= 4.3 Hz, 2H), 2.59 - 2.44 (m, 4H), 2.20 (s, 3H), 2.13 - 2.04 (m, 1H), 1.99 - 1.82 (m, 2H), 1.71 - 1.40 (m, 9H), 1.26 (br s, 1H).

[0957] 144

[0958] Foley HoagUS13043895.1 MTX-03225

[0959] Example 40: 2-(2-cyclopropyl-3-methoxyphenyl)-2-(methyl(cA-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0960] Compound 40A; ' H NMR (400 MHz, methanol-d4) 8 = 7.69 - 7.65 (m, 1H), 7.63 (br d, J = 6.0 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.19 (d, J= 7.7 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.75 (t, J= 6.7 Hz, 1H), 5.50 (s, 1H), 3.85 (s, 3H), 3.80 - 3.69 (m, 1H), 3.66 - 3.52 (m, 2H), 3.44 (br d, J = 7.9 Hz, 1H), 3.37 (br d, J= 6.6 Hz, 1H), 2.91 - 2.74 (m, 3H), 2.63 - 2.39 (m, 4H), 2.25 - 2.12 (m, 1H), 2.08 - 2.01 (m, 1H), 1.74 - 1.53 (m, 8H), 1.38 - 1.28 (m, 1H), 1.17 - 1.08 (m, 2H), 1.07 - 0.99 (m, 1H), 0.65 (br d, J= 4.6 Hz, 1H).

[0961] Compound 40B; ' H NMR (400 MHz, methanol-d4) 8 = 7.70 (d, J= 4.2 Hz, 1H), 7.26 - 7.16 (m, 3H), 6.96 (dd, J= 2.1, 7.2 Hz, 1H), 6.49 (dd, J= 5.2, 7.2 Hz, 1H), 5.36 (s, 1H), 3.83 (s, 3H), 3.62 (t, J= 6.9 Hz, 1H), 3.42 - 3.32 (m, 4H), 2.76 - 2.58 (m, 6H), 2.30 - 2.19 (m, 1H), 2.11 - 2.01 (m, 1H), 1.99 - 1.91 (m, 2H), 1.72 - 1.65 (m, 1H), 1.61 - 1.44 (m, 7H), 1.11 - 1.02 (m, 3H), 0.66 - 0.58 (m, 1H).

[0962] Example 41; 2-(2-cyclopropyl-3-ethoxyphenyl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0963] To a solution of 2-(2-cyclopropyl-3-ethoxyphenyl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro- l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (Method M47, 600 mg, 1.15 mmol, 1 eq) in THF (6 mb), MeOH (2 mb) and H2O (2 mb) was added LiOH.H2O (144.79 mg, 3.45 mmol, 3 eq) at 25°C, and then the mixture was stirred at 30°C for 16 h. The reaction mixture was judged to be complete by LCMS and HC1 (IM) was added. The mixture was concentrated under reduced

[0964] 145

[0965] Foley HoagUS13043895.1 MTX-03225 pressure and purified by preparative HPLC (Condition H; followed by chiral SFC (Condition P) to give two peaks (Peak 1 and Peak 2).

[0966] Peak 1 was randomly assigned as Stereoisomer A (Compound 41A; 61.8 mg, 121.44 umol, 21.1% yield) and obtained as a solid. LCMS; m / z 508.2 (M+, 99.8%).JH NMR (400 MHz, methanol-d-i) 8 = 7.67 (br d, J= 5.9 Hz, 2H), 7.45 - 7.37 (m, 1H), 7.27 - 7.17 (m, 2H), 6.98 (d, J= 7.9 Hz, 1H), 6.76 (t, J = 6.7 Hz, 1H), 5.49 (s, 1H), 4.13 - 3.98 (m, 2H), 3.74 - 3.45 (m, 3H), 3.38 (br s, 2H), 2.93 - 2.80 (m, 2H), 2.78 - 2.44 (m, 4H), 2.35 (br d, J= 5.9 Hz, 1H), 2.12 - 2.00 (m, 2H), 1.72 - 1.48 (m, 8H), 1.44 (t, J = 7.0 Hz, 3H), 1.38 - 1.22 (m, 1H), 1.14 - 1.02 (m, 3H), 0.67 (br d, J= 5.0 Hz, 1H)

[0967] Peak 2 was randomly assigned as Stereoisomer B (Compound 41B; 32.1 mg, 62.11 umol, 10.80% yield) and obtained as a solid. LCMS; m / z 508.2 (M+, 98.2%).1H NMR (400 MHz, methanol-d4) 8 = 7.70 (d, J= 4.6 Hz, 1H), 7.27 - 7.18 (m, 3H), 6.99 - 6.92 (m, 1H), 6.50 (dd, J= 5.4, 7.0 Hz, 1H), 5.40 (s, 1H), 4.12 - 3.98 (m, 2H), 3.63 (br t, J= 6.8 Hz, 1H), 3.47 - 3.33 (m, 4H), 2.76 - 2.62 (m, 6H), 2.34 - 2.22 (m, 1H), 2.08 - 1.90 (m, 3H), 1.72 - 1.65 (m, 1H), 1.60 - 1.41 (m, 10H), 1.13 - 1.05 (m, 3H), 0.71 - 0.60 (m, 1H).

[0968] Example 42: (S)-2-(2-cyclopropylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0969] Peak 1 was obtained from Intermediate # using prep HPLC Condition S followed by chiral SFC condition O and randomly assigned as Stereoisomer A (Compound 42A; (61.3 mg, 122.32 umol, 33.4% yield). LCMS; m / z 465.4 (M+, 97.7%).JH NMR (400 MHz, chloroform-d) 8 = 9.99 (br s, 1H), 8.34 (dd, J=1.8, 4.6 Hz, 1H), 7.86 (d, 7=7.7 Hz, 1H), 7.47 (br d, 7=5.3 Hz, 1H), 7.29 (br d, 7=7.3 Hz, 1H), 7.01 (dd, 7=4.7, 7.8 Hz, 1H), 6.44 (t, J=6.5 Hz, 1H), 4.71 (s, 1H), 3.69 - 3.56 (m, 2H), 3.40 (br s, 2H), 3.13 (br t, 7=7.6 Hz, 1H), 2.76 (br s, 2H), 2.57 - 2.40 (m, 3H), 2.26 (s, 3H), 1.96 (br d, 7=8.2 Hz, 3H), 1.70 - 1.50 (m, 7H), 1.17 (br dd, 7=4.1, 8.0 Hz, 1H), 1.06 - 0.94 (m, 3H).

[0970] Peak 2 was obtained from Intermediate # using using prep HPLC Condition S followed by chiral SFC condition O and randomly assigned as Stereoisomer B (Compound 42B; 54.8 mg, 115.19 146

[0971] Foley HoagUS13043895.1 MTX-03225 umol, 31.5% yield) LCMS; m / z 465.2 (M+, 92.7 %).1H NMR (400 MHz, chloroform-d) 'H NMR (400 MHz, chloroform-d) 8 = 9.86 (br s, 1H), 8.33 (br d, 7=4.2 Hz, 1H), 7.89 (br d, 7=7.5 Hz, 1H), 7.51 (br d, 7=4.6 Hz, 1H), 7.29 (br s, 1H), 6.99 (br d, 7=4.9 Hz, 1H), 6.45 (br t, 7=6.3 Hz, 1H), 4.69 (br s, 1H), 3.65 - 3.48 (m, 2H), 3.37 (br s, 2H), 3.13 (br s, 1H), 2.75 (br s, 2H), 2.52 (br d, 7=4.9 Hz, 1H), 2.40 (br s, 2H), 2.29 (s, 3H), 2.04 - 1.82 (m, 3H), 1.71 - 1.50 (m, 7H), 1.17 - 0.91 (m, 4H).

[0972] Example 43: (S)-2-(2-cyclobutylpyridin-3-yl)-2-(methyl(cis-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[0973] Compound 43A; ' H NMR (400 MHz, methanol-d4) 8 = 8.51 (d, 7=3.3 Hz, 1H), 8.03 (br d, 7=7.4 Hz, 1H), 7.70 (br d, 7=4.4 Hz, 1H), 7.34 - 7.15 (m, 2H), 6.51 (dd, 7=5.4, 7.2 Hz, 1H), 4.56 (br s, 1H), 4.18 (t, 7=8.9 Hz, 1H), 3.59 (br t, 7=6.9 Hz, 1H), 3.42 - 3.34 (m, 3H), 3.15 (br d, 7=11.4 Hz, 1H), 2.78 - 2.72 (m, 2H), 2.62 - 2.52 (m, 2H), 2.51 - 2.42 (m, 4H), 2.35 (q, 7=8.7 Hz, 2H), 2.18 - 2.08 (m, 2H), 2.02 - 1.88 (m, 3H), 1.84 - 1.75 (m, 1H), 1.64 - 1.47 (m, 7H); LCMS (ESI); m / z 479 (MH+). SFC, Rt = 2.90 mm.

[0974] Compound 43B; ' H NMR (400 MHz, methanol-ch) 8 = 8.47 (d, 7=4.2 Hz, 1H), 8.04 (br d, 7=7.6 Hz, 1H), 7.69 (br d, 7=3.5 Hz, 1H), 7.29 - 7.21 (m, 2H), 6.50 (d, 7=7.2 Hz, 1H), 4.46 (br s, 1H), 4.21 (br t, 7=8.6 Hz, 1H), 3.63 - 3.54 (m, 1H), 3.42 - 3.36 (m, 3H), 3.07 (br s, 1H), 2.75 (br d, 7=5.5 Hz, 2H), 2.56 - 2.47 (m, 3H), 2.38 - 2.31 (m, 5H), 2.17 - 1.91 (m, 6H), 1.77 (br d, 7=10.3 Hz, 1H), 1.65 - 1.52 (m, 7H), 1.49 - 1.44 (m, 1H), 1.45 (br s, 1H); LCMS (ESI); m / z 479 (MH+). SFC, Rt = 5.0 min

[0975] Example 44: 2-(2-((R)-5,5-dimethyltetrahydrofuran-3-yl)-5-fluorophenyl)-2-(methyl(cA-3-(4- ((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B and Stereoisomer C and Stereoisomer D

[0976] 147

[0977] Foley HoagUS13043895.1 MTX-03225

[0978] Compound 44A; 'H NMR (400 MHz, chloroform-d) 5=10.08(brs,lH), 7.48(brd,J=5.7Hz,lH), 7.36-7.28(m,3H), 6.94 (dt, J=2.9, 8.3Hz, 1H), 6.45(t,J=6.5Hz,lH), 4.61(s,lH), 4.27-4.20 (m,lH), 4.12 (quin,J=8.3Hz,lH), 3.76(t,J=8.2Hz,lH),3.67-3.56(m,2H), 3.38(brt,J=5.5Hz,2H), 3.22- 3.09(m,lH), 2.83-2.70(m,2H), 2.57-2.48(m,lH), 2.46-2.36(m,lH), 2.30-2.18(m,4H), 2.04- 1.93(m,2H), 1.92-1.78(m,2H), 1.73-1.51(m,7H), 1.39(s,3H), 1.31(s,3H); LCMS; m / z 540 (MH+). Compound 44B;XH NMR (400 MHz, chloroform-d) 5=10.09(brs,lH), 7.50(d,J=5.1Hz,lH), 7.37- 7.27(m,3H), 6.93(dt,J=2.8,8.3Hz,lH), 6.45(dd,J=6.2,6.8Hz,lH), 4.61(s,lH), 4.26-4.19(m,lH), 4.09(td,J=8.4,17.0Hz,lH), 3.81(t,J=8.4Hz,lH), 3.62(quin,J=7.1Hz,lH), 3.57-3.50(m,lH),

[0979] 3.38(brd,J=3.3Hz,2H), 3.21-3.12(m,lH), 2.81-2.70(m,2H), 2.54-2.46(m,lH), 2.41-2.34(m,lH), 2.29(dd,J=7.9,12.1Hz,lH), 2.24(s,3H), 2.00-1.91(m,2H), 1.88-1.80(m,lH),

[0980] 1.75(dd,J=10.0, 12.0Hz, 1H), 1.71-1.47(m,7H), 1.40(s,3H), 1.33(s,3H); LCMS; m / z 540 (MH+).

[0981] Compound 44C;; 'H NMR (400 MHz, chloroform-d) 8= 10.03 (br s, 1H), 7.51 (d, J=5.3 Hz, 1H), 7.37 -7.28 (m, 3H), 6.93 (dt, J=2.8, 8.3 Hz, 1H), 6.46 (t, J=6.5 Hz, 1H), 4.61 (s, 1H), 4.28 -4.18 (m, 1H), 4.17 -4.06 (m, 1H), 3.76 (t, J=8.2 Hz, 1H), 3.65 -3.48 (m, 2H), 3.45 -3.31 (m, 2H), 3.21 -3.10 (m, 1H), 2.87 -2.66 (m, 2H), 2.57 -2.45 (m, 1H), 2.41 -2.32 (m, 1H), 2.31 -2.17 (m, 4H), 2.00 -1.91 (m, 2H), 1.89 -1.78 (m, 2H), 1.75 -1.52 (m, 7H), 1.39 (s, 3H), 1.31 (s, 3H); LCMS; m / z 540 (MH+).

[0982] Compound 44D;; 'H NMR (400 MHz, chloroform-d) 8= 10.14 (br s, 1H), 7.47 (d, J=5.3 Hz, 1H), 7.36 -7.28 (m, 3H), 6.94 (dt, J=2.8, 8.3 Hz, 1H), 6.45 (t, J=6.5 Hz, 1H), 4.61 (s, 1H), 4.25 -4.19 (m, 1H), 4.10 (quin, J=8.4 Hz, 1H), 3.82 (t, J=8.4 Hz, 1H), 3.69 -3.56 (m, 2H), 3.39 (br d, J=4.4 Hz, 2H), 3.21 -3.10 (m, 1H), 2.76 (br d, J=4.4 Hz, 2H), 2.57 -2.49 (m, 1H), 2.47 -2.39 (m, 1H), 2.29 (dd, J=7.9, 12.1 Hz, 1H), 2.20 (s, 3H), 2.02 -1.93 (m, 2H), 1.87 (q, J=8.9 Hz, 1H), 1.75 (dd, J=10.0, 12.0 Hz, 1H),1.7O -1.52 (m, 7H), 1.40 (s, 3H), 1.33 (s, 3H); LCMS; m / z 540 (MH+).

[0983] Example 45: 2-(3-chloro-2-cyclopropylphenyl)-2-(methyl(czs-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B .

[0984] 148

[0985] Foley HoagUS13043895.1 MTX-03225

[0986] Step 1 : tert-butyl 2-(3-chloro-2-cyclopropylphenyl)-2-(methyl(cA-3-(4-((S)-l,2,3,4-tetrahydro-

[0987] 1 , 8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate.

[0988] To a mixture of tert-butyl 2-bromo-2-(3-chloro-2-cyclopropylphenyl)acetate (167.21 mg, 483.73 umol, 1 eq) and cis-N-methyl-3-(4-((S)- l ,2,3,4-tetrahydro- l ,8-naphthyridin-2- yl)butoxy)cyclobutan-l -amine (Method LI, Stereoisomer A, 140 mg, 483.73 umol, 1 eq) in CH3CN (5 mL) was added DIEA (187.55 mg, 1.45 mmol, 252.77 uL, 3 eq) in one portion. The mixture was stirred at 50°C for 0.5 h, filtered and diluted with H2O (15 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine (20 mL x 1), dried with anhydrous Na2SO-i, filtered and concentrated under reduced pressure. The residue was purified by column chromatography ( S 102, Petroleum ether / Ethyl acetate= 100 / 1, 10 / 1 to 5 / 1) to give the title compound (200 mg, 360.91 umol, 74.6% yield) as a solid. LCMS (ESI); m / z 554 (MH+).

[0989] Step 2: 2-(3-chloro-2-cyclopropylphenyl)-2-(methyl(cA-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0990] TLA (20.58 mg, 180.45 umol, 13.36 uL, 1 eq) was added to a stirred solution of tert-butyl 2-bromo- 2-(3-chloro-2-cyclopropylphenyl)acetate (100 mg, 180.45 umol, 1 eq) in CH2Q2 (2 mL) at 25°C under N2. The mixture was stirred at 35 °C for 12 h, concentrated under reduced pressure and the residue was purified by prep-HPLC (column: column: Waters Xbridge Prep OBD Cl 8 150 * 40 mm * 10 um; mobile phase: [water (10 mMNELHCC^-ACN]; B%: 25%-55%, 8 min) to give 100 mg racemic product. The racemic product was separated by SEC (column: column: Phenomenex- 149

[0991] Foley HoagUS13043895.1 MTX-03225

[0992] Cellulose-2 (250 mm*30 mm, 5 um); mobile phase: [0.1%NH3H2O MEOH]; B%: 60%-60%, min) to give two peaks. Peak 1 was obtained as a solid and randomly assigned as Stereoisomer A (14.9 mg, 29.92 umol, 16.58% yield). Peak 2 was obtained as a solid and randomly assigned as Stereoisomer B (17.1 mg, 33.20 umol, 18.40% yield, 96.7%).

[0993] Compound 45A;1H NMR (400 MHz, methanol-74) 8 ppm 0.66 (br s, 1 H) 1.15 - 1.26 (m, 3 H) 1.28 (br d, 7=5.51 Hz, 1 H) 1.42 - 1.52 (m, 3 H) 1.52 - 1.61 (m, 4 H) 1.76 - 1.87 (m, 1 H) 1.88 - 2.10 (m, 3 H) 2.16 - 2.33 (m, 1 H) 2.65 (s, 3 H) 2.66 - 2.71 (m, 1 H) 2.71 - 2.79 (m, 2 H) 3.31 - 3.33 (m, 1 H) 3.35 (br d, 7=7.94 Hz, 1 H) 3.37 - 3.44 (m, 2 H) 3.63 (quin, 7=6.78 Hz, 1 H) 5.43 (s, 1 H) 6.51 (dd, 7=7.06, 5.29 Hz, 1 H) 6.46 - 6.58 (m, 1 H) 7.21 - 7.33 (m, 2 H) 7.44 (d, 7=8.16 Hz,

[0994] 1 H) 7.61 (d, 7=7.94 Hz, 1 H) 7.70 (br d, 7=4.63 Hz, 1 H); LCMS (ESI); m / z 532 (MH+).

[0995] Compound45;; ' H NMR (400 MHz, methanol-74) 8 ppm 0.68 (br s, 1 H) 1.25 (s, 3 H) 1.27 (s, 1 H) 1.52 (br d, 7=9.92 Hz, 3 H) 1.57 (br s, 4 H) 1.87 (s, 1 H) 1.92 - 2.09 (m, 3 H) 2.23 - 2.35 (m, 1 H) 2.66 (s, 3 H) 2.68 - 2.72 (m, 1 H) 2.72 - 2.79 (m, 2 H) 3.34 - 3.37 (m, 1 H) 3.37 - 3.40 (m, 1 H) 3.41 - 3.50 (m, 2 H) 3.54 - 3.71 (m, 1 H) 5.46 (s, 1 H) 6.46 - 6.58 (m, 1 H) 7.28 (br t, 7=7.61 Hz,

[0996] 2 H) 7.46 (d, 7=8.16 Hz, 1 H) 7.61 (d, 7=7.72 Hz, 1 H) 7.70 (br d, 7=4.63 Hz, 1 H) 7.72 - 7.73 (m, 1 H); LCMS (ESI); m / z 532 (MH+).

[0997] Example 46: 2-(2-cyclopropyl-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-(methyl(c7.s-3-(4- ((S)-l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B

[0998] TFA (1.85 g, 16.21 mmol, 1.2 mL, 16.74 eq) was added to a stirred solution of / c / 7-butyl 2-(2-

[0999] 150

[1000] Foley HoagUS13043895.1 MTX-03225 cyclopropyl-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2-(methyl(cis-3-(4-((S)-l,2,3,4- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetate (600 mg, 0.96 mmol, 1 eq) in DCM (6 mL) at 25°C. The mixture was stirred at 30°C for 16 h, judged to be complete by LCMS and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Condition Z2) to obtain a mixture of stereoisomers (130 mg). The mixture was separated by SFC (Condition O) to isolate two product containing peaks (Peak 1 and Peak 2).

[1001] Peak 1 was randomly assigned as Stereoisomer A (Compound 46A; 42.5 mg, 75.39 umol, 7.8% yield) and obtained as a solid. LCMS; m / z 564.3 (M+, 100%).JH NMR (400 MHz, chloroform-d) 8 = 8.87 (br s, 1H), 7.54 (br d, J = 5.3 Hz, 1H), 7.21 (br d, J = 7.6 Hz, 2H), 7.10 (t, J = 7.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.45 - 6.38 (m, 1H), 5.13 (s, 1H), 4.47 (td, J = 3.6, 7.3 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.68 - 3.48 (m, 4H), 3.44 - 3.32 (m, 2H), 3.20 - 3.06 (m, 1H), 2.72 (br t, J = 6.1 Hz, 2H), 2.53 - 2.39 (m, 2H), 2.24 (s, 1H), 2.07 - 1.77 (m, 8H), 1.70 - 1.48 (m, 7H), 1.03 (br d, J = 8.3 Hz, 2H), 0.86 (br d, J = 4.3 Hz, 2H).

[1002] Peak 2 was randomly assigned as Stereoisomer B, (Compound 46B; 40.8 mg, 72.38 umol, 7.5% yield) and obtained as a solid. LCMS; m / z 564.3 (M+, 100%). 'H NMR (400 MHz, chloroform-d) 8 = 8.87 (br s, 1H), 7.61 (br d, J = 5.5 Hz, 1H), 7.28 (br s, 1H), 7.25 (br s, 1H), 7.18 - 7.11 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.47 (t, J = 6.5 Hz, 1H), 5.35 (s, 1H), 4.49 (td, J = 3.6, 7.2 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.67 - 3.49 (m, 4H), 3.45 - 3.25 (m, 3H), 2.80 - 2.69 (m, 2H), 2.56 - 2.45 (m, 2H), 2.40 (br s, 3H), 2.32 - 2.16 (m, 2H), 2.07 - 1.92 (m, 3H), 1.89 - 1.74 (m, 3H), 1.61 (dt, J = 6.1, 13.8 Hz, 7H), 1.07 (br d, J = 8.4 Hz, 2H), 0.94 (br d, J = 5.6 Hz, 1H), 0.76 (br d, J = 5.7 Hz, 1H).

[1003] Example 47: 2-(2-cyclopentylpyridin-3-yl)-2-(methyl(cA-3-(4-((S)-l,2,3,4-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1004] Compound 47A;XH NMR (400 MHz, methanol-ch) 8 = 8.51 (d, J = 3.9 Hz, 1H), 8.04 (br d, J = 7.4 Hz, 1H), 7.69 (d, J = 4.6 Hz, 1H), 7.32 (d, J= 7.2 Hz, 1H), 7.23 (dd, J= 4.8, 7.9 Hz, 1H), 6.55 (dd, J = 5.5, 7.0 Hz, 1H), 4.78 (s, 1H), 3.69 - 3.57 (m, 2H), 3.47 - 3.40 (m, 1H), 3.37 - 3.33 (m, 2H), 2.76 (br t, J= 6.3 Hz, 2H), 2.69 - 2.62 (m, 1H), 2.61 (s, 3H), 2.28 - 2.19 (m, 1H), 2.19 - 2.11

[1005] 151

[1006] FoleyHoagUS13043895.1 MTX-03225

[1007] (m, 1H), 2.09 - 1.96 (m, 3H), 1.96 - 1.86 (m, 4H), 1.86 - 1.69 (m, 4H), 1.64 - 1.52 (m, 5H), 1.52 - 1.47 (m, 2H), 1.29 (s, 1H), 0.10 (s, 1H); LCMS (ESI); m / z 493.4 (MH+).

[1008] Compound 47B;JH NMR (400 MHz, methanol-dj) 8 = 8.49 (d, J = 3.6 Hz, 1H), 8.04 (br d, J = l.Q Hz, 1H), 7.69 (d, J= 4.5 Hz, 1H), 7.29 (d, J= 6.8 Hz, 1H), 7.23 (dd, J= 4.8, 7.9 Hz, 1H), 6.53 (dd, J= 5.4, 7.1 Hz, 1H), 4.72 (s, 1H), 3.71 - 3.59 (m, 2H), 3.43 (br dd, J= 2.8, 5.8 Hz, 1H), 3.35 (dt, J = 1.8, 5.9 Hz, 2H), 3.26 - 3.26 (m, 1H), 2.75 (t, J= 6.3 Hz, 2H), 2.59 (br dd, J= 5.7, 11.3 Hz, 1H), 2.54 (s, 3H), 2.22 - 2.11 (m, 2H), 2.03 (br dd, J= 6.1, 11.3 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.92 - 1.83 (m, 4H), 1.83 - 1.73 (m, 3H), 1.63 - 1.54 (m, 4H), 1.54 - 1.47 (m, 3H); LCMS (ESI); m / z 493.4 (MH+).

[1009] Example 48: 2-(methyl(cis-3-(4-((S)- 1,2,3, 4-tetrahydro-l, 8 -naphthyr idin-2- yl)butoxy)cyclobutyl)amino)-2-(2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)acetic acid

[1010] Stereoisomer A and Stereoisomer B.

[1011] Compound 48A;JH NMR (400 MHz, methanol-d4) 8 = 8.48 (d, 7=4.5 Hz, 1H), 8.05 (br d, 7=7.7 Hz, 1H), 7.69 (br d, 7=4.5 Hz, 1H), 7.29 (d, J=1.2 Hz, 1H), 7.23 (dd, 7=4.7, 7.8 Hz, 1H), 6.53 (dd, 7=5.4, 7.0 Hz, 1H), 4.67 (br s, 1H), 4.05 (dt, 7=3.9, 10.5 Hz, 2H), 3.70 - 3.60 (m, 3H), 3.59 - 3.52 (m, 1H), 3.42 (br d, 7=5.3 Hz, 1H), 3.39 - 3.34 (m, 2H), 3.20 (br d, 7=6.7 Hz, 1H), 2.75 (t, 7=6.4 Hz, 2H), 2.56 (br dd, 7=5.4, 10.6 Hz, 1H), 2.47 (s, 3H), 2.20 - 2.04 (m, 3H), 2.03 - 1.94 (m, 2H), 1.89 - 1.77 (m, 2H), 1.67 (br d, 7=14.3 Hz, 1H), 1.61 - 1.44 (m, 7H), 1.29 (s, 1H); LCMS (ESI); m / z 509.4 (MH+).

[1012] Compound 48B;'H NMR (400 MHz, methanol-d4) 8 = 8.50 (dd, 7=1.4, 4.6 Hz, 1H), 8.05 (dd, 7=1.3, 7.9 Hz, 1H), 7.69 (d, 7=4.4 Hz, 1H), 7.32 (d, 7=6.2 Hz, 1H), 7.25 (dd, 7=4.7, 7.9 Hz, 1H), 6.54 (dd, 7=5.4, 7.1 Hz, 1H), 4.71 (s, 1H), 4.11 - 3.99 (m, 2H), 3.69 - 3.60 (m, 3H), 3.57 - 3.49 (m, 1H), 3.43 (br s, 1H), 3.37 (t, 7=5.9 Hz, 2H), 3.26 (br s, 1H), 2.76 (t, 7=6.4 Hz, 2H), 2.67 - 2.56 (m, 1H), 2.50 (s, 3H), 2.24 - 2.08 (m, 3H), 2.01 - 1.79 (m, 4H), 1.69 - 1.48 (m, 8H), 1.29 (s, 1H); LCMS (ESI); m / z 509.4 (MH+).

[1013] 152

[1014] Foley HoagUS13043895.1 MTX-03225

[1015] Example 49:

[1016] 2-(2-(4,4-dimethyltetrahydrofuran-3-yl)-5-fluorophenyl)-2-(methyl(c7.s-3-((5-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)pentyl)oxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer

[1017] B

[1018] Compound 49A;XH NMR (400 MHz, chloroform-d) 8 = 10.94 (br s, 1H), 7.55 (br d, J = 10.76 Hz, 1H), 7.28 - 7.33 (m, 1H), 7.19 (d, J= 7.21 Hz, 1H), 6.93 (td, J= 8.38, 2.81 Hz, 1H), 6.23 (d, J= 7.21 Hz, 1H), 4.52 (s, 1H), 4.31 (t, J= 8.07 Hz, 1H), 4.05 (dd, J= 8.68, 4.77 Hz, 1H), 3.76 - 3.90 (m, 1H), 3.71 - 3.75 (m, 1H), 3.66 (d, J= 8.19 Hz, 2H), 3.36 - 3.49 (m, 3H), 3.31 (br d, J = 6.24 Hz, 1H), 2.98 - 3.11 (m, 1H), 2.69 (br t, J= 5.81 Hz, 4H), 2.40 - 2.60 (m, 2H), 2.16 (s, 5H), 1.88 (br d, J= 5.50 Hz, 2H), 1.62 (br d, J= 5.87 Hz, 6H), 1.33 (s, 3H), 0.85 (s, 3H). LCMS: m / z = 554.3 [MH+],

[1019] Compound 496;^ NMR (400 MHz, chloroform-d) 8 = 11.08 (br s, 1H), 7.52 (br d, J= 9.66 Hz, 1H), 7.29 (br s, 1H), 7.19 (d, J = 7.09 Hz, 1H), 6.91 (td, 7 = 8.34, 2.87 Hz, 1H), 6.22 (d, 7= 7.21 Hz, 1H), 4.43 (s, 1H), 4.32 (t, 7= 8.13 Hz, 1H), 3.95 (dd, 7= 8.74, 4.58 Hz, 1H), 3.76 (br d, 7 = 8.19 Hz, 2H), 3.61 - 3.71 (m, 2H), 3.42 (br d, 7= 3.18 Hz, 3H), 3.29 (br d, J = 5.75 Hz, 1H), 3.05 (br s, 1H), 2.68 (br t, 7= 5.38 Hz, 4H), 2.46 - 2.59 (m, 2H), 2.26 (s, 5H), 1.84 - 1.91 (m, 2H), 1.46 - 1.71 (m, 6H), 1.23 (s, 3H), 0.77 (s, 3H). LCMS: m / z = 554.3 [MH+],

[1020] Example 50: 2-(3,5-difluoro-2-((S)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(cA-3-(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1021] Compound 50A;; 'H NMR (400 MHz, methanol-d4) 8 = 7.57 (d, 7= 7.1 Hz, 1H), 7.30 - 7.15 (m,

[1022] 153

[1023] Foley HoagUS13043895.1 MTX-03225

[1024] 2H), 6.59 (d, J = 7.1 Hz, 1H), 5.54 (br dd, J = 1.3, 2.9 Hz, 1H), 4.88 - 4.84 (m, 1H), 4.25 - 4.11 (m, 1H), 3.75 - 3.58 (m, 2H), 3.56 - 3.44 (m, 3H), 3.41 - 3.33 (m, 2H), 2.86 - 2.78 (m, 4H), 2.70 (br t, J = 7.7 Hz, 4H), 2.36 - 2.25 (m, 1H), 1.99 - 1.90 (m, 5H), 1.87 - 1.66 (m, 7H), 1.64 - 1.56 (m, 3H). LCMS: m / z = 544.3 [MH+],

[1025] Compound SOB^H NMR (400 MHz, methanol-dr) 8 = 7.57 (d, J= 7.3 Hz, 1H), 7.26 - 7.15 (m, 2H), 6.59 (d, J = 7.7 Hz, 1H), 6.05 (br s, 1H), 5.06 - 4.98 (m, 1H), 4.31 - 4.20 (m, 1H), 3.80 - 3.60 (m, 3H), 3.49 (br t, J= 5.5 Hz, 2H), 3.40 (br d, J= 6.0 Hz, 2H), 2.85 - 2.78 (m, 2H), 2.77 - 2.67 (m, 4H), 2.89 - 2.60 (m, 1H), 2.35 - 2.18 (m, 1H), 2.05 - 1.91 (m, 5H), 1.88 - 1.53 (m, 9H). LCMS: m / z = 544.3 [MH+],

[1026] Example 51: 2-(3,5-difluoro-2-((R)-tetrahydro-2H-pyran-2-yl)phenyl)-2-(methyl(c7.s-3-(4-

[1027] (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1028] Compound 51A;JH NMR (400 MHz, methanol-d4) 8 = 7.62 - 7.53 (m, 1H), 7.27 (br d, J = 9.3 Hz, 1H), 7.17 (ddd, J= 2.4, 8.5, 11.3 Hz, 1H), 6.59 (d, J= 7.5 Hz, 1H), 5.43 (br s, 1H), 4.90 (br s, 1H), 4.16 (br d, J= 11.2 Hz, 1H), 3.73 - 3.59 (m, 2H), 3.54 - 3.46 (m, 3H), 3.41 - 3.34 (m, 2H), 2.87 - 2.64 (m, 8H), 2.39 - 2.26 (m, 1H), 2.20 - 1.89 (m, 6H), 1.87 - 1.67 (m, 6H), 1.65 - 1.53 (m, 3H). LCMS: m / z = 544.3 [MH+],

[1029] Compound SIB^H NMR (400 MHz, methanol-dr) 8 = 7.58 (d, J= 7.3 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.60 (d, J= 7.3 Hz, 1H), 5.98 (br s, 1H), 5.01 (br d, J= 10.8 Hz, 1H), 4.26 (br d, J= 10.8 Hz, 1H), 3.77 - 3.60 (m, 3H), 3.51 - 3.46 (m, 2H), 3.40 (br t, J= 5.5 Hz, 2H), 2.85 - 2.58 (m, 8H), 2.34 - 2.22 (m, 1H), 2.08 - 1.91 (m, 5H), 1.87 - 1.55 (m, 9H). LCMS: m / z = 544.3 [MH+],

[1030] Example 52: 2-(3,5-difluoro-2-cyclopropyl)phenyl)-2-(methyl(cA-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1031] 154

[1032] Foley HoagUS13043895.1 MTX-03225

[1033] Compound 52A;JH NMR (400 MHz, CDCh) 8 = 9.96 (s, 1H), 7.31-7.30 (m, 1H), 7.24 (s, 1H), 6.74 (t, J = 8.0 Hz, 1H), 6.36 (d, J= 3.6Hz, 1H), 5.32 (s, 1H), 3.75 (s, 1H), 3.56 (s, 2H), 3.40 (s, 3H), 3.73-3.40 (m, 8H), 2.38-2.25 (m, 3H), 1.92 (s, 2H), 1.73 (s, 3H), 1.71 (s, 2H),1.26 (s, 1H), 1.08 (d, J= 7.6Hz, 2H), 0.95 (s, 1H), 0.68 (s, 1H). LCMS: m / z = 500.3 [MH+],

[1034] Compound 52B;JH NMR (400 MHz, CDCh) 8 = 7.29 (s, 2H), 6.66 (s, 1H), 6.29 (s, 1H), 5.04 (s, 1H), 3.68 (s, 1H), 3.46 (s, 4H), 3.25 (s, 1H), 2.72 (s, 5H), 2.50 (s, 3H), 2.34 (s, 3H), 1.90-1.83 (m, 5H), 1.65 (s, 2H), 1.28 (s, 1H), 1.05 (s, 2H), 0.84 (s, 2H). LCMS: m / z = 500.3 [MH+],

[1035] Example 53: 2-(3,5-difluoro-2-((S)-tetrahydrofuran-2-yl)phenyl)-2-(methyl(czs-3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1036] Compound53; ' H NMR (400 MHz, methanol-d4) 8 = 7.36 (br d, J=8.82 Hz, 1 H), 7.23 (br d, J=8.38 Hz, 1 H), 7.00 (br t, .7=11.03 Hz, 1 H), 6.41 (d, .7=7,50 Hz, 1 H), 5.29 - 5.36 (m, 1 H), 4.76 (br s, 1 H), 4.04 - 4.12 (m, 1 H), 3.90 (br s, 1 H), 3.59 (t, J=6.95 Hz, 1 H), 3.38 - 3.42 (m, 2 H), 3.32 - 3.36 (m, 2 H), 3.26 (br s, 1 H), 2.72 (t, .7=6.17 Hz, 2 H), 2.52 - 2.59 (m, 6 H), 2.40 (br s, 1 H), 2.05 - 2.20 (m, 5 H), 1.85 - 1.92 (m, 3 H), 1.68 (quin, .7=7.61 Hz, 2 H), 1.51 - 1.58 (m, 2 H). LCMS: m / z = 530.3 [MH+],

[1037] Compound 53B;1H NMR (400 MHz, methanol-d4) 8 = 7.34 (br d, .7=9.04 Hz, 1 H), 7.17 (d, .7=7.72 Hz, 1 H), 7.00 - 7.07 (m, 1 H), 6.37 (d, .7=7.50 Hz, 1 H), 5.23 - 5.29 (m, 1 H), 5.08 (s, 1 H), 4.16 - 4.24 (m, 1 H), 3.83 - 3.90 (m, 1 H), 3.64 (br t, .7=6.73 Hz, 1 H), 3.49 (br s, 1 H), 3.32 - 3.41 (m, 5 H), 2.71 (t, .7=6.39 Hz, 2 H), 2.62 (br d, .7=5.95 Hz, 1 H), 2.53 (s, 4 H), 2.28 - 2.36 (m, 1 H), 2.22 (br d, .7=7,72 Hz, 4 H), 2.10 (br s, 1 H), 1.93 - 2.02 (m, 1 H), 1.84 - 1.92 (m, 2 H), 1.63 - 1.71 (m, 2 H), 1.50 - 1.59 (m, 1 H), 1.48 - 1.59 (m, 1 H). LCMS: m / z = 530.3 [MH+],

[1038] 155

[1039] FoleyHoagUS13043895.1 MTX-03225

[1040] Example 54: 2-(3,5-difluoro-2-((R)-tetrahydrofuran-2-yl)phenyl)-2-(methyl(czs-3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and

[1041] Stereoisomer B.

[1042] Compound 54A;1H NMR (400 MHz, methanol-d4) 8 = 7.36 (br d, J=10.14 Hz, 1 H), 7.25 (d, J=7.50 Hz, 1 H), 6.96 - 7.05 (m, 1 H), 6.42 (d, 7=7.28 Hz, 1 H), 5.33 (br t, 7=7.28 Hz, 1 H), 4.76 (br s, 1 H), 4.05 - 4.13 (m, 1 H), 3.86 - 3.93 (m, 1 H), 3.59 (quin, 7=6.95 Hz, 1 H), 3.37 - 3.42 (m, 2 H), 3.32 - 3.37 (m, 2 H), 3.27 (br s, 1 H), 2.73 (t, 7=6.17 Hz, 2 H), 2.52 - 2.62 (m, 6 H), 2.36 - 2.45 (m, 1 H), 2.13 - 2.22 (m, 3 H), 2.03 - 2.12 (m, 2 H), 1.84 - 1.93 (m, 3 H), 1.63 - 1.73 (m, 2 H), 1.49 - 1.59 (m, 2 H). LCMS: m / z = 530.3 [MH+],

[1043] Compound 54B;JH NMR (400 MHz, methanol-c ) 8 = 7.34 (br d, 7=10.80 Hz, 1 H), 7.19 (br d, 7=7.06 Hz, 1 H), 7.04 (br t, 7=9.37 Hz, 1 H), 6.38 (d, 7=7.28 Hz, 1 H), 5.27 (br t, 7=7.72 Hz, 1 H), 5.08 (br s, 1 H), 4.20 (q, 7=7.13 Hz, 1 H), 3.87 (td, 7=8.21, 5.84 Hz, 1 H), 3.64 (quin, 7=6.89 Hz, 1 H), 3.49 (br s, 1 H), 3.37 - 3.42 (m, 2 H), 3.35 (td, 7=6.34, 1.87 Hz, 2 H), 2.71 (t, 7=6.17 Hz, 2 H), 2.57 - 2.68 (m, 1 H), 2.50 - 2.57 (m, 5 H), 2.27 - 2.37 (m, 1 H), 2.16 - 2.27 (m, 4 H), 2.05 - 2.15 (m, 1 H), 1.92 - 2.02 (m, 1 H), 1.88 (dt, 7=11.63, 5.98 Hz, 2 H), 1.63 - 1.72 (m, 2 H), 1.49 - 1.59 (m, 2 H). LCMS: m / z = 530.3 [MH+],

[1044] Example 55: 2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(czs-3-(3-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)propoxy)cyclobutyl)amino)acetic acid Stereoisomer A and

[1045] Stereoisomer B

[1046] Compound 55A;JH NMR (400 MHz, MeOD) 8 = 7.30-7.28 (m, 2H), 6.94-6.88 (m, 1H), 6.44 (d, J = 7.2 Hz, 1H), 4.65 (s, 1H), 4.02 (d, J = 11.2 Hz, 2H), 3.63-3.42 (m, 3H), 3.41-3.40(m, 3H),

[1047] 156

[1048] Foley HoagUS13043895.1 MTX-03225

[1049] 3.37-3.35 (m, 2H), 3.31-3.30 (m, 1H), 2.73-2.72 (m, 2H), 2.66-2.64 (m, 2H), 2.62-2.61 (m, 1H), 2.42 (s, 3H), 2.26-2.17 (m, 3H), 2.08-2.01 (m, 1H), 1.97-1.23 (m, 5H), 1.69 (d, J= 11.91Hz, 1H), 1.58 (d, J = 12.0 Hz, 1H). LCMS: m / z = 530.3 [MH+],

[1050] Compound 55B;JH NMR (400 MHz, MeOD) 8 = 7.50 (d, J = 7.2 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 7.01-6.98 (m, 1H), 6.56 (d, J= 7.6 Hz, 1H), 4.80 (s, 1H), 4.02 (d, J= 11.2 Hz, 2H), 3.64-3.48 (m, 3H), 3.45 (t, J = 5.2 Hz, 2H), 3.39-3.30 (m, 4H), 2.79 (t, J = 6.17 Hz, 2H), 2.73 (t, J = 7.61 Hz, 2H), 2.66-2.61 (m, 1H), 2.56 (s, 3H), 2.33-2.14 (m, 4H), 2.04-2.00 (m, 1H), 1.96-1.85 (m, 4H), 1.71 (d, J= 12.79 Hz, 1H), 1.59 (d, J= 12.57 Hz, 1H). LCMS: m / z = 530.3 [MH+],

[1051] Example 56: 2-(3,5-difluoro-2-isopropoxyphenyl)-2-(methyl(cA-3-(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1052] Compound 56A;1H NMR (400 MHz, chloroform-d) 8 = 10.46 (br s, 1H), 7.23 (br d, J=9.3 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 6.77 - 6.70 (m, 1H), 6.24 (d, J=7.1 Hz, 1H), 4.67 (s, 1H), 4.52 (td, J=6.1, 12.6 Hz, 1H), 3.63 (br t, J=7.3 Hz, 1H), 3.43 (br t, J=5.5 Hz, 2H), 3.37 (t, J=6.2 Hz, 2H), 3.04 - 2.94 (m, 1H), 2.71 - 2.64 (m, 4H), 2.48 (br dd, J=5.7, 11.0 Hz, 1H), 2.38 (br s, 1H), 2.26 (s, 3H), 1.98 (br s, 2H), 1.91 - 1.83 (m, 2H), 1.81 - 1.72 (m, 2H), 1.65 - 1.56 (m, 2H), 1.38 - 1.33 (m, 6H). LCMS: m / z = 518.2 [MH+],

[1053] Compound 56A; ' H NMR (400 MHz, chloroform-d) 8 = 10.44 (s, 1H), 7.22 (br d, J=9.3 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 6.78 - 6.70 (m, 1H), 6.24 (d, J=7.3 Hz, 1H), 4.68 (s, 1H), 4.52 (td, J=6.2, 12.3 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.43 (br t, J=5.6 Hz, 2H), 3.37 (t, J=6.4 Hz, 2H), 3.04 - 2.96 (m, 1H), 2.71 - 2.65 (m, 4H), 2.49 (br d, J=4.0 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.26 (s, 3H), 2.01 (br s, 2H), 1.87 (br s, 2H), 1.76 (br d, J=6.4 Hz, 2H), 1.66 - 1.57 (m, 2H), 1.35 (t, J=5.6 Hz, 6H). LCMS: m / z = 518.2 [MH+],

[1054] Example 57: 2-(3,5-difluoro-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(cA-3-(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1055] 157

[1056] FoleyHoagUS13043895.1 MTX-03225

[1057] Compound 57A; ' H NMR (400 MHz, methanol-74) 8 ppm 7.46 (d, 7=7.34 Hz, 1 H) 7.22 (br d, 7=8.19 Hz, 1 H) 6.89 - 6.99 (m, 1 H) 6.49 (d, 7=7.34 Hz, 1 H) 4.82 - 4.85 (m, 1 H) 3.92 (br d, 7=11.25 Hz, 2 H) 3.48 - 3.59 (m, 3H) 3.46 - 3.59 (m, 2 H) 3.34 - 3.44 (m, 3 H) 3.25 - 3.33 (m, 3 H) 2.71 (br t, 7=6.11 Hz, 2 H) 2.52 - 2.65 (m, 6 H) 2.16 - 2.29 (m, 2 H) 2.08 (br d, 7=8.93 Hz, 2 H) 1.81 - 1.98 (m, 1 H) 1.80 - 1.98 (m, 2 H) 1.80 - 1.95 (m, 1 H) 1.58 - 1.70 (m, 3 H) 1.41 - 1.55 (m, 3 H). LCMS: m / z = 544.3 [MH+],

[1058] Compound 57B;JH NMR (400 MHz, methanol-74) 8 ppm 7.34 - 7.39 (m, 1 H) 7.36 (br d, 7=7.09 Hz, 1 H) 7.29 (br d, 7=11.25 Hz, 1 H) 6.93 (br t, 7=8.99 Hz, 1 H) 6.49 (d, 7=7.34 Hz, 1 H) 4.69 (s,

[1059] 1 H) 4.02 (br d, 7=10.88 Hz, 2 H) 3.56 - 3.69 (m, 1 H) 3.55 - 3.70 (m, 2 H) 3.36 - 3.50 (m, 7 H) 3.23 (br t, 7=7.34 Hz, 1 H) 2.77 (br t, 7=6.05 Hz, 2 H) 2.53 - 2.67 (m, 3 H) 2.22 - 2.35 (m, 1 H) 2.16 - 2.35 (m, 1 H) 2.02 - 2.11 (m, 1 H) 1.86 - 2.01 (m, 3 H) 1.68 - 1.79 (m, 2 H) 1.53 - 1.66 (m,

[1060] 2 H). LCMS: m / z = 544.3 [MH+],

[1061] Example 58: 2-(4-(cyclopropylmethyl)-2-(tetrahydro-2H-pyran-4-yl)phenyl)-2-(methyl(czs-3-(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butoxy)cyclobutyl)amino)acetic acid Stereoisomer A and Stereoisomer B.

[1062] Compound 58A; ' H NMR (400 MHz, methanol-d4) 8 = 7.59 (d, J=8.2 Hz, 1H), 7.30 (s, 1H), 7.26 (br d, J=6.8 Hz, 1H), 7.16 (br d, J=8.2 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 4.79 (s, 1H), 4.10 - 3.99 (m, 2H), 3.66 (br t, J=11.2 Hz, 2H), 3.59 (br t, J=6.6 Hz, 1H), 3.42 - 3.37 (m, 3H), 3.33 (br s, 1H), 3.23 (br t, J=11.9 Hz, 1H), 2.73 (br t, J=6.3 Hz, 2H), 2.65 (s, 4H), 2.58 - 2.53 (m, 4H), 2.32 (br d, J=8.8 Hz, 1H), 2.02 - 1.85 (m, 5H), 2.02 - 1.85 (m, 1H), 1.73 - 1.63 (m, 4H), 1.58 - 1.49 (m, 2H), 1.00 - 0.92 (m, 1H), 0.53 - 0.46 (m, 2H), 0.19 (q, J=5.0 Hz, 2H). LCMS: m / z = 562.4 [MH+], 158

[1063] Foley HoagUS13043895.1 MTX-03225

[1064] Compound 58B; ' H NMR (400 MHz, methanol-d4) 8 = 7.56 (br d, J=3.5 Hz, 2H), 7.32 (s, 1H), 7.20 (br d, J=7.7 Hz, 1H), 6.59 (br s, 1H), 4.90 (br s, 1H), 4.10 - 3.98 (m, 2H), 3.71 - 3.61 (m, 3H), 3.47 (br t, J=5.5 Hz, 2H), 3.35 (br s, 2H), 3.22 (br s, 1H), 2.81 (br s, 2H), 2.70 (br s, 5H), 2.56 (d, J=6.8 Hz, 2H), 2.37 (br s, 1H), 2.01 (br d, J=11.5 Hz, 2H), 1.95 (br d, J=5.5 Hz, 4H), 1.71 (br s, 4H), 1.59 (br s, 2H), 1.33 - 1.28 (m, 1H), 0.97 (br s, 1H), 0.54 - 0.48 (m, 2H), 0.20 (br d, J=4.9 Hz, 2H). LCMS: m / z = 562.4 [MH+],

[1065] Example B: Fluorescence polarization assays of compounds for avβ8 binding

[1066] Fluorescence Polarization (FP) assays were used to measure compound activity through binding competition with the fluorescein-labeled peptide HGRGDLGRLKK. In the assay, 20 nM of integrin avb8 was incubated with the test compound in 2 mM manganese chloride, 0.1 mM calcium chloride, 20 mM HEPES buffer at pH 7.3, 150 mM sodium chloride, 0.01% Triton X- 100, 2% DMSO, and 3 nM of the fluorescein- labeled peptide. The assays were run in 384- well plates. The integrin protein was pre-incubated with the test compounds for 15 minutes at 22°C before the fluorescein-labeled peptide was added. After the fluorescein-labeled peptide was added, the assay was incubated at 22°C for 1 hour and fluorescence polarization was measured. ICso values were determined by nonlinear regression, 4-parameter curve fitting.

[1067] The ICso values obtained from the FP assay in Example B for each test compound are provided by category as follows: A: IC50 <50 nM; B: IC50 = 50 - 500 nM; C: >500 nM - 1,000 nM; D: >1,000 nM.

[1068] 159

[1069] Foley HoagUS13043895.1 MTX-03225

[1070] 160

[1071] Foley HoagUS13043895.1 MTX-03225

[1072] INCORPORATION BY REFERENCE

[1073] All of the U.S. patents and U.S. patent application publications cited herein are hereby incorporated by reference.

[1074] EQUIVALENTS

[1075] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are encompassed by the following claims.

[1076] 161

[1077] Foley HoagUS13043895.1

Claims

MTX-03225We claim:

1. A compound of formula (I):A-B-C (I) wherein:Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; each Ra3 is independently H, alkyl, -alkylene-OH, -alkylene-alkoxy, heterocyclyl, or heterocycloalkyl; each Ri and Ri’ is independently H, alkyl, halide, alkoxy, CF3, OH, alkylene-OH, NO2, -N(H)R, or NH2; a is 0, 1 or 2; b is 0, 1, 2, 3 or 4; each b’ is independently 0, 1, 2 or 3;B is -alkylene-O-*, where * represents the point of attachment to C;wherein n is 0;Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;Ra is H;R2 is a monocyclic aryl or 5- to 6-membered monocyclic heteroaryl optionally substituted with one or more R4 and optionally substituted with one or more R5, wherein when R2 is not substituted with R4, R2 is substituted with at least one R5; each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O- 162Foley HoagUS13043895.1MTX-03225 heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each R4b, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.The compound of claim 1 , wherein, wherein >i and >2 are each H; p is 0, 1, 2 or 3; andL is -O-.The compound of claim 1 , wherein B is, wherein q is 1, 2 or 3.The compound of claim 3, wherein q is 2 or 3.The compound of any one of claims 1 to 4, wherein163Foley HoagUS13043895.1MTX-03225The compound of any one of claims 1 to 4, wherein7. The compound of any one of claims 1-6, wherein each R4, independently, is cycloalkyl, heterocycloalkyl, -O-heterocycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib.

8. The compound of any one of claims 1-7, wherein each Rib, independently, is halide or lower alkyl.

9. The compound of any one of claims 1-8, wherein R4 is (C3-C6)cycloalkyl, (C3- C6)heterocycloalkyl, -O-(C3-C6)heterocycloalkyl, monocyclic aryl, -(Ci-C3)alkylene-(Cs- C6)heteroaryl-(C3-C6)cycloalkyl, a 10 to 11 membered spirocyclic cycloalkyl, a 10 to 11 membered spirocyclic heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib.

10. The compound of any one of claims 1-9, wherein R2 is substituted with one R4 group.

11. The compound of any one of claims 1-10, wherein R2 is substituted with one or two R5 groups.

12. The compound of any one of claims 1-11, wherein the cycloalkyl in R4 and Rib is Cecycloalkyl and the heterocycloalkyl in R4 and Rib is a 6-membered heterocycloalkyl comprising at least one oxygen heteroatom.

13. The compound of any one of claims 1-12, wherein Rj is halide, alkyl, or cycloalkyl.

14. The compound of any one of claims 1 to 6, wherein R4 is selected from164Foley HoagUS13043895.1MTX-03225165Foley HoagUS13043895.1MTX-0322517. The compound of any one of claims 1 to 16, wherein R2 is selected from:

18. The compound of any one of claims 1 to 17, wherein R2 is selected from:

19. The compound of claim 6, wherein20. The compound of claim 1, wherein R4 is21. A compound of formula (I):A-B-C (I) wherein:166Foley HoagUS13043895.1MTX-03225wherein all instances of Ri are H;B is selected from the group consisting of:n n is 0;Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;R2 is is selected from:m is 0, 1 or 2;Ra is H; each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O- heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene-heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and -167Foley HoagUS13043895.1MTX-03225 alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each Rib, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylene-cycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-aryl-cycloalkyl, - alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1 to 21, wherein Rc is methyl.

23. The compound of any one of claims 1 to 22, wherein each R5 independently is F, Cl, CF3, -J 'XOMe, -OEt, , or .

24. The compound of any one of claims 1 to 22, wherein each Rj independently is F, Cl, CF3, - OMe, or -OEt.

25. A compound selected from any one of Tables 1 A, IB, 2A, 2B, 3A, 3B, 4A, 4B, 5, 6 or 7, or a pharmaceutically acceptable salt thereof.

26. A compound of formula (I):A-B-C(I) wherein:168Foley HoagUS13043895.1MTX-03225Z is CRalRa2 or NRa3; each Rai and Ra2 is independently H, alkyl, halide, alkoxy, CF3, OH, -alkylene- OH, NO2, -N(H)-alkyl, or NH2; each Ra3 is independently H, alkyl, -alkylene-OH, -alkylene-alkoxy, heterocyclyl, or heterocycloalkyl; each Ri and Ri1is independently alkyl, halide, alkoxy, CF3, OH, -alkylene-OH, - alkylene-alkoxy, NO2, -N(H)-alkyl, or NH2; a is 0, 1, or 2; a' is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; b' is 0, 1, 2, or 3;B is -alkylene-(O)-*, where * denotes the point of attachment of B to C;Rc is H or alkyl optionally substituted with halide, alkoxy, or hydroxyl;Ra is H; n is 0;R2 is substituted or unsubstituted aryl or heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26, wherein a and b are each 0.

28. The compound of claim 26, wherein Z is -NH-.

29. The compound of claim 28, wherein B is -(CH2)3-O*-, -(CH2)4-O*- or -(CH2)s-O*-.169Foley HoagUS13043895.1MTX-0322530. The compound of any one of claim 26-29, wherein wherein R2 is a 6-membered aryl or heteroaryl.

31. The compound of any one of claims 26-30, wherein R2 is selected from:m is 0, 1 or 2;Ra is H; each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O-heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene- heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each Rib, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; and each Rj is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylenecycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene- aryl-cycloalkyl, -alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy;.

32. The compound of any one of claims 26-30, wherein R2 is selected from:170Foley HoagUS13043895.1MTX-03225m is 0, 1 or 2;Ra is H; each R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl, -O-cycloalkyl, alkylene-O-heterocycloalkyl, -O-heterocycloalkyl, -O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl, -alkylene- heteroaryl-cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and - alkylene-O-alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each Rib, independently, is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; and each R5 is independently selected from H, CN, halide, CF3, C(H)F2, C(F)H2, alkyl, cycloalkyl, -(O)-cycloalkyl, -(O)-heterocycloalkyl, -alkylene-alkoxy, -alkylenecycloalkyl, -alkylene-cycloalkyl-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene- aryl-cycloalkyl, -alkylene-heteroaryl-cycloalkyl, aryl, hydroxyl, and alkoxy.

33. A compound of Formula (Ila) or Formula (lib)171Foley HoagUS13043895.1MTX-03225whereinZ is CRalRa2 or NRa3; each of Rai, R 2 and Ra3 is H; p is 0, 1, 2 or 3;-L- is -O-;R3IS H; each Rbi and Rb2 is H;Rc is H or lower alkyl;R2 is substituted or unsubstituted 6-membered aryl or heteroaryl; and the absolute configuration at any stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, wherein Z is -CH2-.

35. The compound of claim 34, wherein p is 0, 1, or 2.

36. The compound of claim 35, wherein Rc is methyl.

37. The compound of any one of claims 33-36, wherein R2 is a 6- member aryl or heteroaryl.

38. The compound of claim 37, wherein R2 is a 6-membered aryl.

39. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is:172Foley HoagUS13043895.1MTX-03225R4 is independently selected from alkyl, -C(F2)CH3, cycloalkyl, heterocycloalkyl, - alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-heterocycloalkyl,-O- alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, aryl , -alkylene-heteroaryl- cycloalkyl, spirocyclic cycloalkyl, spirocyclic heterocycloalkyl, and -alkylene-O- alkylene-cycloalkyl; wherein the cycloalkyl, heterocycloalkyl, or spirocyclic heterocycloalkyl in R4 is optionally substituted with one or more Rib; each R4bis halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; and each Rsa, R5b, R5cand Rs d, is independently selected from H, CN, halide, alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy, wherein the alkyl in each of R5a, R5b, Rscand Rsa, is optionally substituted with halide (e.g., CF3, C(H)F2, C(F)H2), alkoxy, aryl, cycloalkyl or heterocyclyl.

40. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is, and R4 is cycloalkyl, -O-cycloalkyl, or heterocycloalkyl optionally 173Foley HoagUS13043895.1MTX-03225 substituted with one or more R4b; each Rib is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl, spirocyclic cycloalkyl, or heterocycloalkyl optionally further substituted with one or more halide; Rsa is H; R5bis H, CN, halide, cycloalkyl or lower alkyl optionally substituted with one or more halide (e.g., R4b is CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with cycloalkyl, heterocyclyl, or halide, wherein the heterocyclyl in R5cis optionally further substituted with lower alkyl or cycloalkyl; and R5ais H, halide, alkoxy, -O-alkyl, heterocyclyl or -O-heterocyclyl.

41. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is, and R4 is -O-alkyl (e.g., -O-C(CH3)(CH3)), cycloalkyl (e.g., cyclopropyl), 5-6 member heterocycloalkyl comprising at least one O heteroatom and optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl or spirocyclobutyl) optionally substituted with halide, hetoerocycloalkyl or lower alkyl optionally substituted with one or more halide; R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl), or 5-6 member heteroaryl, the 5-6 membered heteroaryl inR5cbeing optionally substituted with halide, lower alkyl or cycloalkyl (e.g., cyclopropyl); and R5a is H, halide, alkoxy, -O-alkyl, 5-6 member heterocycloalkyl comprising at least one O heteroatom or -O-heterocycloalkyl.. In certain embodiments, R4 is -O-lower alkyl, cyclopropyl, or a 5- or 6- member hetoerocyclolkyl ring containing one oxygen atom, wherein the heterocycloalkyl ring is optionally substituted with halide, lower alkyl, or spirocyclic cycloaklyl or spirocyclic heterocycloalkyl each optionally substituted with halide or alkyl; R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H, or lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl), or 5-6 member heteroaryl, the 5-6 membered heteroaryl in R5cbeing optionally substituted with halide, lower alkyl or cycloalkyl (e.g., cyclopropyl); and R5a174Foley HoagUS13043895.1MTX-03225 is H, halide, alkoxy, -O-alkyl, 5-6 member heterocycloalkyl comprising at least one O heteroatom or -O-heterocycloalkyl.

42. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is, R4 is cycloalkyl (e.g., cyclopropyl), optionally substituted with one or more R4b; each Rib is halide, lower alkyl optionally further substituted with one or more halide, cycloalkyl (including spirocycl cycloalkyl), or heterocycloalkyl optionally further substituted with one or more halide; R5bis H, halide (e.g., F) or lower alkyl (e.g., methyl); and R5band R5aare both H.

43. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is, and R4 is substituted or unsubstituted cycloalkyl (e.g., cyclopropyl); and R5bis halide (e.g., F).

44. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 iswherein R4 is - cycloalkyl (e.g., C3-C6 cycloalkyl), or 5-6 member heterocycloalkyl comprising at least one O heteroatom, optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl); R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cIS H; and R5dis H.175Foley HoagUS13043895.1MTX-0322545. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 is, wherein R4 is -cycloalkyl (e.g., C3-C6 cycloalkyl), or 5-6 member heterocycloalkyl comprising at least one O heteroatom, optionally substituted with halide, alkyl, cycloalkyl (e.g., spirocyclopropyl); R5bis H, halide, or lower alkyl optionally substituted with halide (e.g., R5bis CF3, C(H)F2, C(F)H2); R5cis H; and R5d is H.

46. The compound of any one of claims 1-12, 14-16, 20, 17, 26-30, and 33-38, wherein R2 isR4 is cycloalkyl or heterocycloalkyl optionally substituted with cycloalkyl (e.g., spirocyclic cyclopropyl or cyclopropyl); and R5bis H, halide, lower alkyl optionally substituted with halide, cycloalkyl (e.g., cyclopropyl) or CN.

47. The compound of any one of claims 33-38 of Formula (IIa-1)(lla-1).

48. The compound of claim 47, whereinZ is CRalRa2, -O-, or NRa3; each of Rai, Ra2 and Ra3 is H; p is 0, 1, 2 or 3;R2 is substituted or unsubstituted 6-membered aryl or heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof;176Foley HoagUS13043895.1MTX-03225 or a pharmaceutically acceptable salt thereof.

49. The compound of any one of claims 33-38, of Formula (IIa-2)(IIa-2).

50. The compound of claim 49, whereinZ is CRalRa2, -O-, or NRa3; each of Rai, R 2 and Ra3 is H; p is 0, 1, 2 or 3;R2 is substituted or unsubstituted 6-membered aryl or heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.

51. The compound of any one of claims 33-38, of Formula (IIb-1)(IIb-1).

52. The compond of claim 51 , whereinZ is CRalRa2, -O-, or NRa3; each of Rai, Ra2 and Ra3 is H; p is 0, 1, 2 or 3;R2 is substituted or unsubstituted 6-membered aryl or heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.177Foley HoagUS13043895.1MTX-0322553. The compound of any one of claims 33-38, of Formula (IIb-2):(llb-2).

54. The compound of claim 53, whereinZ is CRalRa2 or NRa3; each of Rai, Ra2 and Ra3 is H; p is 0, 1, 2 or 3;R2 is substituted or unsubstituted bicyclic heteroaryl; and the absolute configuration at any unspecified stereocenter is R, S, or a mixture thereof; or a pharmaceutically acceptable salt thereof.Foley HoagUS13043895.1MTX-03225179Foley HoagUS13043895.1MTX-03225180Foley HoagUS13043895.1MTX-03225181Foley HoagUS13043895.1MTX-03225Foley HoagUS13043895.1MTX-03225183Foley HoagUS13043895.1MTX-03225184Foley HoagUS13043895.1MTX-03225185Foley HoagUS13043895.1MTX-03225186Foley HoagUS13043895.1MTX-03225187Foley HoagUS13043895.1MTX-03225188Foley HoagUS13043895.1MTX-03225189Foley HoagUS13043895.1MTX-03225190Foley HoagUS13043895.1MTX-03225191Foley HoagUS13043895.1MTX-03225192Foley HoagUS13043895.1MTX-03225193Foley HoagUS13043895.1MTX-0322557. A pharmaceutical composition, comprising a compound of any one of claims 1-56; and a pharmaceutically acceptable excipient or carrier.

58. The pharmaceutical composition of claim 57, wherein the pharmaceutically acceptable excipient or carrier is formulated for oral therapeutic administration of the compound.

59. A method of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-56 or a pharmaceutical composition of claim 57 or 58, thereby treating or preventing the disease.194Foley HoagUS13043895.1

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