Inhibiting alpha-v beta-8 integrin

Abstract

This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ8 integrin.

Description

MTX-04725 Inhibiting Alpha-V Beta-8 Integrin RELATED APPLICATION This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 683,113, filed August 14, 2024. TECHNICAL FIELD

[0001] This disclosure relates to novel chemical compounds and methods useful for inhibitingv 8integrin. BACKGROUND

[0002] In the tumor microenvironmentv 8is expressed on immune cells, mainly antigen presenting cells (APCs) and regulatory T cells (Tregs) as well as on the tumor cells and cancerassociated fibroblast. The major function of v 8 is activation of growth factor TGF- 1 and 3.The TGF- s are biosynthesized and stored in tissues as latent forms. The TGF- homodimer iskept latent by association with its dimeric prodomain (pro-TGF- ). The prodomain-derivedhomodimer prevents TGF- from binding TGF- receptor and is called latency-associatedpeptide (LAP). The latent TGF- complex is stored in the extracellular matrix or on the cellsurface for subsequent, integrin-dependent activation. The integrinv 8heterodimer bindsarginine–glycine–aspartic acid motifs (RGD domain) of the latent- TGF- -1 and 3 to liberate theactive TGF- cytokine from latent complex.

[0003] TGF- is a pleiotropic cytokine mediating multiple biological process includingdevelopment and homeostasis. TGF- is a key player in cell growth, differentiation, andapoptosis. It regulates extracellular matrix (ECM) production contributing to tissue repairprocesses. In the immune system TGF- is necessary for the development of distinct immunecell types, as well to promote immunosuppression. Homeostatic role of TGF- on immunity iscritical to prevent excessive inflammatory responses and essential for maintaining tolerance toself-antigens to prevent autoimmunity. As TGF- is ubiquitously expressed it activity needs tobe tightly regulated and when exacerbated lead to disease states. Dysregulation of TGF-signaling is involved in multiple disorders, especially cancer and fibrosis. 1MTX-04725

[0004] In cancer, the TGF- pathway has been implicated in many human neoplasticdiseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation,TGF- acts as a tumor suppressor; however, in tumor cells, TGF- loses its anti-proliferativeresponse and promotes cancer progression. The TGF- -promoted tumorigenesis is mainly drivenby downregulation of anti-tumor immunity. The immunosuppressive effect leads to tumorimmune tolerance. Additionally, TGF- facilitates epithelial to mesenchymal transition (EMT)and angiogenesis to increase tumor invasiveness. The integrin avb8 expression in cancerscorrelates with TGF- activity. It modulates inflammatory phenotype of the APCs and Tregs, themain cell types fundamental for T / NK cell driven anti-tumor activity. Thev 8integrin locallyactivates TGF- to regulate cross-talk between APCs and effector cells to skew immunity frominflammation to tolerance.

[0005] Inhibition of the integrin v 8-driven TGF- activation is proposed to reverse tumortolerance and enhance anti-tumor T / NK cell responses. In agreement with TGF- blockage, avb8inhibition can enhance outcomes in checkpoint inhibitors regimens or reverse checkpoint inhibitor resistance.

[0006] Ubiquitous expression and multifunctionality of TGF- limits application ofstrategies based on TGF- systemic blockage, as those approaches result is unwanted sideeffects. Blockage of TGF- activity by antagonizing the integrin v 8 increases the safety and hastherapeutic advantage over global TGF- inhibition. It allows for tissue localized and isoformselective TGF- blockage in specific immunological milieu. Therefore, there remains a need fortherapeutic compounds for inhibitingv 8integrin. SUMMARY

[0007] This disclosure relates to novel chemical compounds and methods useful for inhibitingv 8integrin. In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:MTX-04725wherein: theL is C4-6-alkyl optionally substituted with 1 to 6 R4; each of R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, C1-4alkyl, halogen, C1-4alkyloxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyloxy, C1-4- alkyloxy-C1-4alkyloxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, R2is H, or C1-4alkyl optionally substituted with 1 to 4 R5; R3ais halogen, C1-4alkyloxy, C3-5cycloalkoxy, cyano, or C1-4alkyl optionally substituted with one or more halogen; R3bis H, halogen, CF3or CN; R3cis H, halogen, CN, or C1-4alkyl; and R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, 5-6 member heteroaryl, C6aryl, -O- (C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), -O-(5-6 member heteroaryl), -O-(C6aryl), - CH2-(C3-6cycloalkyl), -CH2- (4-6-membered heterocycloalkyl), -CH2- (5-6 member heteroaryl), or - CH2-(C6aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6; R3eis H, halogen or C1-4alkyl optionally substituted with one or more halogen; or R3aand R3b, R3band R3c, R3cand R3d, or R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8;MTX-04725 each R4is independently H, halogen, C1-4alkyloxy or C1-4alkyl optionally substituted with one or more halogen, or two geminal R4groups together can form a spiro-cyclopropyl; each R5is independently halogen or C1-4alkyl optionally substituted with halogen; each R6is independently C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, C1-4alkyloxy, C3-6cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, oxo, 5-6-membered heteroaryl, or NRaRb; each R7is independently C1-4alkyl optionally substituted with one or more F, C1-4alkoxy or F; each R8is independently halogen, C1-4alkyl, C3-6cycloalkyl, or two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; each of Raand Rbis independently hydrogen, or C1-4alkyl optionally substituted with one or more halogen; a and b are each independently 0 or 1 provided a+b is 1 or 2; and m is 0, 1 or 2.

[0008] In some embodiments, the compound is a compound of Formula (II), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound is a compound of Formula (III), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound is a compound of Formula (IV), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound is a compound of Formula (V), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound is a compound of Formula (VI), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) above,pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound is a compound of Formula (VII), wherein Q, L, m, R2, R3a, R3b, R3c, R3d, R3e, and R7are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound is a compound selected from the following: ,pharmaceutically acceptable salt thereof.

[0015] In another aspect, the invention features a method of inhibiting avb8 integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method is for treating a solid tumor in a patient in need thereof.

[0016] In another aspect, the invention features a method of treating solid tumor in a patient, the method comprising administering to the patient in need thereof (a) a therapeutically effective amountMTX-04725 of any compound described herein, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.

[0017] In embodiments, the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.

[0018] In embodiments, the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.

[0019] In embodiments, the second active agent is an immune checkpoint inhibitor (e.g., an anti- PD-1 or an anti-PD-L1 therapy). In embodiments, an immune checkpoint inhibitor is selected from: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. DETAILED DESCRIPTION Definitions

[0020] 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.

[0021] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0022] 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.

[0023] 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 listedMTX-04725 with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0024] 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.

[0025] 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.MTX-04725

[0026] 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.

[0027] 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.

[0028] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans- isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0029] 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.

[0030] 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.

[0031] The terms “ v 8”, “avB8”, “avb8”, “alpha-v beta-8” and “alpha v beta 8” and the like asused herein all refer tov 8.MTX-04725

[0032] 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; (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.

[0033] 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.)

[0034] 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 purificationMTX-04725 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).

[0035] 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.

[0036] 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).

[0037] 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.

[0038] Whenever a term (e.g., alkyl or aryl) or either of their prefix roots (e.g., alk- or ar-) appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, heteroarylene is the divalent moiety of heteroaryl, and heterocycloalkylene is the divalent moiety of heterocycloalkyl. Similarly, affixing the suffix “-oxy” to a group indicates the group is attached to the parent molecular structure through an oxygen atom (- O-) such as “alkyloxy,” “alkoxy” or “cycloalkoxy” as used herein.MTX-04725

[0039] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0040] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, “Me” and – CH3both refer to methyl.

[0041] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene - (CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0042] "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. Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl(C7), and cyclooctyl (C8).

[0043] 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 chainMTX-04725 lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0044] 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. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, 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.

[0045] 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.

[0046] 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,MTX-04725 carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0047] The term “heterocycloalkyl” as used herein, is a non-aromatic heterocyclyl wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. The heterocycloalkyl group can be substituted or unsubstituted as recited, e.g., for heterocyclyls as described herein.

[0048] The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:

[0049] wherein X’ is a bond or represents an oxygen or a sulfur, and R15represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10or a pharmaceutically acceptable salt, R16represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R10, where m and R10are as defined above. Where X’ is an oxygen and R15or R16is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and R16is a hydrogen, the formula represents a “formate.” On the other hand, where X’ is a bond, and R15is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15is a hydrogen, the above formula represents an “aldehyde” group.

[0050] 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, and for example substituted with one or more substituents selected from alkyl,MTX-04725 cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. 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.

[0051] As used herein, the term “nitro” means -NO2; the term “halogen” designates -F, -Cl, -Br, or -I; the term “hydroxyl” means -OH; and the term “cyano” means –CN;.

[0052] 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.

[0053] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Accordingly, prodrugs include compounds that are transformed in vivo to yield a disclosed compound or any other pharmaceutically acceptable form of the compound. In embodiments, a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Prodrugs can typically be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.MTX-04725

[0054] Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound). Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise —NO, —NO2, —ONO, or — ONO2moieties.

[0055] 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. Exemplary Compounds of the Invention

[0056] This disclosure relates to novel chemical compounds and methods useful for inhibiting v8integrin.

[0057] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein. Further, and unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.

[0058] In embodiments, a compound described herein is a selective inhibitor ofv 8integrin. In embodiments, a compound described herein selectively inhibits v 8 integrin over, e.g., v 6 integrin (e.g., a selectivity of at least about 10×, 50×, 100×, or 1000× as measured according to an assay (e.g., fluorescence polarization assay)).

[0059] Certain exemplary formulas, compounds, and structural features are described herein. Any structural features and embodiments described herein can be used in any combination with any other structural feature(s) and embodiments(s) described herein.MTX-04725 Formula (I)

[0060] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:L is C4-6-alkyl optionally substituted with 1 to 6 R4; each of R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, C1-4alkyl, halogen, C1-4alkyloxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyloxy, C1-4- alkyloxy-C1-4alkyloxy, CF3, CHF2, CH2F, CN, NO2, NRaRb or C1-4alkyl-NRaRb, R2is H, or C1-4alkyl optionally substituted with 1 to 4 R5; R3ais halogen, C1-4alkyloxy, C3-5cycloalkoxy, cyano, or C1-4alkyl optionally substituted with one or more halogen; R3bis H, halogen, CF3or CN; R3cis H, halogen, CN, or C1-4alkyl; and R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, 5-6 member heteroaryl, C6aryl, -O- (C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), -O-(5-6 member heteroaryl), -O-(C6aryl), - CH2-(C3-6cycloalkyl), -CH2- (4-6-membered heterocycloalkyl), -CH2- (5-6 member heteroaryl), or -MTX-04725 CH2-(C6aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6; R3eis H, halogen or C1-4alkyl optionally substituted with one or more halogen; or R3aand R3b, R3band R3c, R3cand R3d, or R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8; each R4is independently H, halogen, C1-4alkyloxy or C1-4alkyl optionally substituted with one or more halogen, or two geminal R4groups together can form a spiro-cyclopropyl; each R5is independently halogen or C1-4alkyl optionally substituted with halogen; each R6is independently C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, C1-4alkyloxy, C3-6cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, oxo, 5-6-membered heteroaryl, or NRaRb; each R7is independently C1-4alkyl optionally substituted with one or more F, C1-4alkoxy or F; each R8is independently halogen, C1-4alkyl, C3-6cycloalkyl, or two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; each of Raand Rbis independently hydrogen, or C1-4alkyl optionally substituted with one or more halogen; a and b are each independently 0 or 1 provided a+b is 1 or 2; and m is 0, 1 or 2. Q and R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2

[0061] In embodiments, the Q is a tetrahydroquinoline ring system. For example, in some embodiments, thesome embodimeIn some embodiments,MTX-04725.

[0063] In some embodiments, each of R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, C1-4alkyl, halogen, C1-4alkyloxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyloxy, C1-4- alkyloxy-C1-4alkyloxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl- NRaRb. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently halogen, alkoxy, alkyl optionally substituted with one or more halogen or H. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently F, methyl optionally substituted with one or more F, methoxy or H. In embodiments, each of R1c1, R1c2, R1d1, R1d2, R1e1, and R1e2is independently H. In some embodiments, each of R1band R1b1is independently H, methoxy, or methyl optionally substituted with one or more F. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H, C1-4alkyl, halogen, C1-4alkyloxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyloxy, C1-4- alkyloxy-C1-4alkyloxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are eachMTX-04725 independently H, methoxy, halogen or methyl optionally substituted with one or more halogen. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H, methoxy, methyl or F. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H or F. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H or methoxy. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H or methyl. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, and R1band R1b1are each independently H or -CF3. In some embodiments, each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H. In some embodiments, each of R1band R1b1is independently H, methoxy, or methyl optionally substituted with one or more F.

[0064] In embodiments, each R1ais independently H. In embodiments, each R1bis independently H. In embodiments, each R1bis independently OMe. In embodiments, each of R1c, R1dand R1e, is independently H. In embodiments, each of R1a1, R1a2, R1b1, and R1b2is independently H. -L-

[0065] In some embodiments, L is C5-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is C6-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is C4- alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is linear C5-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is linear C6-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is linear C4-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is an unsubstituted C5-alkyl. In some embodiments, L is an unsubstituted C6-alkyl. In some embodiments, L is an unsubstituted C4-alkyl. In some embodiments, L is an unsubstituted linear C5-alkyl. In some embodiments, L is an unsubstituted linear C6-alkyl. In some embodiments, L is an unsubstituted linear C4-alkyl. In some embodiments, L is a linear C5-alkyl optionally substituted with one or more F. In some embodiments, L is a linear C6-alkyl optionallyMTX-04725 substituted with one or more F. In some embodiments, L is a linear C4-alkyl optionally substituted with one or more F.

[0066] In some embodiments, L is C5-alkyl optionally substituted with 1 to 6 R4. In some embodiments, L is, wherein R4a1, R4a2, R4b1, and R4b2are each independently H, halogen or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, L is, wherein R4a1, R4a2, R4b1, and R4b2 are each independently H, F or methyl optionally substituted with one or more F. In some embodiments, L iswherein R4a1and R4a2are each independently H or F, and R4b1, and R4b2are each independently H. In some embodiments, L is, wherein R4a1and R4a2are each H, and R4b1, and R4b2 are each independently F or H. In some embodiments, R4a1 and R4a2 are each H. In some embodiments, R4b1is H or F. In some embodiments, R4b2is F. In some embodiments, R4b1is H. In some embodiments, R4b1is F. In some embodiments, R4b1and R4b2are each H. In some embodiments, R4a1is H or F. In some embodiments,2is F. In some embodiments, R4a1is H. In some embodiments, R4a1is F. In embodiments, L is C4-6-alkyl optionally substituted with 1 to 4 R4.

[0067] In embodiments, L is C6-alkyl optionally substituted with 1 to 4 R4. In embodiments, L is C6-alkyl optionally substituted with 1 to 2 R4. In embodiments, L is C6-alkyl optionally substituted with 1 R4.MTX-04725

[0068] In some embodiments, R2is H or methyl. In embodiments, R2is H. In embodiments, R2is methyl, optionally substituted with 1-3 R5. In embodiments, R2is ethyl, optionally substituted with 1-3 R5. R3a, R3b, R3c, R3d, and R3e

[0069] In some embodiments, R3ais halogen, C1-4alkyloxy, C3-5cycloalkoxy, cyano, or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3ais Cl, F, cyano, OMe, C1-4alkyl optionally substituted with one or more F. In some embodiments, R3ais OMe. In some embodiments, R3ais Cl. In some embodiments, R3ais -CN. In some embodiments, R3ais C1-4alkyl optionally substituted with one or more halogen or -O-C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3ais C1-4alkyl. In some embodiments, R3ais ethyl. In some embodiments, R3ais methyl. In some embodiments, R3ais C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3ais C1-4alkyl optionally substituted with one or more F. In some embodiments, R3ais -O-C1-4alkyl optionally substituted with one or more F. In some embodiments, R3ais ethoxy. In some embodiments, R3ais methoxy. In some embodiments, R3ais - OCHF2. In some embodiments, R3ais - OCF3. In some embodiments, R3ais H.

[0070] In some embodiments, R3bis H, CN, or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3bis H, CN, or C1-4alkyl optionally substituted with one or more F. In some embodiments, R3bis H, halogen, CF3or CN. In some embodiments, R3bis H. In some embodiments, R3bis halogen. In some embodiments, R3bis F. In some embodiments, R3bis CF3. In some embodiments, R3bis CN.

[0071] In some embodiments, R3cis H. In some embodiments, R3cis C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3cis C1-4alkyl optionally substituted with one or more F. In some embodiments, R3cis halogen. In some embodiments, R3cis F.

[0072] In some embodiments, R3dis C1-4alkyl, C3-6cycloalkyl, 4-6-membered heterocycloalkyl, - O-(C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), 5-6 member heteroaryl, or C6aryl, wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6. In some embodiments, R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, -O-(C3-6cycloalkyl), -O-(4-6- membered heterocycloalkyl), 5-6 member heteroaryl, C6aryl, -O-(5-6 member heteroaryl), or -O-(C6MTX-04725 aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6.

[0073] In some embodiments, R3dis C1-4alkyl, optionally substituted with 1 to 4 R6. In some embodiments, R3dis iso-propyl. In some embodiments, R3dis –O-(C1-4alkyl), optionally substituted with 1 to 4 R6. In some embodiments, R3dis -O-CH(CH3)(CH3). In some embodiments, R3dis oxo.

[0074] In some embodiments, R3dis 4-6-membered heterocycloalkyl, optionally substituted with 1 to 4 R6. In some embodiments, R3dis a 4-6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, O and S optionally substituted with 1 to 4 R6. In some embodiments, R3dis a 4-6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, and O optionally substituted with 1 to 4 R6. In some embodiments, R3dis a 4-6-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6.

[0075] In some embodiments, R3dis a 6-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6. In some embodiments, R3dis a tetrahydropyran optionally substituted with 1 to 4 R6. In some embodiments, R3dis. In some embodiments, R3dis a morpholino optionally substituted with 1 to 4 R6. In some embodiments,

[0076] In some embodiments, R3dis a 5-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6. In some embodiments, R3dis a tetrahydrofuran optionally substituted with 1 to 4 R6. In some embodiments, R3dis.

[0077] In some embodiments, R3dis a 4-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6. In some embodiments, R3dis an oxetaneoptionally substituted with 1 to 4 R6. In some embodiments, R3d is. In someembodiments, R3dis a thietane optionally substituted with 1 to 4 R6. In some embodiments, R3disMTX-04725

[0078] In some embodiments, R3dis -O-(C3-6cycloalkyl) optionally substituted with 1 to 4 R6. In some embodiments, R3dis -O-(6 member heterocycle comprising one or more O, S or N heteroatoms) optionally substituted with 1 to 4 R6. In some embodiments, R3dis -O- (tetrahydropyran) optionally substituted with 1 to 4 R6. In some embodiments, R3dis -O-(5-6- membered heteroaryl) optionally substituted with 1 to 4 R6.

[0079] In some embodiments, R3dis a 5-6 membered heteroaryl optionally substituted with 1 to 4 R6. In some embodiments, R3dis a 5-member heteroaryl optionally substituted with 1 to 4 R6. In some embodiments, R3dis an imidazole. In some embodiments, R3dis .some embodiments, R3dis a 6- member heteroaryl optionally substituted with 1 to 4 R6. In some embodiments, R3dis pyridinyl. In some embodiments, R3dis. In some embodiments, R3dis R3dis C6aryl optionally substituted with 1 to 4 R6.

[0080] In some embodiments, R3dis phenyl, anisolyl, or benzyl optionally substituted with 1 to 4 R6. In some embodiments, R3dis unsubstituted phenyl. In some embodiments, R3dis unsubstituted phenyl. In some embodiments, R3dis unsubstituted benzyl. In some embodiments, R3dis unsubstituted benzyl. In some embodiments, R3dis anisolyl optionally substituted with 1 to 4 R6. In some embodiments, R3dis an unsubstituted anisolyl.

[0081] In some embodiments, R3dis oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, pyrrolidinone, piperazinyl-C1-4alkyl, C1-4alkoxyl, -O-(tetrahydro-2H-pyranyl) or anisolyl.

[0082] In some embodiments, R3dis a C3-5cycloalkyl optionally substituted with 1 to 4 R6. In some embodiments, R3dis an unsubstituted C3-5cycloalkyl. In some embodiments, R3dis cyclopropyl. In some embodiments, R3dis cyclobutyl. In some embodiments, R3dis cyclohexyl.

[0083] In some embodiments, R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, 5-6 member heteroaryl, C6aryl, -O-(C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), -O-(5-6 member heteroaryl), -O-(C6aryl), -CH2-(C3-6cycloalkyl), -CH2- (4-6-membered heterocycloalkyl), - CH2- (5-6 member heteroaryl), or -CH2-(C6aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6.MTX-04725

[0084] In some embodiments, R3eis H, halogen or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3eis H. In some embodiments, R3eis halogen. In some embodiments, R3eis F. In some embodiments, R3eis Cl. In some embodiments, R3eis C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R3eis C1-4alkyl optionally substituted with one or more F. In some embodiments, R3eis methyl. In some embodiments, R3eis methyl optionally substituted with one or more F.

[0085] In some embodiments, R3aand R3b, R3band R3c, R3cand R3d, or R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8.

[0086] In some embodiments, R3aand R3b, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formMTX-04725wherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

[0087] In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b,MTX-04725 together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b. In some embodiments, R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b.

[0088] In some embodiments, R3band R3c, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen andMTX-04725 sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with theMTX-04725 atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

[0089] In some embodiments, R3band Rc, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, form wherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formdenotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formMTX-04725 wherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments,band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c. In some embodiments, R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c.

[0090] In some embodiments, R3cand R3d, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formMTX-04725 wherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they arewherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. In some embodiments, R3cand R3dtogether with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.MTX-04725

[0091] In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formdenotes a bond to R3cand ** denotes a bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes aMTX-04725 bond to R3d. In some embodiments, R3cand R3d, together with the atoms to which they are attached,wherein * denotes a bond to R3cand ** denotes a bond to R3d.

[0092] In some embodiments, R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formR3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e,MTX-04725 optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

[0093] In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atomsMTX-04725 to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e. In some embodiments, R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e.

[0094] In some embodiments, each R6is independently C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, C1-4alkyloxy, C3-6cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, oxo, 5-6-membered heteroaryl, or NRaRb.

[0095] In some embodiments, R6is C1-4alkyl. In some embodiments, R6is C2-4alkenyl. In some embodiments, R6is C3-6cycloalkyl. In some embodiments, R6is cyclopropyl. In some embodiments,MTX-04725 R6is cyclobutyl. In some embodiments, each R6is cyclohexyl. In some embodiments, R6is C1-4alkyloxy. In some embodiments, R6is C3-6cycloalkoxy. In some embodiments, R6is F. In some embodiments, R6is CF3. In some embodiments, R6is CHF2. In some embodiments, R6is CH2F. In some embodiments, R6is OCF3. In some embodiments, R6is OCHF2. In some embodiments, R6is OCH2F. In some embodiments, R6is OH. In some embodiments, R6is oxo. In some embodiments, R6is 5-6-membered heteroaryl. In some embodiments, R6is NRaRb. In some embodiments, R6is oxo. In some embodiments, R6is C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R6is C1-4alkyl optionally substituted with one or more F. In some embodiments, R6is methyl. In some embodiments, R6is halogen. In some embodiments, R6is F. R4

[0096] In some embodiments, each R4is independently H, halogen, C1-4alkyloxy or C1-4alkyl optionally substituted with one or more halogen, or two geminal R4groups together can form a spiro- cyclopropyl. In some embodiments, R4is H. In some embodiments, R4is halogen. In some embodiments, R4is F. In some embodiments, R4is Cl. In some embodiments, R4is Br. In some embodiments, R4is C1-4alkyloxy. In some embodiments, R4is methoxy. In some embodiments, R4is C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R4is C1-4alkyl optionally substituted with one or more F. In some embodiments, R4is H or halogen. In embodiments, R4is halogen. In embodiments, R4is F.

[0097] In some embodiments, two geminal R4groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R4groups together can form a spiro-cyclopropyl or together can form a spirocyclic 3 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R4groups together can form a spiro-cyclobutyl or together can form a spirocyclic 4 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R4groups together can form a spiro- cyclopropyl or together can form a spirocyclic 5 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen,MTX-04725 oxygen and sulfur. In some embodiments, two geminal R4groups together can form a spiro- cyclohexyl or together can form a spirocyclic 6 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two R4form a geminal dimethyl. R5

[0098] In some embodiments, each R5is independently halogen or C1-4alkyl optionally substituted with halogen. In some embodiments, R5is halogen. In some embodiments, R5is F. In some embodiments, R5is C1-4alkyl optionally substituted with halogen. In some embodiments, R5is C1-4alkyl optionally substituted with F. In some embodiments, R5is H or methyl. In embodiments, R2is H. In embodiments, R2is methyl, optionally substituted with 1-3 R5. In embodiments, R2is ethyl, optionally substituted with 1-3 R5. In embodiments, R5is halogen. In embodiments, R5is F. In embodiments, R5is C1-4alkyl optionally substituted with halogen. In embodiments, R5is C1-4alkyl optionally substituted with F. In embodiments, R5is C1-2alkyl optionally substituted with F R6

[0099] In some embodiments, each R6is independently C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, C1-4alkyloxy, C3-6cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, oxo, 5-6- membered heteroaryl, or NRaRb. In some embodiments, R6is C1-4alkyloxy. In some embodiments, R6is F. In some embodiments, R6is CF3. In some embodiments, R6is CHF2. In some embodiments, R6is CH2F. In some embodiments, R6is OCF3. In some embodiments, R6is OCHF2. In some embodiments, R6is OCH2F. In some embodiments, R6is OH. In some embodiments, R6is methoxy. In some embodiments, R6is oxo. In some embodiments, R6is 5-6- membered heteroaryl. In some embodiments, R6is NRaRb. In some embodiments, R6is C1-4alkyl optionally substituted with one or more halogen. In some embodiments, R6is C1-4alkyl optionally substituted with one or more F. In some embodiments, R6is methyl optionally substituted with one or more halogen. In some embodiments, R6is methyl optionally substituted with one or more F. In some embodiments, R6is ethyl optionally substituted with one or more F. In some embodiments, R6is C2-4alkenyl. In some embodiments, R6is C3-6cycloalkoxy. In some embodiments, R6is C3-MTX-047256cycloalkyl. In some embodiments, R6is cyclopropyl. In some embodiments, each R6is cyclobutyl. In some embodiments, R6is cyclopentyl. In some embodiments, R6is cyclohexyl.

[0100] In some embodiments, two geminal R6groups together form a spirocyclic cyclopropyl or 3 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R6groups together form a spirocyclic cyclobutyl or 4 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R6groups together form a spirocyclic cyclopentyl or 5 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R6groups together form a spirocyclic cyclohexyl or 6 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. R7, a, b and m

[0101] In some embodiments, a is 0 and b is 1. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, a+b is 1 or 2. In some embodiments, a is 0 and b is 0.

[0102] In some embodiments, m is 0, 1, 2, 3 or 4. In some embodiments, a + b is 1 and m is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, a + b is 2 and m is 0, 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, a is 1, b is 1 and m is 0 or 1. In some embodiments, a is 1, b is 1 and m is 0. In some embodiments, a is 1, b is 1 and m is 1.

[0103] In some embodiments, each R7is independently C1-4alkyl optionally substituted with one or more halogen, or halogen. In some embodiments, each R7is independently C1-4alkyl. In some embodiments, each R7is independently methyl. In some embodiments, each R7is independently C1-4alkyl optionally substituted with one or more F, or F. In some embodiments, each R7is independently F. In embodiments, each R7is independently methyl or F. In some embodiments, each R7is independently methyl or ethyl optionally substituted with one or more halogen. In some embodiments, each R7is independently methyl or ethyl optionally substituted with one or more F.MTX-04725

[0104] In some embodiments, each R7is independently C1-4alkyl optionally substituted with one or more F, C1-4alkoxy or F. In some embodiments, R7is C1-4alkyl. In some embodiments, R7is C1-4alkyl substituted with one or more halogen. In some embodiments, R7is C1-4alkyl substituted with one or more F. In some embodiments, R7is C1-4alkoxy. In some embodiments, R7is F. R8

[0105] In some embodiments, each R8is independently halogen, C1-4alkyl, C3-6cycloalkyl, or two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3- 6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

[0106] In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is C1-4alkyl. In some embodiments, R8is methyl optionally substituted with one or more halogen. In some embodiments, R8is methyl optionally substituted with one or more F. In some embodiments, R8is C3-6cycloalkyl.

[0107] In some embodiments, two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. R8

[0108] In some embodiments, each R8is independently halogen, C1-4alkyl, C3-6cycloalkyl, or two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, each R8is independently halogen, C1-4alkyl optionally substituted with halogen, hydroxyl or oxo. In some embodiments, R8is halogen. In some embodiments, R8is C1-4alkyl. In some embodiments, one or more R8is methyl. In some embodiments, R8is C3-6cycloalkyl. In some embodiments, two geminal R8groups together form a spiro-C3-6cycloalkyl.

[0109] In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is methyl. In some embodiments, R8is methoxy. In some embodiments, R8is CN. In some embodiments, R8is C1-4alkyl optionally substituted with one or more halo. In someMTX-04725 embodiments, R8is C1-4alkyl optionally substituted with one or more F. In some embodiments, R8is methyl optionally substituted with one or more F. In some embodiments, two geminal R8groups together form a geminal dimethyl.

[0110] In some embodiments, two geminal R8groups together form a spirocyclic 3-6 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R8groups together form a spirocyclic cyclopropyl or 3 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R8groups together form a spirocyclic cyclobutyl or 4 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R8groups together form a spirocyclic cyclopentyl or 5 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, two geminal R8groups together form a spirocyclic cyclohexyl or 6 member heterocyclic ring, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Raand Rb

[0111] In some embodiments, each of Raand Rbis independently hydrogen, or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, each of Raand Rbis independently hydrogen, or C1-4alkyl optionally substituted with one or more F. In some embodiments, each of Raand Rbis independently hydrogen, or methyl, ethyl, propyl or butyl each optionally substituted with one or more halogen. In some embodiments, each of Raand Rbis independently hydrogen, or methyl optionally substituted with one or more halogen. In some embodiments, each of Raand Rbis independently hydrogen, or methyl optionally substituted with one or more F. Additional Exemplary Compounds

[0112] Still further exemplary embodiments include compounds of Formula (I) that are also compounds of the chemical formulae below, which may be present in any combination as valency permits are described herein.MTX-04725

[0113] In some embodiments, the compound is a compound of Formula (II), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound is a compound of Formula (II-A), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound is a compound of Formula (II-B), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound is a compound of Formula (III), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound is a compound of Formula (III-A), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound is a compound of Formula (III-B), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound is a compound of Formula (IV), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound is a compound of Formula (IV-A), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound is a compound of Formula (IV-A), wherein R4a1and R4a2are each independently H or F and R4b1and R4b2are each independently H; or R4b1and R4b2are each independently H or F and R4a1and R4a2are each independently H. In some embodiments, the compound is a compound of Formula (IV-A), wherein R3ais Cl, -CN, -OCH3, methyl or ethyl; and R3bis F. In some embodiments, the compound is a compound of Formula (IV-A), wherein R3dis isopropyl.

[0122] In some embodiments, the compound is a compound of Formula (IV-B), wherein R3a, R3b, R3c, R3d, R3e, R4a1, R4a2, R4b1and R4b2are each as described with respect to Formula (I) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the compound is a compound of Formula (V), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof, wherein R3cand Rdtogether form a tetrahydropyran or tetrahydrofuran optionally substituted with one or two methyl.

[0124] In some embodiments, the compound is a compound of Formula (V-A), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (V) above,MTX-04725or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound is a compound of Formula (V-B), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (V) above,or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound is a compound of Formula (V-A), wherein R3cand R3dtogether form a tetrahydropyran or tetrahydrofuran optionally substituted with a methyl, gem- dimethyl or a spirocyclic C3-6 cycloalkyl or spirocyclic 3-6 member heterocyclyl ring. In some embodiments, the compound is a compound of Formula (V-A), wherein R3ais methyl, ethyl, methoxy, Cl or -CN, R3bis H or F and R3eis H.

[0127] In some embodiments, the compound is a compound of Formula (VI), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) above,MTX-04725

[0128] In some embodiments, the compound is a compound of Formula (VI-A), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (VI) above,pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the compound is a compound of Formula (VI-B), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (VI) above,MTX-04725pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the compound is a compound of Formula (VI-C), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (VI) above,pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the compound is a compound of Formula (VI-D), wherein R3a, R3b, R3c, R3d, and R3e, are each as described with respect to Formula (I) or (VI) above,MTX-04725pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the compound is a compound of Formula (VII), wherein Q, L, m, R2, R3a, R3b, R3c, R3d, R3e, and R7are each as described with respect to Formula (I) above,or a pharmaceutically acceptable salt thereof. Exemplary Compounds

[0133] Exemplary compounds include those described in Table 1 and Table 2 herein and pharmaceutically acceptable salts thereof.

[0134] In embodiments, a compound may be used as a mixture of stereoisomers (e.g., a mixture of diastereomers or a mixture of enantiomers). In embodiments, a stereochemically enrichedMTX-04725 composition comprising a compound described herein (e.g., a composition of a compound is substantially free of any other stereoisomer of that compound).

[0135] Unless otherwise indicated, there stereochemistry shown in individual compound chemical structures herein was arbitrarily assigned. In some embodiments, the absolute stereochemistry of one or more compounds may be the same or different from the stereochemistry depicted in individual molecular chemical formula. Where the absolute stereochemistry of a stereocenter is not indicated, it is understood that embodiments of the compound encompass (R)- and (S)- configurations in the alternative. Likewise, such compounds may be used in methods described herein as compositions comprising stereochemical mixtures or as stereochemically-enriched compositions (e.g., compositions of a compound substantially free of any other stereoisomer of that compound).MTX-04725MTX-04725MTX-04725MTX-04725MTX-04725Table 2MTX-04725MTX-04725MTX-04725MTX-04725MTX-04725MTX-04725MTX-04725MTX-04725

[0136] In some embodiments, the compound is a compound selected from the following:MTX-04725or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound is a compound selected from the following:MTX-04725or a pharmaceutically acceptable salt thereof. Deuterated Compounds

[0138] Compounds described herein can comprise atoms that exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The term “isotopologue” refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and / or level of isotopic enrichment at one or more positions, e.g.,MTX-04725 hydrogen vs. deuterium. The present invention is meant to include all suitable isotopic variations of the compounds of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H), as well as compositions enriched in isotopologues of any compound described herein.

[0139] In embodiments, one or more of the hydrogens of the compounds described herein is replaced by a deuterium. When a position is designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. When a position is designated as “2H” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “2H” or “deuterium” indicates at least 50.1% incorporation of deuterium). Accordingly, the invention also features compositions enriched in deuterated compounds.

[0140] In embodiments, compositions of any compound provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Exemplary Pharmaceutical Compositions

[0141] Compounds described herein (e.g., compounds of any one of Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B, (VI-C), (VI-D), or (VII)) or pharmaceutically acceptable salts thereof can be formulated in various pharmaceutical compositions. A compound described herein (e.g., a compound of Formula (I) (including compounds of Formulas (II)-(VII) and any compound of Table 1 as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingredient (API) combined with one or more other ingredients to form a drug substance pharmaceutical composition. The drug substance (DS) pharmaceutical composition can comprise the API (e.g., a compound of Formula (I) or pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier(s), diluent(s) or excipient(s) can be selected to be compatibleMTX-04725 with the other ingredients of the formulation and appropriately safe and effective for an intended therapy. A desired weight concentration of a compound described herein (e.g., compounds of any one of Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B, (VI-C), (VI-D), or (VII)) or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API) can be combined with the other inactive ingredients to form a drug substance (DS) in a formulation batch. Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms. Such compositions may be prepared by bringing into association the active pharmaceutical ingredient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).

[0142] In certain embodiments, the invention provides a pharmaceutical composition formulated for oral delivery of an αvβ8integrin inhibitor, the composition comprising the αvβ8integrin inhibitor compound described herein (e.g., compounds of any one of Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B, (VI-C), (VI-D), or (VII) such as any compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof) as an API and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ8integrin inhibitor compound. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IIIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IIIB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, theMTX-04725 invention provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IVA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (IVB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (V-B), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VI-A), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VI-B), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VI-C), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VI-D), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).

[0143] In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).

[0144] Pharmaceutically acceptable compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be prepared byMTX-04725 various procedures. For example, the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.

[0145] Pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof per unit dose. Such a unit may contain, a desired amount of a compound (e.g., a compound of the Formula (I)) or pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Such unit doses may therefore be administered at a desired dose interval. The concentration of active compound in the drug composition will depend on various applicable parameters and considerations such as the 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.

[0146] 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. Pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof formulated for oral delivery can be prepared in a unit dosage form, such as a capsule at a desired dosage strength (e.g., of the compound of Formula (I) or a pharmaceutically acceptable salt thereof). For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. For oral administration in the form of a tablet or capsule, a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier. Other examples of excipients, diluents, and carriers that are suitable for suchMTX-04725 formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose derivatives. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, natural sugars, natural and synthetic gums, and the like. Lubricants and / or glidants can be used in these dosage forms.

[0147] 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, or other enteric agents.

[0148] The compound can be administered as a component of an elixir, suspension, syrup, wafer, 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.

[0149] The compounds can be formulated as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. For example, a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be dissolved in a suitable buffer. A pharmaceutical composition comprising a desired concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies). Exemplary Therapeutic Methods

[0150] Compounds described herein can be useful for the treatment of various diseases and disorders that benefit from antagonizing the integrin v 8. For example, inhibiting the integrin v 8-driven TGF activation is proposed to reverse tumor tolerance and enhance anti-tumor T / NK cellresponses. For example,v 8inhibition can enhance outcomes in checkpoint inhibitors regimens orMTX-04725 reverse checkpoint inhibitor resistance. In embodiments, a compound described herein can modulate an anti-tumor immune response (e.g., in checkpoint-inhibitor resistant tumors).

[0151] In embodiments, the invention features a method of inhibitingv 8integrin in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any one of Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B, (VI-C), (VI-D), or (VII), such as any compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof.

[0152] In embodiments, the invention features a method of treating a cancer (e.g., a solid tumor) in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any one of Formulae (I), (II- A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B), (VI- C), (VI-D), or (VII) such as any compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof. In embodiments, a method further comprises administration of a therapeutically effective amount of a second active agent. Solid Tumors

[0153] In embodiments, administration of a compound described herein (e.g., a compound of any one of Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), (VI-B, (VI-C), (VI-D), or (VII) such as any compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof can be useful for treating a solid tumor in a patient in need thereof, optionally in combination with one or more additional therapies (e.g., a second active agent).

[0154] In embodiments, a solid tumor is resistant to one or more previous lines of therapy (e.g., a solid tumor is a treatment-resistant tumor). In embodiments, a solid tumor is resistant to immune checkpoint therapy.

[0155] In embodiments, a cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillaryMTX-04725 carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, non small cell lung cancer (NSCLC), small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma (NB), or retinoblastoma. In embodiments, a solid tumor is an advanced stage solid tumor (e.g., a locally advanced solid tumor). In embodiments, a solid tumor is a metastatic solid tumor.

[0156] In embodiments, a cancer (e.g., solid tumor) is anal cancer, bile duct cancer (cholangiocarcinoma), bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, or uterine cancer.

[0157] In embodiments, a cancer (e.g., solid tumor) is breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, or urothelial carcinoma.

[0158] In embodiments, a cancer (e.g., a solid tumor) is advanced (e.g., locally advanced). In embodiments, a cancer (e.g., a solid tumor) is metastatic. In embodiments, a cancer (e.g., solid tumor) is anal cancer. In embodiments, a cancer (e.g., solid tumor) is bile duct cancer (cholangiocarcinoma). In embodiments, a cancer (e.g., solid tumor) is bladder cancer. In embodiments, a cancer (e.g., solid tumor) is breast cancer. In embodiments, a cancer (e.g., solid tumor) is cervical cancer. In embodiments, a cancer (e.g., solid tumor) is colorectal cancer. In embodiments, a cancer (e.g., solid tumor) is endometrial cancer. In embodiments, a cancer (e.g., solid tumor) is esophageal cancer. In embodiments, an esophageal cancer is adenocarcinoma. In embodiments, an esophageal cancer is squamous cell carcinoma. In embodiments, a cancer (e.g., solid tumor) is fallopian tube cancer. In embodiments, a cancer (e.g., solid tumor) is gastric cancer. In embodiments, a cancer (e.g., solid tumor) is glioma. In embodiments, a cancer (e.g., solid tumor) is liver cancer. In embodiments, a liver cancer is hepatocellular carcinoma. In embodiments, a cancer (e.g., solid tumor) is lung cancer. In embodiments, a lung cancer is squamous cell carcinoma of the lung. In embodiments, a lung cancer is non small cell lung cancer (NSCLC). In embodiments,MTX-04725 a cancer (e.g., solid tumor) is melanoma. In embodiments, a cancer (e.g., solid tumor) is nasopharyngeal carcinoma. In embodiments, a cancer (e.g., solid tumor) is neuroblastoma. In embodiments, a cancer (e.g., solid tumor) is osteosarcoma. In embodiments, a cancer (e.g., solid tumor) is ovarian cancer. In embodiments, a cancer (e.g., solid tumor) is pancreatic cancer. In embodiments, a cancer (e.g., solid tumor) is primary peritoneal carcinoma. In embodiments, a cancer (e.g., solid tumor) is prostate cancer. In embodiments, a cancer (e.g., solid tumor) is renal cell carcinoma (RCC). In embodiments, a renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In embodiments, a renal cell carcinoma is papillary renal cell carcinoma (PRCC). In embodiments, a cancer (e.g., solid tumor) is skin cancer. In embodiments, a skin cancer is cutaneous squamous cell carcinoma (CSCC). In embodiments, a skin cancer is basal cell carcinoma (BCC). In embodiments, a cancer (e.g., solid tumor) is squamous cell carcinoma of the head and neck (SCCHN). In embodiments, a cancer (e.g., solid tumor) is testicular cancer. In embodiments, a cancer (e.g., solid tumor) is urothelial carcinoma. In embodiments, a cancer (e.g., solid tumor) is uterine cancer.

[0159] In embodiments, a patient has a cancer (e.g., a solid tumor such as those described herein) that is therapy resistant. In embodiments, a therapy resistant cancer (e.g., a solid tumor) is checkpoint resistant. In embodiments, a therapy resistant cancer (e.g., a solid tumor) is resistant to an anti-PD-1 or anti-PD-L1 therapy (collectively, a PD-(L)1 resistant cancer). Exemplary Combination Therapies and Second Active Agents

[0160] In embodiments, a compound described herein (e.g., a compound of any one of Formulas Formulae (I), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI- A), (VI-B, (VI-C), (VI-D), or (VII) such as any compound of Table 1 or Table 2) or a pharmaceutically acceptable salt thereof, may be used in combination therapies. In embodiments, administration of a compound or pharmaceutically acceptable salt described herein enhances response to one or more additional therapies (e.g., a second active agent). For example, administration of a compound or pharmaceutically acceptable salt described herein can improve response to additional therapy (e.g., a second active agent).

[0161] For example, a compound or pharmaceutically acceptable salt described herein may be administered in combination with one or more additional therapies (e.g., a second active agent) in the treatment of certain diseases and disorders.MTX-04725

[0162] In embodiments, a compound or pharmaceutically acceptable salt described herein may be administered in combination with an immunotherapy. In embodiments, an immunotherapy is a cancer immunotherapy. In embodiments, a cancer immunotherapy is an immune checkpoint therapy (e.g., therapy comprising administration of an immune checkpoint inihbitor). In embodiments, a cancer immunotherapy is a cellular immunotherapy such as adoptive T cell transfer therapy (e.g., Chimeric Antigen Receptor (CAR) T cell therapy, CAR natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy). In embodiments, a cancer immunotherapy is a cancer vaccine. In embodiments, a cancer immunotherapy is monoclonal antibody therapy (e.g., an antibody useful for immune checkpoint therapy such as those described herein). In embodiments, a cancer immunotherapy is cytokine therapy (e.g., interferon or interleukin therapy).

[0163] In embodiments, a compound or pharmaceutically acceptable salt described herein is administered with a second active agent to a patient in need thereof for the treatment of a solid tumor (e.g., as described herein).

[0164] In embodiments, a second active agent is an immune checkpoint inhibitor. In embodiments, an immune checkpoint inhibitor targets PD-1 (e.g., inhibition via anti-PD-1, anti-PD- L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF- 1 / CSF-1R.

[0165] In embodiments, a checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or a binding agent. In embodiments, a checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

[0166] In embodiments, an immune checkpoint inhibitor is an agent that inhibits PD-1, TIM-3, CTLA-4, LAG-3, TIGIT, IDO or CSF-1 / CSF-1R.

[0167] In embodiments, an immune checkpoint inhibitor is selected from: pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), dostarlimab (Jemperli®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), and relatlimab, as well as biosimilars thereof.MTX-04725

[0168] In embodiments, a second active agent is an anti-PD-1 therapy or an anti-PD-L1 therapy (collectively referred to as anti-PD(L)-1 therapy).

[0169] In embodiments, an anti-PD(L)-1 therapy is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, avelumab, durvalumab, PDR001, Cemiplimab, BGB-A317, LY3300054, BI 754091, IBI308, INCSHR-1210, JNJ-63723283, JS- 001, MEDI0680 (AMP-514), MGA-012, PF-06801591, CX-072, FAZ053, and PD-L1 millamolecule, as well as biosimilars thereof.

[0170] In embodiments, an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, BGB-A317, BI 754091, CX-072, durvalumab, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS- 001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, cemiplimab, dostarlimab, any of the antibodies disclosed in WO2014 / 179664, as well as biosimilarsthereof. In embodiments, an anti-PD(L)-1 therapy is selected from the group consisting of BGB-A317, BI 754091, CX-072, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, LY3300054, MEDI- 0680, MGA-012, nivolumab, PD-L1 millamolecule, PDR001, pembrolizumab, PF-06801591, cemiplimab, and dostarlimab, as well as biosimilars thereof.

[0171] In embodiments, an anti-PD(L)-1 therapy is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dostarlimab, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR- 301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ- 053, CK-301, AK 104, GLS-010, JTX-4014, SHR-1210, AMP-224, AUN-P12, CA-170, BMS- 986189, and any of the PD-1 antibodies disclosed in WO2014 / 179664. In embodiments, an anti- PD(L)-1 therapy is selected from durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, and PD-L1 millamolecule, or derivatives thereof.

[0172] In embodiments, an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. In embodiments, an anti-PD(L)- 1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, and dostarlimab. In embodiments, an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, and durvalumab.

[0173] In embodiments, a second active agent is an anti-CTLA-4 therapy. In embodiments, an anti-CTLA-4 therapy is ipilimumab.MTX-04725

[0174] In embodiments, a second active agent is an anti-LAG-3 therapy. In embodiments, an anti-LAG-3 therapy is selected from: LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), TSR-033, and FS118.

[0175] In embodiments, a second active agent is an anti-TIM-3 therapy. In embodiments, an anti-TIM-3 therapy is selected from: MBG453, Sym023, and TSR-022.

[0176] In embodiments, a second active agent is an anti-CSF-1 / R therapy. In embodiments, an anti-CSF-1 / R therapy is selected from: lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), and pexidartinib (PLX3397).

[0177] In embodiments, a second active agent is an anti-TIGIT therapy. In embodiments, an anti-TIGIT therapy is selected from: BMS-986207, ociperlimab, tiragolumab, vibostolimab, domvanalimab, EOS448, COM902, and AGEN307.In embodiments, a second active agent is an anti-CEACAM therapy. In embodiments, an anti-TIGIT therapy is selected from: CM24 and NEO- 201. Examples General Schemes General Scheme 1:wherein Q, L, R2, R4, R7, m, R3e, R3d, R3c, R3b, R3aare defined as in Formula (I) and L2is a C3-5alkyl optionally substituted with 1-6 R4

[0178] A general method of preparing compounds of Formula (I) is outlined in General Scheme 1. Treatment of an amine, such as a substituted piperidine, with an aldehyde (R4= H) or ketone (R4= C1-4alkyl) in a solvent, such as MeOH, with a reducing agent, such as NaBH(OAc)3, in the presence of a Lewis acid catalyst, such as ZnCl2, at an elevated temperature, such as 65 °C, is a method that could be used to provide compounds of Formula (I). Stereoisomeric mixtures ofMTX-04725 compounds of Formula (I) could be separated into individual stereoisomers by chromatographic methods such as SFC or HPLC. Abbreviations Abbreviation Chemical Name 9-BBN 9-Borabicyclo[3.3.1]nonane dimer Ac acetyl ACN acetonitrile AIBN 2,2-Azobis(2-methylpropionitrile) Boc tert-butyloxycarbonyl Cbz Benzyloxycarbonyl Chemical shift DAST Diethylaminosulfur trifluoride dba dibenzylideneacetone DCE Dicholorethane DCM Dichloromethane Dess-Martin periodinane 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIBAL, DIBAL-H Diisobutyl aluminum hydride DMF dimethyl formamide DMAP 4-Dimethylaminopyridine DMSO dimethyl sulfoxide dppf 1,1-bis(diphenylphosphino)ferrocene EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray ionization ELSD Evaporative Light Scattering Detector Et Ethyl FA Formic acid HFIP 1,1,1,3,3,3-hexafluoropropan-2-ol HMDS Bis (trimethylsilyl)amine HPLC high performance liquid chromatography Hz Hertz i-Pr isopropyl J Coupling constant (in NMR) LC Liquid chromotagraphy LCMS Liquid chromotagraphy – mass spectrometry LDA lithium diisopropyl amide LiHMDS lithium bis(trimethylsilyl)amide Me methyl MPLC Medium pressure liquid chromotagraphy Ms Methanesulfonyl MTBE tert-butyl methyl ether N NormalMTX-04725 NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP N-Methyl-2-pyrrolidone NMR Proton nuclear magnetic resonance PDA Photodiode array detector PCy3 tricyclohexylphosphine prep- preparative ppm Parts per million Q-phos Pentaphenyl (di-tert-butylphosphino)ferrocene RP Reverse phase rt Room temperature s- secondary SPhos 2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl SFC supercritical fluid chromatography TBAB Tetra-n-butylammonium bromide TBAF Tetra-n-butylammonium fluoride TBAI Tetra-n-butylammonium iodide t-Bu tert-butoxy TEA triethylamine TFA trifluoroacetic acid Tf Trifluoromethanesulfonyl THF Tetrahydrofuran TMS Tetramethylsilane TMS- Trimethylsilyl- Ts p-toluenesulfonyl UPCC Ultraperformance convergence chromatography UV Ultraviolet light XPhos Pd-G2 Chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’- biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) Analytical Methods, Materials, and Instrumentation

[0179] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Default methods, materials and instrumentation are listed below. HNMR instrumental information:

[0180] Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz (Hz). Tetramethylsilane (TMS) was used as an internal standard.MTX-04725 LCMS instrumental information and analysis method:

[0181] Mass spectra were collected using an Agilent 6120 Single Quad Mass Spectrometer (ESI). Purity and low resolution mass spectral data were measured using Agilent 1260 Infinity II high-performance liquid chromatography (HPLC) system with Photo Diode Array Detector, Agilent 1260 Infinity II Evaporative Light Scattering Detector (ELSD) and Agilent 6120 Mass Spectrometer. Data was acquired using Chemstation C.01.10 and purity characterized by UV wavelength 220 nm, ELSD and ESI.

[0182] Method A: Column: Kinetex C182.1 x 50 mm, 5 um; Flow rate 1.0 mL / min; Mobile phase A: water with 0.04% TFA, Mobile phase B: ACN with 0.02% TFA; Gradient: 5% B from 0- 0.40 min, then a gradient of 5-95% B over 2.60 min, then hold on 95% B for 1.00 min, then 95-5% B over 0.01 min.

[0183] Method B: Column: Xbridge C182.1 x 50 mm column (5 um particles); Flow rate 0.8 mL / min; Mobile phase A: water with 10 mM NH4HCO3; Mobile phase B: ACN; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B from 0.40-3.40 min, then hold 95% B for 0.45 min, then 95-5% B over 0.01 min. SFC instrumental and analytical methods information:

[0184] Instrument: Waters UPCC with PDA detector

[0185] Conditions: Mobile phase A: CO2; Mobile phase B: MeOH with 0.1% isopropylamine (or EtOH with 0.1% isopropylamine, or isopropanol with 0.1% isopropylamine).

[0186] Columns: Daicel CHIRALPAK AD-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALCEL OD-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALCEL OJ-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK IG-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK AS-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK IC-3, 50 x 4.6 mm I.D., 3 um; Phenomenex Lux Cellulose-2, 50 × 4.6 mm I.D., 3 um; Regis (S,S)-Whelk-O 1, 50 × 4.6 mm I.D., 3.5 um

[0187] Column temperature: 35°C

[0188] Gradient: 5% B from 0.0-0.2 min, then a gradient of 5-50% B from 0.2-1.2 min, then hold 50% B for 1.0 min, then a gradient of 50-5% B from 2.2-2.6 min, then hold 50% B for 0.4 min.

[0189] Flow rate: 3.4 mL / min

[0190] Automated back pressure regulator (ABPR): 1800 psiMTX-04725

[0191] Alternatively, products may be analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm, using one of the following methods noted in the procedures:

[0192] “Chiral SFC A”: column: (R,R)-Whelk-O1, 4.6*100mm, 5 μm (Decial), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0193] “Chiral SFC B” method: column: AD 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0194] “Chiral SFC C”: column: AS 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0195] “Chiral SFC D”: column: OD 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0196] “Chiral SFC E”: column: Cellulose-SC 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0197] “Chiral SFC F”: column: OZ 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% m

[0198] “Chiral SFC G”: column: IC 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.ethanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0199] “Chiral SFC H”: column: (S,S)-Whelk-O1, 4.6*100mm, 5 μm (Decial), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0200] “Chiral SFC I”: column: OX-H, 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.MTX-04725

[0201] “Chiral SFC J”: column: IG, 4.6*100mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Preparative HPLC Method

[0202] Instruments: Gilson 281 semi-preparative HPLC system

[0203] Conditions: Mobile Phase A: water with 0.2% formic acid (or water with 0.1% TFA, or water with 0.05% HCl, or water with 10 mM NH4HCO3 or water with 0.04% ammonium hydroxide); Mobile Phase B: acetonitrile

[0204] Columns: Phenomenex Luna C18100 x 30 mm x 5um, Phenomenex Gemini C18100 x 30 mm x 5 um; Waters Xbridge BEH C18100 x 30 mm x 10 um

[0205] Column temperature: ambient

[0206] LC gradient: gradient of 5% to 50% B over 10 min, then hold 50% B for 2 min, then a gradient of 50-100% B over 0.1 min, then hold at 100% for 2 min, then a gradient of 100% to 5% over 0.1 min, then hold at 5% for 2 min

[0207] LC flow rate: 25 mL / min

[0208] UV wavelength: 220 nm and 254 nm

[0209] Alternatively, crude samples may be dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm, using one of the following methods noted in the procedures:

[0210] “Prep-HPLC A”: column: XBridge C18, 21.2 x 250 mm, 10 μm; Mobile phase A: water (10 mM ammonium hydrogen carbonate), Mobile phase B: acetonitrile; gradient elution as in text; flow rate: 20 mL / min.

[0211] “Prep-HPLC B”: column: XBridge C18, 21.2 x 250 mm, 10 μm; Mobile phase A: water (10 mM formic acid), Mobile phase B: acetonitrile; gradient elution as in text; flow rate: 20 mL / min.

[0212] “Prep HPLC C”: column: XBridge OBD C18, 19 * 100 mm, 5 μm; mobile phase: A water, B CH3CN; gradient elution as in text; flow rate: 20 mL / min. Preparative Chiral HPLC Method

[0213] Instruments: Gilson-281 semi preparative HPLC system; UV: Gilson-156 UVMTX-04725

[0214] Conditions: Mobile Phase A: n-heptane; Mobile Phase B: EtOH with 0.1% ammonium hydroxide (or 2-propanol with 0.1% ammonium hydroxide, or EOH with 0.1% TFA, or 2-propanol with 0.1% TFA).

[0215] Columns: Daicel CHIRALPAK AD, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IH, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OD, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OJ, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IC, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IG, 10 um, 30 mm x 250 mm; Phenomenex Lux Cellulose-2, 10 um, 30 mm x 250 mm; Regis (S,S) Whelk-O1, 10 um, 30 mm x 250 mm

[0216] Column temperature: ambient

[0217] LC gradient: A:B = 80:20 or other ratio of isocratic elution mode

[0218] LC flow rate: 25 mL / min binary pump

[0219] UV wavelength: 220 nm and 254 nm Preparative Chiral SFC Methods

[0220] Instruments: SFC: Waters 80Q preparative SFC; UV: Waters 2489 UV

[0221] Conditions: Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% ammonium hydroxide (or EtOH with 0.1% ammonium hydroxide, or 2-propanol with 0.1% ammonium hydroxide, or MeCN / EtOH / ammonium hydroxide 50:50:0.1)

[0222] Columns: Daicel CHIRALPAK AD, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IH, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OD, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OJ, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IC, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IG, 10 um, 30 mm x 250 mm; Phenomenex Lux Cellulose-2, 10 um, 30 mm x 250 mm; Regis (S, S) Whelk-O1, 10 um, 30 mm x 250 mm;

[0223] Column temperature: 40 °C

[0224] LC gradient: A:B = 80:20 or other ratios of isocratic elution mode

[0225] LC flow rate: 70 g / min binary pump

[0226] UV wavelength: 220 nm

[0227] System back pressure: 100 barMTX-04725

[0228] Alternatively, racemic products could be separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm using one of the following methods noted in the procedures

[0229] “Prep chiral SFC A”: column: (R,R)-Whelk-O1, 20*250mm, 5 μm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0230] “Prep chiral SFC B”: column: AD 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0231] “Prep chiral SFC C”: column: AS 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0232] “Prep chiral SFC D”: column: OD 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0233] “Prep chiral SFC E”: column: Cellulose-SC 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0234] “Prep chiral SFC F”: column: OZ 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0235] “Prep chiral SFC G”: column: IC 20*250mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0236] “Prep chiral SFC H”: column: (S,S)-Whelk-O1, 20*250mm, 5 μm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0237] “Prep chiral SFC I”: column: OX-H, 20*250mm, 5 μm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.MTX-04725

[0238] “Prep chiral SFC J”: column: IG, 20*250mm, 5 μm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Left-Side Intermediates Preparation of tert-butyl 7-(4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylateStep 1: Synthesis of tert-butyl 7-allyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[0239] To a mixture of tert-butyl 7-chloro-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate (5 g, 18.61 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.82 g, 46.51 mmol) in dioxane (80 mL) and H2O (8 mL) was added Cs2CO3(12.12 g, 37.21 mmol) and Pd(dppf)Cl2.CH2Cl2(2.28 g, 2.79 mmol) at 20 °C. The mixture was allowed to stir at 80 °C for 12 h under an atmosphere of N2. The reaction was quenched by the slow addition of ice water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). tert-Butyl 7-allyl-3,4-dihydro-2H-1,8- naphthyridine-1-carboxylate (4.54 g, 16.55 mmol, 88.94% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.32 (br d, J = 7.5 Hz, 1H), 6.84 (br d, J = 7.6 Hz, 1H), 6.14-6.01 (m, 1H), 5.21-5.06 (m, 2H), 4.13 (q, J = 7.1 Hz, 1H), 3.76 (br t, J = 5.9 Hz, 2H), 3.52 (br d, J = 6.5 Hz, 2H), 2.73 (br t, J = 6.4 Hz, 2H), 1.92 (quin, J = 6.0 Hz, 2H), 1.53 (s, 10H), 1.27 (br t, J = 7.1 Hz, 2H). Step 2: Synthesis of tert-butyl 7-(5-ethoxy-4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylateMTX-04725

[0240] To a mixture of tert-butyl 7-allyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.90 g, 6.94 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.82 g, 13.87 mmol) in DMF (40 mL) was added NiCl2(89.88 mg, 693.52 umol), Na2CO3(735.06 mg, 6.94 mmol) and phenylsilane (3.00 g, 27.74 mmol). The reaction mixture was purged with N23 times, and then the mixture was allowed to stir at 70 °C for 16 h under an atmosphere of N2. The reaction was quenched by the addition of addition of H2O (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 1 / 1). tert-butyl 7-(5-ethoxy-4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (1.5 g, 3.76 mmol, 54.28% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.31 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.79-3.72 (m, 2H), 2.82-2.68 (m, 4H), 2.22-2.09 (m, 2H), 1.99-1.89 (m, 4H), 1.52 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H). Step 3: Synthesis of tert-butyl 7-(4,4-difluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate

[0241] To a solution of tert-butyl 7-(5-ethoxy-4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (1.4 g, 3.51 mmol) in THF (20 mL) was added LiBH4(153.08 mg, 7.03 mmol) at 0 °C. After addition, the mixture was allowed to stir at 0 °C for 2 h. The reaction was quenched by the addition of H2O (50 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. tert-Butyl 7-(4,4-difluoro-5-hydroxypentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.11 g, 3.11 mmol, 88.64% yield) was obtained as white solid.1H NMR (400 MHz, CDCl3) = 7.32 (d, J = 7.6 Hz, 1H), 6.87-6.79 (m, 1H), 3.83-3.70 (m, 4H), 2.85-2.69 (m, 4H), 2.04-1.87 (m, 6H), 1.52 (s, 9H). Step 4: Synthesis of tert-butyl 7-(4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate

[0242] To a solution of (COCl)2(213.68 mg, 1.68 mmol, 147.36 uL) in DCM (6 mL) was added DMSO (197.30 mg, 2.53 mmol, 197.30 uL) at -70 °C. The reaction mixture was allowed to stir at - 70 °C for 0.25 h, and then a solution of tert-butyl 7-(4,4-difluoro-5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (300 mg, 841.74 umol) in DCM (3 mL) was added at -70 °C. The reaction mixture was allowed to stir at -70 °C for 0.5 h and then TEA (511.05 mg, 5.05 mmol, 702.95 uL) was added. The reaction mixture was allowed to stir at 25 °C for 0.25 h and then wasMTX-04725 quenched by the addition of H2O (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic solutions were combined, washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. tert-butyl 7-(4,4-difluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (350 mg, crude) was obtained as yellow oil. Preparation of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylateStep 1: Synthesis of tert-butyl(pent-4-en-1-yloxy)diphenylsilane

[0243] To a solution of pent-4-en-1-ol (30 g, 348.30 mmol, 35.46 mL) in DCM (300 mL) was added imidazole (47.42 g, 696.61 mmol) and tert-butylchlorodiphenylsilane (107.00 g, 389.29 mmol) at 0 °C. The reaction mixture was allowed to stir at 25 °C for 16 h. The reaction mixture was quenched by the addition of water (200 mL) and extracted with DCM (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). tert-Butyl(pent-4-en-1-yloxy)diphenylsilane (100 g, 246.51 mmol, 70.77% yield) was obtained as colorless oil.1H NMR (400MHz, CDCl3) = 7.71-7.65 (m, 4H), 7.44- 7.35 (m, 6H), 5.81 (tdd, J =6.7, 10.3, 17.0 Hz, 1H), 5.07-4.93 (m, 2H), 3.69 (t, J =6.3 Hz, 2H), 2.16 (q, J =7.1 Hz, 2H), 1.72-1.63 (m, 2H), 1.06 (s, 9H). Step 2: Synthesis of tert-butyl 7-(5-((tert-butyldiphenylsilyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate

[0244] To a solution of tert-butyl(pent-4-en-1-yloxy)diphenylsilane (18.11 g, 55.82 mmol) in THF (60 mL) was added 9-BBN (0.5 M in THF, 163.73 mL), the reaction mixture was allowed to stir at 30 °C for 12 h. This resulting solution was added into a mixture of tert-butyl 7-chloro-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate (10 g, 37.21 mmol), PCy3 (1.04 g, 3.72 mmol, 1.21 mL), Pd(dba)2(2.14 g, 3.72 mmol) and K2CO3(10.29 g, 74.42 mmol) in THF (300 mL) and water (15 mL). The reaction mixture was allowed to stir at 70 °C for 16 h. Water (1000 mL) was added and the mixture was extracted with ethyl acetate (800 mL x 2). The organic solutions were combinedMTX-04725 and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 3 / 1). tert-Butyl 7-(5-((tert-butyldiphenylsilyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (160 g, 188.97 mmol, 84.6% yield, 66% purity) was obtained as brown oil. LCMS (ESI) m / z = 559.3 (M+1). Step 3: Synthesis of tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate

[0245] To a solution of tert-butyl 7-(5-((tert-butyldiphenylsilyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (11 g, 19.68 mmol) in THF (400 mL) was added TBAF (1 M in THF, 78.74 mL) and the reaction mixture was allowed to stir at 50 °C for 16 h. Water (500 mL) was added and the mixture was extracted with ethyl acetate (300 mL x 2). The organic solutions were combined, washed with (500 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 300 mL / min). tert-butyl 7-(5- hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3.6 g, 56.18 mmol, 57.08% yield) was obtained as a yellow solid.1H NMR (400 MHz, MeOH-d4) = 7.46 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 3.77-3.70 (m, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.80-2.65 (m, 4H), 1.95-1.88 (m, 2H), 1.76-1.68 (m, 2H), 1.60-1.53 (m, 2H), 1.51 (s, 9H), 1.46-1.38 (m, 2H). Step 4: Synthesis of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate

[0246] To a solution of oxalyl dichloride (11.88 g, 93.63 mmol, 8.20 mL) in DCM (80 mL) was added DMSO (7.32 g, 93.63 mmol, 7.32 mL) at -70 °C. The mixture was allowed to stir at -70 °C for 10 min, and then a solution of tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (10 g, 31.21 mmol) in DCM (20 mL) was added dropwise at -70 °C. The reaction mixture was allowed to stir at -70 °C for 1.5 h, then TEA (18.95 g, 187.25 mmol, 26.06 mL) was added and the resulting mixture was allowed to stir at -70 °C for 20 min. The reaction mixture was quenched by the addition of water (100 mL) at 0 °C and the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 100). tert-Butyl 7-(5-oxopentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.5 g, 20.41 mmol, 65.41% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) = 9.81-9.76 (m, 1H), 7.30 (br d, J = 7.5 Hz, 1H), 6.81 (brMTX-04725 d, J = 7.6 Hz, 1H), 3.76 (br t, J = 5.9 Hz, 2H), 2.76-2.71 (m, 4H), 2.51-2.46 (m, 2H), 1.96-1.89 (m, 2H), 1.82-1.70 (m, 4H), 1.52 (s, 9H). LCMS (ESI) m / z = 319.2 (M+1).

[0247] Compounds in the following table were prepared from the starting material shown by methods similar that described above for the synthesis of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate:Preparation of tert-butyl 7-(4-fluoro-5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1-(2H)-carboxylateStep 1: Synthesis of diethyl 2-allyl-2-fluoromalonate

[0248] To a solution of diethyl 2-fluoromalonate (10.0 g, 56.0 mmol) in dry DMF (90 mL) was added NaH (3.37 g, 84 mmol) at 0 °C. The mixture was allowed to stir for 1 hour, then 3-bromoprop- 1-ene (8.07 g, 67.2 mmol) was added and the mixture was allowed to stir at rt for 3 hours. The reaction was quenched by the addition of NH4Cl (aq) and extracted with EtOAc (2 x 40 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 25 : 1) to give diethyl 2-allyl-2-fluoromalonate (7.0 g) as a colorless oil. Yield 57% (ESI 219.2 [M+H] +). Step 2: Synthesis of diethyl 2-(3-(8-tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)propyl)2-fluoromalonate

[0249] A mixture of diethyl 2-allyl-2-fluoromalonate (7.0 g, 32.0 mmol) and 9-BBN (0.5M in THF, 128 mL, 64.0 mmmol) was allowed to stir at 50°C for 2 hours. To the mixture were added tert- butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (8.58 g, 32.0 mmol), tricyclohexyl phosphine (896 mg, 3.2 mmol), Pd(OAc)2(717 mg, 3.2 mmol) and KOH (2.69 g, 48.0 mmol). TheMTX-04725 reaction mixture was allowed to stir at 70°C for 1 hour, quenched by the addition of H2O (50 mL) and extracted with EtOAc (2x 50 mL). The organic solutions were combined, concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~40%) to give diethyl 2-(3-(8-tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)2- fluoromalonate as a pale brown oil (9.49 g). Yield 67% (ESI 453.2 [M+H] +). Step 3: Synthesis of 5-(8-tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2- (ethoxycarbonyl)-2-fluoropentanoic acid

[0250] To a solution of diethyl 2-(3-(8-tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)propyl)2-fluoromalonate (9.49 g, 21.0 mmol) in EtOH (60 mL) was added LiOH-H2O (861 mg, 21.0 mmol) at 0 °C. The mixture was allowed to warm to rt and stir for 1 hour, then added TFA was added to adjust the pH to 6~7. The mixture was concentrated in vacuo to give 5-(8-tert- butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2-(ethoxycarbonyl)-2-fluoropentanoic acid as a pale brown oil (6.7 g). Yield 75% . (ESI 425.2 [M+H] +). Step 4: Synthesis of tert-butyl 7-(5-ethoxy-4-fluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1-(2H)-carboxylate

[0251] To a solution of 5-(8-tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2- (ethoxycarbonyl)-2-fluoropentanoic acid (6.7 g, 15.8 mmol)) in DMF (50 mL) was added K2CO3(4.36 g, 31.6 mmol). The mixture was allowed to stir at 110 °C for 2 hours, then quenched by the addition of H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 4 : 1) to give tert-butyl 7-(5-ethoxy-4-fluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1-(2H)-carboxylate as a pale brown oil (3.23 g). Yield 54% (ESI 381.2 [M+H] +). Step 5: Synthesis of tert-butyl 7-(4-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1- (2H)-carboxylate

[0252] To a solution of tert-butyl 7-(5-ethoxy-4-fluoro-5-oxopentyl)-3,4-dihydro-1,8- naphthyridine-1-(2H)-carboxylate (3.23 g, 8.5 mmol) in dry THF (30 mL) and EtOH (3 mL) was added LiBH4(2M in THF, 8.5 mL, 17 mmol) at 0 °C. The reaction was allowed to stir at rt for 2 hours, quenched by the addition of NH4Cl (aq) and extracted with EtOAc (2x 30 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 2 : 1) to give tert-butyl 7-(4-fluoro-5-hydroxypentyl)-3,4-dihydro- 1,8-naphthyridine-1-(2H)-carboxylate as a pale brown oil (2.3 g). Yield 80% (ESI 339.2 [M+H] +).MTX-04725 Step 6: Synthesis of tert-butyl 7-(4-fluoro-5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1-(2H)- carboxylate

[0253] To a solution of tert-butyl 7-(4-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1-(2H)-carboxylate (2.3 g, 6.8 mmol) in DCM (30 mL) was added Dess-Martin periodinane (5.77 g, 13.6 mmol) at 0 °C and the reaction mixture was allowed to stir at 0 °C for 2 hours. The reaction was quenched by the addition of NH4Cl (aq) and extracted with DCM (2 x 30 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 1 : 1) to give tert-butyl 7-(4-fluoro-5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1- (2H)-carboxylate as a pale brown oil (1.6 g). Yield 70% (ESI 337.2 [M+H] +). Preparation of 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanal

[0254] To a solution of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-2H-1,8-naphthyridine-1- carboxylate (1 g, 3.14 mmol) in DCM (10 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL), the reaction was allowed to stir at 25 °C for 12 h. The mixture was concentrated and the residue was dissolved in DCM (10 mL), the pH was adjusted to 8 with basic resin, and the mixture was filtered and concentrated. 5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanal (0.5 g, crude) was obtained as brown oil. LCMS: (ESI) m / z = 219.2 (M+1).MTX-04725 Preparation of tert-butyl 7-(4-fluoro-5-oxopentyl)-5-methoxy-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylateStep 1: Synthesis of diethyl 2-allyl-2-fluoromalonate

[0255] To a mixture of NaH (5.0 g, 0.21 mmol) in DMF (100 mL) at 0°C, was added diethyl 2- fluoromalonate (25.0 g, 0.14 mmol). The mixture was allowed to stir at 0°C for 0.5 h, then 3- bromoprop-1-ene (20.4 g, 0.17 mmol) was added and the mixture was allowed to stir at 25°C for 16 hours. The reaction was quenched by the addition of H2O (50 mL) and extracted with EtOAc (3x 100mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc : pet ether= 0%~10%) to give diethyl 2-allyl-2-fluoromalonate as a colorless oil (9.8 g). Yield 32% (ESI 219 [M+H] +). Step 2: Synthesis of diethyl 2-fluoro-2-(3-(4-methoxy-1,8-naphthyridin-2-yl)propyl)malonate

[0256] A mixture of diethyl 2-allyl-2-fluoromalonate (9.8 g, 44.95 mmol) and 9-BBN (0.5 M in THF, 180 mL) was allowed to stir at 60°C for 1 h. To the mixture were added 2-chloro-4-methoxy- 1,8-naphthyridine (13.1 g, 67.43 mmol), tricyclohexyl phosphine (1.26 g, 4.5 mmol), Pd(OAc)2(1.02 g, 4.5 mmol) and KOH (2.52 g, 45.0 mmol). The mixture was allowed to stir at 60°C for 2 hours. The reaction was quenched by the addition of H2O (50 mL) and extracted with EtOAc (3x 100 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc : pet ether= 0%~20%) to give diethyl 2-fluoro-2-(3-(4-methoxy-1,8- naphthyridin-2-yl)propyl)malonate as a colorless oil (9.1 g). Yield 53% (ESI 379 [M+H] +). Step 3: Synthesis of 2-(ethoxycarbonyl)-2-fluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentanoic acidMTX-04725

[0257] To a solution of diethyl 2-fluoro-2-(3-(4-methoxy-1,8-naphthyridin-2-yl)propyl)malonate (9.1 g, 24.1 mmol) in EtOH (100 mL) was added LiOH (1.0 g, 24.1 mmol). The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give 2-(ethoxycarbonyl)-2-fluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentanoic acid as a colorless oil (7.8 g). Yield 93% (ESI 351 [M+H] +). Step 4: Synthesis of ethyl 2-fluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentanoate

[0258] A mixture of 2-(ethoxycarbonyl)-2-fluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentanoic acid (7.8 g, 22.3 mmol) and K2CO3(6.2 g, 44.6 mmol) in DMF (150 mL) was allowed to stir at 110°C for 2 hours. The reaction was quenched by the addition of H2O (100 mL) and extracted with EtOAc (100 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc : pet ether = 0%~30%) to give ethyl 2-fluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentanoate as a pale yellow oil (6.50 g). Yield 95% (ESI 307 [M+H]+). Step 5: Synthesis of ethyl 2-fluoro-5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentanoate

[0259] A mixture of ethyl 2-fluoro-5-(4-methoxy -1,8-naphthyridin-2-yl)pentanoate (7.1 g, 23.18 mmol) and Pd / C (10% wt, 710 mg) in MeOH (100 mL) was allowed to stir at rt under an atmophere of H2for 2 hours. The reaction was filtered and the filtrate was concentrated in vacuo to give ethyl 2- fluoro-5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanoate as a pale orange oil (6.5 g, 90% yield). ESI 311 [M+H] +. Step 6: Synthesis of tert-butyl 7-(5-ethoxy-4-fluoro-5-oxopentyl)-5-methoxy-3,4-dihydro-1,8– naphthyri dine-1(2H)-carboxylate

[0260] A solution of ethyl 2-fluoro-5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanoate (6.5 g, 20.97 mmol), Boc2O (9.1 g, 41.94 mmol) and DMAP (2.6 g, 20.97 mmol) in THF (100 mL) was allowed to stir at 75°C for 3 hours. The reaction was quenched by the addition of H2O (100 mL) and extracted with EtOAc (100 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc : pet ether = 0%~30%) to give tert-butyl 7-(5-ethoxy-4-fluoro-5- oxopentyl)-5-methoxy-3,4-dihydro-1,8–naphthyridine -1(2H)-carboxylate as a pale brown oil (6.6 g). Yield 77% (ESI 411 [M+H]+) Step 7: Synthesis of tert-butyl 7-(4-fluoro-5-hydroxypentyl)-5-methoxy-3,4-dihydro-1,8- naphthyridine-1 (2H)-carboxylateMTX-04725

[0261] A mixture of tert-butyl 7-(5-ethoxy-4-fluoro-5-oxopentyl)-5-methoxy-3,4-dihydro-1,8– naphth yridine-1(2H)-carboxylate (6.6 g, 16.1 mmol) and LiBH4(700 mg, 32.2 mmol) in 60 mL of THF was allowed to stir at 60 °C for 2 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc : pet ether = 50%~80%) to give tert-butyl 7-(4-fluoro-5 -hydroxypentyl)-5- methoxy-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxylate as an orange oil (5.2 g). Yield 88% (ESI 368 (M+H) +). Step 8: Synthesis of tert-butyl 7-(4-fluoro-5-oxopentyl)-5-methoxy-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate

[0262] To a solution of oxalyl dichloride (1.7 g, 13.63 mmol) in DCM (10 mL) at -78°C, was added DMSO (1.1 g, 0.82 mmol). The mixture was allowed to stir at -78°C for 0.5 h, then tert-butyl 7-(4-fluoro-5-hydroxypentyl)-5-methoxy-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.0 g, 5.45 mmol) was added. The mixture was allowed to stir at -78°C for 2 hours. TEA (2.8 g, 27.25 mmol) was added and the mixture was allowed to stir at rt for 16 hours. The reaction was quenched by the addition of H2O (10 mL) and extracted with DCM (3x 30 mL). The organic solutions were combined and concentrated under vacuum to give tert-butyl 7-(4-fluoro-5-oxopentyl)-5-methoxy-3,4- dihydro-1,8-naphthyridine-1(2 H)-carboxylate as a colorless oil (2.0 g). Yield 99% (ESI 367 [M+H] +). Preparation of tert-butyl (S)-7-(3-fluoro-5-((methylsulfonyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylateStep 1: Synthesis of 5-(benzyloxy)pent-1-en-3-ol

[0263] To a solution of 3-(benzyloxy)propanal (25 g, 152.3 mmol) in dry THF (100 mL) at 0°C, was added vinylmagnesium bromide (2.0 M in THF, 110 mL, 220.0 mmol) dropwise and the resulting reaction mixture was allowed to stir at rt for 1 hour. The reaction was quenched by the addition of sat. aq. NH4Cl solution (50 mL) and extracted with EtOAc (100 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and evaporated in vacuo.MTX-04725 The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~20%) to give 5- (benzyloxy)pent-1-en-3-ol as a colorless oil (12.0 g). Yield 41% (ESI 175(M+H-18) +). Step 2: Synthesis of (((3-fluoropent-4-en-1-yl)oxy)methyl)benzene

[0264] To a solution of 5-(benzyloxy)pent-1-en-3-ol (11.5 g, 60 mmol) in DCM (50 mL) at - 78°C was added DAST (14.5 g, 90 mmol). The reaction mixture was allowed to stir at -78°C for 2 hours, quenched by the addition of aq. NaHCO3solution (50 mL) and extracted with DCM (50 mL x3). The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give (((3-fluoropent-4-en-1-yl)oxy)methyl)benzene as a colorless oil (4.2 g). Yield 36% (ESI 195(M+H) +). Step 3: Synthesis of tert-butyl 7-(5-(benzyloxy)-3-fluoropentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate

[0265] To a solution of (((3-fluoropent-4-en-1-yl)oxy)methyl)benzene (4.2 g, 21.6 mmol) in THF (10 mL) at 0°C, was added 9-BBN (0.5M in THF, 87 mL, 43.5 mmol). The reaction mixture was allowed to stir at 50°C for 1 hour and then allowed to cool to rt. To the mixture was added tert- butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (8.69 g, 32.4 mmol), Pd(OAc)2(484 mg, 2.16 mmol), PCy3(605 mg, 2.16 mmol) and KOH (1.82 g, 32.4 mmol). The reaction mixture was allowed to stir at 70°C for 2 hours, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~20%) to give tert-butyl 7-(5-(benzyloxy)-3-fluoropentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a brown oil (3.9 g). Yield 42% (ESI 429 (M+H) +). Step 4: Synthesis of tert-butyl 7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate

[0266] A mixture of tert-butyl 7-(5-(benzyloxy)-3-fluoropentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (3.9 g, 9.0 mmol) and 10% Pd / C (390 mg) in MeOH (80 mL) was allowed to stir at 50 °C under an atmosphere of H2for 12 hours. The solids were removed by filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~40%) to give tert-butyl 7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate as a colorless oil (2.2 g). Yield 71% (ESI 339 (M+H) +). Step 5: Synthesis of tert-butyl (S)-7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate and tert-butyl (R)-7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylateMTX-04725

[0267] The racemic compound tert-butyl 7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (1.0 g) was separated by Prep chiral SFC J to give two isomers as white solids: peak 1 (351 mg), arbitrarily assigned as tert-butyl (S)-7-(3-fluoro-5-hydroxypentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate and peak 2 (365 mg), arbitrarily assigned as tert-butyl (R)-7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate. Preparation of tert-butyl (S)-7-(3-fluoro-5-((methylsulfonyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate

[0268] To a solution of tert-butyl (S)-7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (1.0 g, 3.0 mmol) and TEA (909 mg, 9.0 mmol) in THF (30 mL) at 0°C, was added MsCl (690 mg, 6.0 mmol). The reaction mixture was allowed to stir at rt for 2 hours, quenched by the addition of H2O (20 mL) and extracted with EtOAc (20 mL x3). The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl (S)-7-(3-fluoro-5-((methylsulfonyl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate as a colorless oil (1.2 g). Yield 97% (ESI 417(M+H) +).

[0269] By a similar procedure from racemic tert-butyl 7-(3-fluoro-5-hydroxypentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate was prepared racemic tert-butyl 7-(3-fluoro-5- ((methylsulfonyl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a colorless oil (1.2 g). Yield 97% (ESI 417(M+H) +).

[0270] By a similar procedure from tert-butyl (R)-7-(3-fluoro-5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate was prepared give tert-butyl (S)-7-(3-fluoro-5- ((methylsulfonyl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate.MTX-04725 Preparation of (R)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-ol and (S)-6-(1,2,3,4- tetrahydro-1,8-naphthyridin-2-yl)hexan-1-olStep 1: Synthesis of 7-((tert-butyldiphenylsilyl)oxy)heptan-1-ol

[0271] To a solution of heptane-1,7-diol (20.0 g, 152 mmol) in dry THF (160 mL) at 0°C under an atmosphere of Ar, was added NaH (7.28 g, 182 mmol). The reaction mixture was allowed to stir at 0°C for 40 min and then TBDPSCl (45.8 g, 167 mmol) and TBAI (5.6 g, 15.2 mmol) were added. The reaction mixture was allowed to warm to rt and stir for 18 hours. The reaction was quenched by the addition of H2O (20 mL) and aq. HCl (1M) was added to adjust the pH to 6~7. The mixture was extracted with EtOAc (2 x 200 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 5 : 1) to give 7-((tert- butyldiphenylsilyl)oxy)heptan-1-ol as a colorless oil (26.0 g). Yield 46% (ESI 393 [M+Na] +). Step 2: Synthesis of 7-((tert-butyldiphenylsilyl)oxy)heptanal

[0272] To a solution of (COCl)2 (22.3g, 175 mmol) in dry DCM (280 mL) was added DMSO (21.9 g, 280 mmol) dropwise at -78 °C under an atmosphere of Ar. The reaction was allowed to stir at -78 °C for 30 min, and then a solution of 7-((tert-butyldiphenylsilyl)oxy)heptan-1-ol (26 g, 70.3 mmol) in dry DCM (100 mL) was added slowly. The reaction mixture was allowed to stir at -78 °C for 1 hour, TEA (59 mL, 421 mmol) was added, and the reaction mixture was allowed to warm to rt and stir for 18 hours. The reaction was quenched by the addition of H2O (50 mL) and extracted with DCM (50 mL x3). The organic solutions were combined, washed with NH4Cl (aq.) and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 7-((tert- butyldiphenylsilyl)oxy)heptanal as a colorless oil (19.0 g). Yield 73% (ESI 391 [M+Na] +). Step 3: Synthesis of 9-((tert-butyldiphenylsilyl)non-1-en-3-olheptanal

[0273] To a solution of 7-((tert-butyldiphenylsilyl)oxy)heptanal (19.0 g, 51.6 mmol) in dry THF (200 mL) was added vinylmagnesium bromide (2 M in THF, 52 mL, 104 mmol) slowly at 0 °C. TheMTX-04725 reaction mixture was allowed to stir at rt for 18 hours, quenched by the addition of H2O (20 mL), and the pH was adjusted to 6-7 by the addition of aq. HCl (1M). The mixture was extracted with EtOAc (2 x 100 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 10 : 1) to give 9-((tert- butyldiphenylsilyl)non-1-en-3-olheptanal as a colorless oil (13.0 g). Yield 64% (ESI 419 [M+Na] +). Step 4: Synthesis of 9-((tert-butyldiphenylsilyl)oxy)-1-(2-chloropyridin-3-yl)nonan-3-one

[0274] To a mixture of 9-((tert-butyldiphenylsilyl)non-1-en-3-olheptanal (13.0 g, 32.8 mmol) and 2-chloro-3-iodopyridine (23.5 g, 98.4 mmol) in DMF (120 mL) was added Pd(OAc)2(1.47 g, 6.56 mmol), tetrabutylammonium chloride (1.82 g, 6.65 mmol) and NaHCO3(8.26 g, 98.4 mmol). The reaction mixture was allowed to stir at 100 °C under an atmosphere of N2for 18 hours, quenched by the addition of aq. NH4Cl (50 mL) and extracted with EtOAc (2 x 50 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (pet ether: EtOAc 10 : 1) to give 9-((tert-butyldiphenylsilyl)oxy)-1-(2-chloropyridin-3-yl)nonan-3-one as a colorless oil (8.26 g). Yield 50% (ESI 508 [M+H] +). Step 5: Synthesis of 9-((tert-butyldiphenylsilyl)oxy)-1-(2-chloropyridin-3-yl)nonan-3-amine

[0275] To a solution of 9-((tert-butyldiphenylsilyl)oxy)-1-(2-chloropyridin-3-yl)nonan-3-one (8.26 g, 16.3 mmol) in MeOH (70 mL) was added ammonium acetate (12.6 g, 163 mmol). The mixture was allowed to stir at rt for 10 min, and then sodium cyanoborohydride (3.03 g, 48.9 mmol) was added and the reaction mixture was allowed to stir at rt for 20 hours. The reaction was quenched by the addition of aq. NaHCO3(100 mL) and extracted with DCM (200 mL). The organic solutions were combined and concentrated in vacuo to give 9-((tert-butyldiphenylsilyl)oxy)-1-(2- chloropyridin-3-yl)nonan-3-amine as a brown oil (7.7 g). Yield 93% (ESI 509 [M+H]). Step 6: Synthesis of (S)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-ol and (R)-6- (1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-ol

[0276] A mixture of 9-((tert-butyldiphenylsilyl)oxy)-1-(2-chloropyridin-3-yl)nonan-3-amine (7.7 g, 15.2 mmol) and Cs2CO3(9.88 g, 30.4 mmol) in DMF (70 mL) was allowed to stir at 130 °C for 4 hours. Solids were removed by filtration. The filtrate was concentrated and purified by prep-HPLC B (30-60% MeCN) to give 6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-ol as a colorless oil (2.1 g). Yield 59% (ESI 235 (M+H) +). The racemic product was separated by Prep chiral SFC B to give the two isomers peak 1, arbitrarily assigned as (S)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexan-1-ol (1.0 g), and peak 2, arbitrarily assigned as (R)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin- 2-yl)hexan-1-ol (930 mg), each as a colorless oil.MTX-04725 Preparation of (R)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl methanesulfonate

[0277] To a solution of (R)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexan-1-ol (710 mg, 3.0 mmol) and TEA (909 mg, 9.0 mmol) in THF (30 mL) at 0°C, was added MsCl (416 mg, 3.6 mmol). The reaction was allowed to stir at 0°C for 1 hour, quenched by the addition of H2O (20 mL) and extracted with EtOAc (20 mL x3). The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give (R)-6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl methanesulfonate as a colorless oil (680 mg). Yield 72% (ESI 313 (M+H) +). Right-Side Intermediates Preparation of 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzeneStep 1: Synthesis of 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene

[0278] To a solution of 1-bromo-2-chloro-5-fluoro-4-methyl-benzene (5 g, 22.37 mmol) in DCE (75 mL) was added AIBN (367.41 mg, 2.24 mmol) and NBS (4.78 g, 26.85 mmol). The reaction mixture was allowed to stir at 80 °C for 12 h. Water (100 mL) was added, and the mixture was extracted with DCM (100 mL x 2). The organic solutions were combined, washed with H2O (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0~0% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 1-bromo-4- (bromomethyl)-2-chloro-5-fluoro-benzene (9 g, 29.77 mmol, 66.5% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) = 7.51 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 4.42 (d, J = 0.6 Hz, 2H).MTX-04725 Preparation of 8-bromo-6-isopropylchromaneStep 1: Synthesis of 2,6-dibromo-4-isopropylphenol

[0279] To a mixture of 4-isopropylphenol (5 g, 36.71 mmol) in AcOH (50 mL) was added bromine (12.91 g, 80.77 mmol, 4.16 mL) at 0 °C. The mixture was degassed and purged with N23 times, and then the mixture was allowed to stir at 25 °C for 16 h under an atmosphere of nitrogen. The reaction was quenched by the addition of H2O (60 mL) and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 2,6-dibromo-4-isopropyl-phenol (10 g, 34.02 mmol, 92.65% yield) as yellow oil.1H NMR (400 MHz, CDCl3) ppm 7.27 (s, 2 H) 5.69 (br s, 1 H) 2.69-2.89 (m, 1 H) 1.19 (d, J = 6.88 Hz, 6 H). LCMS (ESI) m / z = 293. (M+1). Step 2: Synthesis of 1,3-dibromo-2-(3-bromopropoxy)-5-isopropylbenzene

[0280] A mixture of 2,6-dibromo-4-isopropyl-phenol (3.2 g, 10.88 mmol), 1,3-dibromopropane (6.59 g, 32.65 mmol, 3.33 mL), K2CO3(3.01 g, 21.77 mmol) in MeCN (130 mL) was degassed and purged with N23 times, and then the mixture was allowed to stir at 50 °C for 16 h under an atmosphere of nitrogen. The reaction was quenched by the addition of H2O (150 mL) and extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1,3-dibromo-2-(3-bromopropoxy)-5- isopropyl-benzene (6 g, 14.46 mmol, 66.42% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) ppm 7.27 (s, 1 H) 7.19 (s, 1 H) 4.02-4.08 (m, 2 H) 3.66 (t, J = 6.63 Hz, 2 H) 2.75 (dt, J = 13.88, 6.94 Hz, 1 H) 2.28-2.38 (m, 2 H) 1.14 (d, J = 7.00 Hz, 6 H). Step 3: Synthesis of 8-bromo-6-isopropylchromane

[0281] To a mixture of 1,3-dibromo-2-(3-bromopropoxy)-5-isopropyl-benzene (2 g, 4.82 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 2.12 mL) at -70 °C and the mixture was allowed to stir for 4 h under an atmosphere of nitrogen. The reaction was quenched by the addition of H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed withMTX-04725 brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 8-bromo-6-isopropyl- chromane (900 mg, 3.53 mmol, 73.18% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) ppm 7.40 (s, 1 H) 7.35 (s, 1 H) 3.72-3.77 (m, 2 H) 2.76-2.97 (m, 3 H) 2.40-2.46 (m, 2 H) 1.21-1.23 (m, 6 H). Preparation of 4-bromo-2-fluoro-1-isopropylbenzeneStep 1: Synthesis of 2-(4-bromo-2-fluorophenyl)propan-2-ol

[0282] MeMgBr (3 M, 35.76 mL) was added dropwise to a solution of methyl 4-bromo-2-fluoro- benzoate (10 g, 42.91 mmol) in THF (100 mL) at 0 °C under an atmosphere of nitrogen. The mixture was allowed to stir for 1 h at 20 °C. The reaction was quenched by the addition of ice water (500 mL) slowly, adjusted to pH = 5 with 6 N HCl, and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO ®; 80 g SepaFlash ® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). 2-(4-bromo-2-fluoro-phenyl)propan-2-ol (11 g, 47.19 mmol, 54.99% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDCl3) = 7.52 (t, J = 8.6 Hz, 1H), 7.34- 7.23 (m, 2H), 1.67 (d, J = 0.9 Hz, 6H). Step 2: Synthesis of 4-bromo-2-fluoro-1-isopropylbenzene

[0283] Et3SiH (10.98 g, 94.39 mmol, 15.08 mL) was added dropwise to a solution of 2-(4- bromo-2-fluoro-phenyl)propan-2-ol (11 g, 47.19 mmol) in TFA (22 mL) / DCM (220 mL) and the mixture was allowed to stir at 40 °C for 16 h. The reaction was quenched by the addition of ice water (100 mL) slowly, adjusted to pH = 8, and extracted with DCM (80 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g SepaFlash ® Silica Flash Column, Eluent of 0~70% Ethyl acetate / Petroleum ether gradient @ 120MTX-04725 mL / min). 4-bromo-2-fluoro-1-isopropyl-benzene (8 g, 36.85 mmol, 78.09% yield) was obtained as yellow oil. Preparation of (2-bromo-6-fluoro-4-isopropylphenyl)(trifluoromethyl)sulfaneStep 1: Synthesis of 2-bromo-6-fluoro-4-isopropylbenzenethiol

[0284] To a solution of 1-bromo-3-fluoro-5-isopropyl-benzene (10 g, 46.07 mmol) in THF (100 mL) was added LDA (2 M, 46.07 mL) at -70 °C. The reaction mixture was allowed to stir at -70 °C for 0.5 h. Sulfur (7.39 g, 230.33 mmol) in THF (20 mL) was added and the reaction mixture was allowed to stir at -70 °C for 1.5 h. The mixture was poured into ice water (80 mL), the pH of the mixture was adjusted to 4 with HCl (1N), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with H2O (100 mL x 2) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to give 2-bromo-6-fluoro-4-isopropyl- benzenethiol (10 g, crude) as red oil. LCMS: (ESI) m / z = 250.0 (M+1). Step 2: Synthesis of (2-bromo-6-fluoro-4-isopropylphenyl)(bromodifluoromethyl)sulfane

[0285] To a solution of NaH (4.01 g, 100.34 mmol, 60% purity) in DMF (60 mL) was added 2- bromo-6-fluoro-4-isopropyl-benzenethiol (10 g, 40.14 mmol) and PPh3 (10.53 g, 40.14 mmol) in DMF (20 mL) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 0.5 h, and then CF2Br2(33.57 g, 120.41 mmol) was added. The reaction mixture was allowed to stir at 25 °C for 1.5 h. The reaction mixture was quenched by the addition of ice water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0~0% petroleum ether / Ethyl acetate), and 1-bromo-2- [bromo(difluoro)methyl]sulfanyl-3-fluoro-5-isopropyl-benzene (6 g, 15.87 mmol, 39.6% yield) was obtained as colorless oil. LCMS: (ESI) m / z = 379 (M+1). Step 3: Synthesis of (2-bromo-6-fluoro-4-isopropylphenyl)(trifluoromethyl)sulfane

[0286] To a solution of 1-bromo-2-[bromo(difluoro)methyl]sulfanyl-3-fluoro-5-isopropyl- benzene (6 g, 15.87 mmol) in DCE (120 mL) was added AgBF4(9.27 g, 47.61 mmol). The reaction mixture was allowed to stir at 60 °C for 12 h. Water (100 mL) was added and the mixture wasMTX-04725 extracted with DCM (50 mL x 2). The organic solutions were combined, washed with H2O (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0~0% petroleum ether / Ethyl acetate). 1-bromo-3- fluoro-5-isopropyl-2-(trifluoromethylsulfanyl)benzene (3.8 g, 11.98 mmol, 75.5% yield) was obtained as yellow oil LCMS: (ESI) m / z = 318.1 (M+1). Preparation of 1-bromo-3,4-difluoro-5-isopropyl-2-methoxybenzeneStep 1: Synthesis of 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene

[0287] A solution of 1-bromo-2,3-difluoro-4-methoxybenzene (25 g, 112.10 mmol), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (47.09 g, 280.25 mmol), PPh3(8.82 g, 33.63 mmol), K3PO4(71.39 g, 336.30 mmol) and Pd(OAc)2(2.52 g, 11.21 mmol) in dioxane (500 mL) and water (50 mL) was allowed to stir at 100 °C for 10 h under an atmosphere of nitrogen. The mixture was cooled to 25 °C and partitioned between MTBE (300 mL) and water (500 mL). The mixture was filtered. The aqueous solution was extracted with MTBE (150 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by MPLC (Biotage®, 220 g SepaFlash® Silica Flash Column, eluent of petroleum ether gradient @ 150 mL / min). The crude product was purified by RP-MPLC (neutral, MeCN / H2O) to give 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (14.4 g, 78.18 mmol, 66.4% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) = 6.99 (dt, J = 2.4, 8.4 Hz, 1H), 6.70 (dt, J = 2.0, 8.2 Hz, 1H), 5.24 (br d, J = 0.6 Hz, 1H), 5.22 (br d, J = 1.3 Hz, 1H), 3.91 (s, 3H), 2.13 (d, J = 0.7 Hz, 3H). Step 2: Synthesis of 2,3-difluoro-1-isopropyl-4-methoxybenzene

[0288] A suspension of 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (7.2 g, 39.09 mmol) and Pd / C (2 g, 10% purity) in MeOH (150 mL) was allowed to stir at 25 °C for 3 h under H2(40 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was purified by MPLC (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of petroleum ether gradient @ 120 mL / min) to give 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (6.3 g, 33.83 mmol, 86.6% yield) as colorless oil.1H NMR (400 MHz, CDCl3) = 6.89 (dt, J = 2.3, 8.3 Hz, 1H), 6.69 (dt, J = 2.0, 8.2 Hz, 1H), 3.89 (s, 3H), 3.25-3.11 (m, 1H), 1.25 (d, J = 7.0 Hz, 6H).MTX-04725 Step 3: Synthesis of 1-bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene

[0289] A solution of 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (2 g, 10.74 mmol) and NBS (2.29 g, 12.89 mmol) in AcOH (30 mL) was allowed to stir at 80 °C for 16 h. The reaction mixture was quenched by the addition of water (100 mL) at 0 °C and extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (100 x 3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / MTBE = 100 / 1 to 0 / 100). 1-bromo-3,4-difluoro-5- isopropyl-2-methoxybenzene (1.8 g, 2.04 mmol, 18.96% yield, 30% purity) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.18-7.14 (m, 1H), 6.92-6.86 (m, 2H), 6.72-6.66 (m, 2H), 3.97 (d, J = 1.0 Hz, 3H), 3.89 (s, 6H), 3.27-3.10 (m, 3H), 1.25 (d, J = 6.9 Hz, 18H). Preparation of 2-bromo-4-isopropyl-1-methoxybenzeneStep 1: Synthesis of 2-bromo-4-isopropylphenol

[0290] To a solution of 4-isopropylphenol (5 g, 36.71 mmol) in HFIP (50 mL), was added NBS (6.86 g, 38.55 mmol). The reaction mixture was allowed to stir at 25 °C for 2 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 2). This reaction was carried out three times in parallel. The organic solutions were combined, washed with H2O (50 mL x 2) and brine (20 mL x 2), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 10 / 1). 2-bromo- 4-isopropyl-phenol (14.5 g, 67.41 mmol, 91.81% yield) was obtained as a yellow oil. Step 2: Synthesis of 2-bromo-4-isopropyl-1-methoxybenzene

[0291] To a solution of 2-bromo-4-isopropyl-phenol (14.5 g, 67.41 mmol) in DMF (200 mL), was added MeI (14.35 g, 101.12 mmol, 6.30 mL) and K2CO3(18.63 g, 134.83 mmol). The reaction mixture was allowed to stir at 50 °C for 2 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 10 / 1). 2-bromo-4-isopropyl-1-methoxy-benzene (14 g, 61.11 mmol, 90.64% yield)MTX-04725 was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3) = 7.27 (d, J=2.13 Hz, 1 H) 6.97 (dd, J = 8.38, 2.13 Hz, 1 H) 6.69 (d, J = 8.38 Hz, 1 H) 3.72 (s, 3 H) 2.70 (dt, J = 13.85, 6.89 Hz, 1 H) 1.08 (d, J = 7.00 Hz, 6 H). Preparation of 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methyltetrahydro-2H-pyranStep 1: Synthesis of 1-bromo-3-fluoro-5-iodo-2-methoxybenzene

[0292] To a solution of 1-bromo-3-fluoro-2-methoxybenzene (7.5 g, 36.58 mmol) and NIS (12.35 g, 54.87 mmol) in AcOH (100 mL) was added H2SO4(4 mL) dropwise at 25 °C and the reaction mixture was allowed to stir at 25 °C for 2 h. Water (500 mL) was added and the reaction mixture was extracted with ethyl acetate (300 mL x 2). The organic solutions were combined, washed with Na2SO3(100 mL x 2) and brine (100 ml), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (80 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate / petroleum ether gradient @ 150 mL / min). 1-bromo-3- fluoro-5-iodo-2-methoxybenzene (20.89 g, 63.13 mmol, 86.3% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) ppm 7.66 (t, J = 1.81 Hz, 1 H) 7.39 (dd, J = 10.01, 2.00 Hz, 1 H) 3.95 (d, J = 1.63 Hz, 3 H). Step 2: Synthesis of 4-(3-bromo-5-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol

[0293] i-PrMgCl (2 M, 11.33 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5-iodo- 2-methoxybenzene (5 g, 15.11 mmol) in THF (100 mL) at 0 °C. The reaction mixture was allowed to stir for 1 h at 0 °C and then cooled to -78 °C. Dihydro-2H-pyran-4(3H)-one (2.27 g, 22.66 mmol, 2.08 mL) was added dropwise and the resulting reaction mixture was allowed to stir for 1 h at -78 °C and 1 h at 20 °C. The reaction was quenched by the addition of aqueous NH4Cl (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 150 mL / min). 4-(3-bromo-5-fluoro-4- methoxyphenyl)tetrahydro-2H-pyran-4-ol (4.72 g, 15.47 mmol, 51.2% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 287.0 (M-18+1).MTX-04725 Step 3: Synthesis of 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methyltetrahydro-2H-pyran

[0294] A slurry of TiCl4(1.93 g, 10.16 mmol) in DCM (50 mL) at 0 °C was cooled to -40 °C and treated with ZnMe2(1 M, 10.16 mL) at -40 °C. The resulting mixture was allowed to stir for 0.5 h at -40 °C, then a solution of 4-(3-bromo-5-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol (1.55 g, 5.08 mmol) in DCM (10 mL) was added dropwise to the mixture. The resulting mixture was allowed to stir for 0.5 h at -40 °C and for 11 h at 25 °C. The reaction mixture was added dropwise to ice water (200 mL) at 0 °C, then the mixture was extracted with ethyl acetate (150 mL x 3). The organic solutions were combined, washed with aqueous NaHCO3(100 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 150 mL / min). 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4- methyltetrahydro-2H-pyran (880 mg, 2.90 mmol, 57.1% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDCl3) = 7.27-7.24 (m, 1H), 7.01 (dd, J = 2.3, 12.8 Hz, 1H), 3.96 (d, J = 1.3 Hz, 3H), 3.79-3.64 (m, 4H), 2.05-1.96 (m, 2H), 1.76-1.68 (m, 2H), 1.27 (s, 3H). Preparation of 1-bromo-2-(difluoromethoxy)-3-fluoro-5-isopropylbenzeneStep 1: Synthesis of 2-bromo-6-fluoro-4-isopropylphenol

[0295] To a solution of 1-bromo-3-fluoro-5-isopropyl-2-methoxybenzene (1 g, 4.05 mmol) in DCM (10 mL) was added BBr3(3.04 g, 12.14 mmol, 1.17 mL) at 0 °C. The reaction mixture was allowed to stir at 25 °C for 12 h. The mixture was poured into ice water (20 mL) and allowed to stir for 0.5 h, then the mixture was extracted with dichloromethane (20 mL x 2). The organic solutions were combined and concentrated. 2-bromo-6-fluoro-4-isopropylphenol (1 g, crude) was obtained as yellow oil. Step 2: Synthesis of 1-bromo-2-(difluoromethoxy)-3-fluoro-5-isopropylbenzene

[0296] To a solution of 2-bromo-6-fluoro-4-isopropylphenol (100 mg, 429.04 umol) in DMF (2 mL) was added Cs2CO3(419.37 mg, 1.29 mmol), sodium 2-chloro-2,2-difluoroacetate (327.06 mg, 2.15 mmol) and H2O (0.4 mL). The reaction mixture was allowed to stir at 100 °C for 12 h. Water (5 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutionsMTX-04725 were combined, washed with H2O (5 mL x 2) and brine (5 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. 1-bromo-2-(difluoromethoxy)-3-fluoro-5-isopropylbenzene (0.05 g, crude) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.29-7.26 (m, 1H), 7.01 (dd, J = 1.8, 11.0 Hz, 1H), 6.57 (t, J = 74.1 Hz, 1H), 2.91-2.83 (m, 1H), 1.25 (d, J = 7.0 Hz, 6H). Preparation of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine

[0297] To a solution of 5-bromo-3-fluorobenzene-1,2-diol (2.50 g, 12.08 mmol) and 1,2- dibromoethane (5.67 g, 30.19 mmol) in anhydrous DMF (25 mL) was added K2CO3(6.68 g, 48.31 mmol). The reaction mixture was allowed to stir at 80 °C for 5 hours, then diluted with water (80 mL) and extracted with EtOAc (40 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give 7-bromo-5-fluoro-2,3- dihydrobenzo[b][1,4]dioxine as a white solid (2.48 g). Yield 88%. Preparation of 2-(3-bromo-5-fluoro-4-methoxy-phenyl)-2-methyl-tetrahydropyranStep 1: Synthesis of 1-(3-bromo-5-fluoro-4-methoxyphenyl)-5-hydroxypentan-1-one

[0298] To a solution of 1-bromo-3-fluoro-5-iodo-2-methoxy-benzene (10 g, 30.22 mmol) in THF (100 mL) was added i-PrMgCl (2 M, 16.62 mL) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 0.5 h, and then tetrahydropyran-2-one (7.56 g, 75.55 mmol, 6.81 mL) was added. The reaction was allowed to stir at 25 °C for 1.5 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic solutions were combined and concentrated.1-(3-bromo-5- fluoro-4-methoxyphenyl)-5-hydroxypentan-1-one (15 g, crude) was obtained as crude yellow oil, which was used directly for next step. LCMS: (ESI) m / z = 305.0 (M+1). Step 2: Synthesis of 5-(3-bromo-5-fluoro-4-methoxy-phenyl)hex-5-en-1-olMTX-04725

[0299] To a solution of bromo-methyl-triphenyl- 5-phosphane (42.14 g, 117.98 mmol) in THF(150 mL) was added t-BuOK (17.65 g, 157.31 mmol) at 0 °C. The mixture was allowed to stir at 0 °C for 0.5 h, then 1-(3-bromo-5-fluoro-4-methoxy-phenyl)-5-hydroxy-pentan-1-one (12 g, 39.33 mmol) was added and the reaction was allowed to stir at 50 °C for 11.5 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with H2O (100 mL) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0~20% petroleum ether / Ethyl acetate), 5-(3-bromo-5-fluoro-4-methoxy-phenyl)hex-5-en-1-ol (1.8 g, 5.94 mmol, 15.10% yield) was obtained as yellow oil. LCMS: (ESI) m / z = 303.0 (M+1). Step 3: Synthesis of 2-(3-bromo-5-fluoro-4-methoxy-phenyl)-2-methyl-tetrahydropyran

[0300] To a solution of 5-(3-bromo-5-fluoro-4-methoxy-phenyl)hex-5-en-1-ol (1.8 g, 5.94 mmol) in DCE (30 mL) was added AgOTf (1.53 g, 5.94 mmol), the reaction was allowed to stir at 50 °C for 16 h. Water (50 mL) was added, the mixture was extracted with DCM (20 mL x 2). The organic solutions were combined, washed with H2O (20 mL) and brine (20 mL x 2), dried over Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20~50% petroleum ether / Ethyl acetate). 2-(3-bromo-5-fluoro-4-methoxy-phenyl)-2-methyl- tetrahydropyran (1.5 g, 4.95 mmol, 83.33% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.33 (t, J = 1.81 Hz, 1 H) 7.12 (dd, J = 12.26, 2.13 Hz, 1 H) 3.95 (d, J = 1.25 Hz, 3 H) 3.68-3.79 (m, 1 H) 3.42-3.52 (m, 1 H) 2.07-2.17 (m, 1 H) 1.59-1.78 (m, 3 H) 1.41-1.52 (m, 2 H) 1.35 (s, 3 H). LCMS: (ESI) m / z = 303 (M+1). Chiral Separation pyran

[0301] 2-(3-bromo-5-fluoro-4-methoxy-phenyl)-2-methyl-tetrahydropyran (2.3 g, 7.59 mmol) was separated by chiral HPLC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 5 um); mobile phase: A: n-heptane; Mobile Phase B: ethanol, 5%-5%, 10 min).MTX-04725

[0302] Peak 1, arbitrarily assigned as (S)-2-(3-bromo-5-fluoro-4-methoxyphenyl)-2- methyltetrahydro-2H-pyran (0.68 g, 2.24 mmol, 59.13% yield) was obtained as yellow oil. SFC: Rt = 2.120 min, 100%

[0303] Peak 2, arbitrarily assigned as (R)-2-(3-bromo-5-fluoro-4-methoxyphenyl)-2- methyltetrahydro-2H-pyran (0.6 g, 1.98 mmol, 52.17% yield) was obtained as yellow oil. SFC: Rt = 2.411 min, 98.66%. Preparation of 7-bromo-5-fluoro-3,3-dimethylisochromaneStep 1: Synthesis of (2-amino-5-bromo-3-fluorophenyl)methanol

[0304] To a solution of 2-amino-5-bromo-3-fluorobenzoic acid (10.0 g, 42.73 mmol) in THF (100 mL) was added BH3-THF (1M, 128.2 mL, 128.2 mmol) at 0°C under an atmosphere of nitrogen. The reaction was allowed to stir at rt for 18 hours. The reaction was quenched by the addition of MeOH (30 mL) and the solvent was removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 10%~50%) to give (2-amino-5-bromo-3- fluorophenyl)methanol as a colorless oil (8.5 g). Yield 90% (ESI 220 (M+H) +). Step 2: Synthesis of (5-bromo-3-fluoro-2-iodophenyl)methanol

[0305] To a solution of (2-amino-5-bromo-3-fluorophenyl)methanol (8.5 g, 38.63 mmol) in THF (85 mL) was added 6M HCl aqueous solution (85 mL). The reaction solution was cooled to -35 °C and NaNO2solution (4.3 g in 20 mL water, 61.81 mmol) was added dropwise over 15 min. The reaction was allowed to stir at -35 °C for 30 min. KI (19.2 g in 30 mL water, 115.9 mmol) was added in portions. The reaction mixture was allowed to warm to rt and stirred for 30 min. The mixture was diluted with water (100 mL) and EtOAc (100 mL). The organic solution was separated, washed withMTX-04725 Na2SO3solution and brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give (5-bromo-3-fluoro-2-iodophenyl)methanol as a colorless oil (5.9 g). Yield 46% (ESI 331.0 (M+H) +). Step 3: Synthesis of ((5-bromo-3-fluoro-2-iodobenzyl)oxy)(tert-butyl)dimethylsilane

[0306] To a solution of (5-bromo-3-fluoro-2-iodophenyl)methanol (5.9 g, 17.83 mmol) in DMF (30 mL) was added imidazole (1.82 g, 26.74 mmol), DMAP (218 mg, 1.78 mmol) and TBSCl (4.03 g, 26.74 mmol). The reaction was allowed to stir at rt for 12 hours, then diluted with water (50 mL), and extracted with EtOAc (3 x 60 mL). The organic solutions were combined, washed with water (3 x 20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give ((5-bromo-3-fluoro-2-iodobenzyl)oxy)(tert- butyl)dimethylsilane as a colorless oil (7.8 g). Yield 98% (ESI 445.1 (M+H) +). Step 4: Synthesis of ethyl 2-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6- fluorophenyl)acetate

[0307] To a mixture of ((5-bromo-3-fluoro-2-iodobenzyl)oxy)(tert-butyl)dimethylsilane (7.8 g, 17.53 mmol), Pd2(dba)3(815 mg, 0.88 mmol) and Q-phos (640 mg, 0.88 mmol) in THF (20 mL) was added (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution 1 M in THF (43.8 mL, 43.8 mmol). The reaction was allowed to stir at 30°C for 2 hours. The mixture was quenched by the addition of NaHCO3solution and the solids were removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give ethyl 2-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluorophenyl)acetate as a pale red oil (3.2 g). Yield 45% (ESI 405 (M + H) +). Step 5: Synthesis of 1-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluorophenyl)-2- methylpropan-2-ol

[0308] To a solution of ethyl 2-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6- fluorophenyl)acetate (3.2 g, 7.90 mmol) in anhydrous THF (30 mL) at 0°C under an atmosphere of Ar, was added methylmagnesium chloride (1N in THF, 23.7 mL, 23.7 mmol) dropwise. The reaction was allowed to stir at 0°C for 30 min, then allowed to warm to rt and stir for 2 hours. The reaction mixture was quenched by the addition of NH4Cl solution (20 mL) and extracted with EtOAc (2 × 50 mL). The organic solutions were combined, washed with bine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~20%) to give 1-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluorophenyl)-2- methylpropan-2-ol as a colorless oil (2.4 g). Yield 78% (ESI 391 (M+H) +).MTX-04725 Step 6: Synthesis of 1-(4-bromo-2-fluoro-6-(hydroxymethyl)phenyl)-2-methylpropan-2-ol

[0309] To a solution of 1-(4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluorophenyl)-2- methylpropan-2-ol (2.4 g, 6.14 mmol) in THF (20 mL) was added TBAF (1N in THF, 12.3 mL, 12.3 mmol). The mixture was allowed to stir at rt for 2 hours, then diluted with H2O (50 mL) and extracted with EtOAc (3x 50 mL). The organic solutions were combined, washed with bine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~30%) to give 1-(4-bromo-2-fluoro-6- (hydroxymethyl)phenyl)-2-methylpropan-2-ol as a yellow oil (1.3 g). Yield 76% (ESI 277 (M+H) +). Step 7: Synthesis of 7-bromo-5-fluoro-3,3-dimethylisochromane

[0310] To a solution of 1-(4-bromo-2-fluoro-6-(hydroxymethyl)phenyl)-2-methylpropan-2-ol (1.3 g, 4.69 mmol) and PPh3(1.84g, 7.04 mmol) in THF (20 mL) at 0°C, was added DIAD (1.42 g, 7.04 mmol). The mixture was allowed to stir at 0°C for 30 min, then warmed to rt overnight. The reaction was diluted with H2O (30 mL) and extracted with EtOAc (3x 30 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give 7-bromo-5- fluoro-3,3-dimethylisochromane as a yellow oil (680 mg). Yield 56% (ESI 259 (M+H) +). Preparation of methyl 2-(3-fluoro-5-isopropyl-2-(methylthio)phenyl)acetateStep 1: Synthesis of (2-bromo-6-fluoro-4-isopropylphenyl)(methyl)sulfane

[0311] To a solution of 1-bromo-3-fluoro-5-isopropyl-benzene (2.5 g, 11.52 mmol) and (methyldisulfanyl)methane (3.25 g, 34.55 mmol, 3.10 mL) in THF (50 mL) was added LDA (1 M, 28.79 mL). The reaction mixture was allowed to stir at -78 °C for 3 h. The reaction was quenched by the addition of ice water (50 mL) slowly and extracted with ethyl acetate (25 mL x 2). The organic solutions were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum gradient @ 80 mL / min) to give (2-bromo-6-fluoro-4-isopropylphenyl)(methyl)sulfane (4.7 g, 17.86 mmol) as yellow oil.1HMTX-04725 NMR (400 MHz, CD3OD) = 7.36 (s, 1H), 7.04 (dd, J = 1.6, 10.3 Hz, 1H), 2.88 (td, J = 6.9, 13.8 Hz, 1H), 2.40 (s, 3H), 1.23 (d, J = 7.0 Hz, 6H). Step 2: Synthesis of tert-butyl 2-(3-fluoro-5-isopropyl-2-(methylthio)phenyl)acetate

[0312] To a solution of (2-bromo-6-fluoro-4-isopropylphenyl)(methyl)sulfane (1 g, 3.80 mmol) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1 M, 15.20 mL) in THF (15 mL) was added Pd(t-Bu3P)2(194.19 mg, 379.98 umol). The reaction mixture was allowed to stir at 70 °C for 2 h. The reaction was quenched by the slow addition of ice water (15 mL) and the mixture was extracted with ethyl acetate (9 mL x 2). The organic solutions were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum gradient @ 80 mL / min). tert-butyl 2-(3-fluoro-5-isopropyl-2- (methylthio)phenyl)acetate (0.7 g, 2.35 mmol, 61.73% yield) was obtained as yellow oil.1H NMR (400 MHz, CD3OD) = 6.90 (d, J = 1.4 Hz, 1H), 6.85 (dd, J = 1.8, 10.5 Hz, 1H), 3.78 (s, 2H), 2.78 (td, J = 6.9, 13.8 Hz, 1H), 2.19 (s, 3H), 1.13 (d, J = 7.0 Hz, 6H). Step 3: Synthesis of methyl 2-(3-fluoro-5-isopropyl-2-(methylthio)phenyl)acetate

[0313] A solution of tert-butyl 2-(3-fluoro-5-isopropyl-2-(methylthio)phenyl)acetate (750 mg, 3.10 mmol) in HCl / MeOH (4 M, 10 mL) was allowed to stir for 16 h at 70 °C. The reaction mixture was concentrated and diluted with water (30 mL) at 20 °C, and then extracted with ethyl acetate (20 mL x 2). The organic solutions were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-(3-fluoro-5-isopropyl-2- (methylthio)phenyl)acetate (0.68 g, 2.65 mmol, 85.71% yield) as yellow oil.1H NMR (400 MHz, CDCl3) = 6.93 (s, 1H), 6.91 (d, J = 1.9 Hz, 1H), 3.92 (s, 2H), 3.72 (s, 3H), 2.97-2.81 (m, 1H), 2.35 (s, 3H), 1.24 (d, J = 7.0 Hz, 6H). Preparation of (S)-methyl 2-(3-fluoro-2-methoxy-5-(2-methyltetrahydro-2H-pyran-2- yl)phenyl)acetateMTX-04725

[0314] To a solution of (2S)-2-(3-bromo-5-fluoro-4-methoxy-phenyl)-2-methyl-tetrahydropyran (0.63 g, 2.08 mmol) and Pd(t-Bu3P)2(212.40 mg, 416.00 umol) in THF (5 mL) was added bromo-(2- methoxy-2-oxo-ethyl)zinc (1 M, 12.48 mL), the reaction was allowed to stir at 70 °C for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0~20% Ethyl acetate / petroleum ether), (S)-methyl 2-(3-fluoro-2-methoxy-5- (2-methyltetrahydro-2H-pyran-2-yl)phenyl)acetate (0.45 g, 1.52 mmol, 73.01% yield) was obtained as yellow oil. LCMS: (ESI) m / z = 297.1 (M+1).

[0315] Compounds in the table below were prepared by a similar method to that described above from the starting materials shown:Preparation of (3-(4-bromo-2,6-difluorobenzyl)oxetan-3-yl)methanolStep 1: Synthesis of methyl 3-(4-bromo-2,6-difluorobenzyl)oxetane-3-carboxylate

[0316] To a solution of methyl oxetane-3-carboxylate (929 mg, 8.0 mmol) in THF (10 mL) at - 78°C, was added KHMDS (0.5 M in toluene, 16.8 mL, 8.4 mmol) dropwise. The reaction mixture was allowed to stir at -60°C for 2 hours, then 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.43 g, 5.0 mmol) in THF (1 mL) was added and the reaction was allowed to stir at -60°C for another 2 hours. The reaction was quenched by the addition of sat. NH4Cl solution (10 mL) and extracted with EtOAc (10 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAcMTX-04725 / pet ether = 0~10%) to give methyl 3-(4-bromo-2,6-difluorobenzyl)oxetane-3-carboxylate as a yellow oil (842 mg). Yield 52% (ESI 321.0 (M+H)+).1H NMR (400 MHz, CDCl3) 7.10-7.08 (m, 2H), 4.89-4.85 (m, 2H), 4.59-4.55 (m, 2H), 3.75 (s, 3H), 3.32 (s,2H). Step 2: Synthesis of (3-(4-bromo-2,6-difluorobenzyl)oxetan-3-yl)methanol

[0317] To a solution of methyl 3-(4-bromo-2,6-difluorobenzyl)oxetane-3-carboxylate (1.12 g, 3.49 mmol) in THF (10 mL) was added LiBH4(2M in THF, 7.0 mL). The reaction mixture was allowed to stir at rt for 2 hours. The reaction was quenched by the addition of MeOH (10 mL) and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~40%) to give (3-(4-bromo-2,6-difluorobenzyl)oxetan-3-yl)methanol as a colorless oil (840 mg). Yield 82% (ESI 314.9 (M+Na) +).1H NMR (400 MHz, CDCl3) 7.13-7.10 (m, 2H), 4.55- 4.50 (m, 2H), 4.42-4.38 (m, 2H), 3.80 (s, 2H), 3.00 (s, 2H). Preparation of methyl (S)-2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(piperidin-4-yl)acetate and methyl (R)-2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(piperidin-4-yl)acetateStep 1: Synthesis of tert-butyl 4-(2-(tert-butoxy)-1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- oxoethyl)piperidine-1-carboxylate

[0318] To a mixture of tert-butyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetate (5 g, 17.71 mmol) in THF (150 mL) was added LiHMDS (1 M, 35.42 mL) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 1 h. tert-butyl 4-iodopiperidine-1-carboxylate (16.53 g, 53.13 mmol) wasMTX-04725 added and the resulting mixture was allowed to stir at 0 °C for 0.5 h and then at 20 °C for 14.5 h. The reaction mixture was quenched by the addition of water (200 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum gradient @ 80 mL / min) to give tert-butyl 4-(2-(tert-butoxy)-1-(3-fluoro-5- isopropyl-2-methoxyphenyl)-2-oxoethyl)piperidine-1-carboxylate (15.7 g) as yellow oil. LCMS (ESI) m / z = 354.2 (M-56-56+1). Step 2: Synthesis of methyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(piperidin-4-yl)acetate

[0319] A solution of tert-butyl 4-(2-(tert-butoxy)-1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- oxoethyl)piperidine-1-carboxylate (4.7 g, 10.09 mmol) in HCl (4 M in MeOH, 20 mL) was allowed to stir at 50 °C for 4 h. The reaction mixture was concentrated in vacuo. Methyl 2-(3-fluoro-5- isopropyl-2-methoxyphenyl)-2-(piperidin-4-yl)acetate (4.2 g, crude) was obtained as yellow oil.NMR (400 MHz, CD3OD) = 7.02-6.95 (m, 2H), 3.88 (d, J = 1.6 Hz, 3H), 3.73-3.64 (m, 3H), 3.41 (br d, J = 13.1Hz, 1H), 3.26-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.97-2.79 (m, 2H), 2.42-2.08 (m, 3H), 1.60-1.43 (m, 2H), 1.37-1.26 (m,1H), 1.25-1.16 (m, 6H). LCMS (ESI) m / z = 324.3 (M+1). Step 3: SFC Separation of methyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(piperidin-4- yl)acetate

[0320] Methyl 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-(4-piperidyl) acetate (1 g, 3.09 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [Heptane-EtOH (1 : 1) with 0.1% IPA]; B%: 5%-5%, 10 min).

[0321] Peak 1, arbitrarily assigned as (S)-methyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- (piperidin-4-yl) acetate (400 mg, 1.24 mmol, 80.00% yield) was obtained as a white solid. LCMS (ESI) m / z = 324.3 (M+1). SFC: Rt = 2.617 min, 100%.

[0322] Peak 2, arbitrarily assigned as (R)-methyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- (piperidin-4-yl) acetate (450 mg, 1.39 mmol, 90.00% yield) was obtained as a white solid. LCMS (ESI) m / z = 324.3 (M+1). SFC: Rt = 3.265 min, 95.2%. Preparation of methyl 2-(3-fluoro-2-hydroxy-5-isopropylphenyl)-2-(piperidin-4-yl)acetateMTX-04725

[0323] To a solution of tert-butyl 4-(1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-methoxy-2- oxoethyl)piperidine-1-carboxylate (0.7 g, 1.65 mmol) in DCM (12 mL) was added BBr3(1.24 g, 4.96 mmol, 477.77 uL) at 0 °C. The reaction mixture was allowed to stir at 25 °C for 12 h and then the mixture was poured into water (30 mL), concentrated and purified by prep-HPLC (Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water (TFA 0.1%), B MeCN: 1%-30%, 8 min, Flow Rate 25 mL / min). methyl 2-(3-fluoro-2-hydroxy-5-isopropylphenyl)-2-(piperidin-4-yl)acetate (440 mg, 1.42 mmol, 85.9% yield) was obtained as yellow oil. LCMS (ESI) m / z = 296.2 (M+1). Preparation of methyl 2-(6-chloro-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4-yl)acetateStep 1: Synthesis of methyl 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropanoate

[0085] To a solution of LDA (2 M, 23.08 mL) in THF (200 mL) at -78 °C, methyl isobutyrate (4.72 g, 46.17 mmol, 5.29 mL) was added slowly and the mixture was allowed to stir at -78 °C for 1 h. Then a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (12 g, 41.97 mmol) in THF (100 mL) was added dropwise at -78 °C. The mixture was allowed to stir at -78 °C for 1 h and then at 20 °C for 14 h. Two batches were carried out in parallel. The reaction was quenched by the addition of sat. NH4Cl (500 mL) at 0 °C and extracted with ethyl acetate (500 mL x 2). The organic solutions were combined, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. Flash Column, Eluent of 0~20% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give methyl 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropanoate (18.4 g, 59.91 mmol, 71.4% yield) as aMTX-04725 yellow oil.1H NMR (400MHz, CDCl3) = 7.11-7.02 (m, 2H), 3.69 (s, 3H), 2.90 (t, J = 1.4 Hz, 2H), 1.20 (t, J = 1.0 Hz, 6H). Step 2: Synthesis of 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropan-1-ol

[0324] A solution of methyl 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropanoate (9.2 g, 29.95 mmol) in toluene (150 mL) was allowed to stir at -78 °C. DIBAL-H (1 M, 59.91 mL) was added slowly at -78 °C and the mixture was allowed to stir at -78 °C for 3 h. Two batches were carried out in parallel. The reaction was poured into ice-water (500 mL) and the pH was adjusted to 2~3 with aq. HCl (3 M) at 0 °C. The mixture was extracted with ethyl acetate (300 mL x 2). The organic solutions were combined, washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Biotage®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate / petroleum ether gradient @120 mL / min) to give 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropan-1-ol (15 g, 53.74 mmol, 89.7% yield) as a yellow oil.1H NMR (400MHz, CDCl3) = 7.11-7.04 (m, 2H), 3.34 (s, 2H), 2.63 (s, 2H), 0.92 (s, 6H). Step 3: Synthesis of 7-bromo-5-fluoro-3,3-dimethylchromane

[0325] A suspension of 3-(4-bromo-2,6-difluorophenyl)-2,2-dimethylpropan-1-ol (15 g, 53.74 mmol) and Cs2CO3 (35.02 g, 107.48 mmol) in DMF (220 mL) was allowed to stir at 100 °C for 16 h. The mixture was filtered and the filtrate was partitioned between ethyl acetate (200 mL) and ice- water (600 mL). The pH of the mixture was adjusted to 6~7 by the addition of aq. HCl (3N). The aqueous solution was extracted with ethyl acetate (200 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Biotage®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~12% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give 7- bromo-5-fluoro-3,3-dimethylchromane (13 g, 50.17 mmol, 93.4% yield) as a white solid.1H NMR (400MHz, CDCl3) = 6.80-6.76 (m, 1H), 6.78 (dd, J = 1.9, 8.5 Hz, 1H), 3.74 (s, 2H), 2.43 (s, 2H), 1.04 (s, 6H). Step 4: Synthesis of 7-bromo-6-chloro-5-fluoro-3,3-dimethylchromane

[0326] To a mixture of 7-bromo-5-fluoro-3,3-dimethyl-chromane (2 g, 7.72 mmol) in THF (25 mL) was added LDA (1 M, 11.58 mL) at -70 °C and then the mixture was allowed to stir at -70 °C for 1 h. A solution of perchloroethane (2.19 g, 9.26 mmol, 1.05 mL) in THF (10 mL) was added at - 70 °C, and the reaction mixture was allowed to stir at -70 °C for 1.5 h. Water (20 mL) was addedMTX-04725 and the mixture was extracted with ethyl acetate (20 mL x 2). The organic solutions were combined, washed with H2O (50 mL x 2) and brine (40 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 7-bromo-6-chloro-5-fluoro-3,3-dimethyl-chromane (2.2 g, 7.49 mmol, 97.1% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 6.97 (d, J = 1.9 Hz, 1H), 3.75 (s, 2H), 2.47 (s, 2H), 1.04 (s, 6H). Step 5: Synthesis of tert-butyl 2-(6-chloro-5-fluoro-3,3-dimethylchroman-7-yl)acetate

[0327] To a solution of 7-bromo-6-chloro-5-fluoro-3,3-dimethyl-chromane (1.5 g, 5.11 mmol) in THF (30 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M, 20.44 mL) and Pd(t- Bu3P)2(652.83 mg, 1.28 mmol). The reaction mixture was allowed to stir at 70 °C for 2 h. The mixture was quenched by the addition of H2O (30 mL). The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (30 mL x 2). The organic solutions were combined and concentrated. The residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0~70% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give tert-butyl 2-(6-chloro-5-fluoro-3,3-dimethyl-chroman-7-yl)acetate (1.2 g, 3.65 mmol, 71.4% yield) as yellow oil.1H NMR (400 MHz, CDCl3) = 6.63-6.54 (m, 1H), 3.74-3.54 (m, 4H), 2.50 (br s, 2H), 1.46 (br d, J = 4.4 Hz, 9H), 1.04 (br s, 6H). LCMS (ESI) m / z = 273.0, 275.0 (M-56+1). Step 6: Synthesis of tert-butyl 4-(2-(tert-butoxy)-1-(6-chloro-5-fluoro-3,3-dimethylchroman-7- yl)-2-oxoethyl)piperidine-1-carboxylate

[0328] To a solution of tert-butyl 2-(6-chloro-5-fluoro-3,3-dimethyl-chroman-7-yl)acetate (600 mg, 1.82 mmol) in DMF (15 mL) was added tert-butyl 4-iodopiperidine-1-carboxylate (1.70 g, 5.47 mmol) and t-BuOK (614.29 mg, 5.47 mmol). The reaction mixture was allowed to stir at 25 °C for 12 h. Water (15 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 2). The organic solutions were combined, washed with H2O (15 mL x 2) and brine (15 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). Tert-butyl 4-[2-tert-butoxy-1-(6-chloro-5-fluoro- 3,3-dimethyl-chroman-7-yl)-2-oxo-ethyl]piperidine-1-carboxylate (430 mg, 839.76 umol, 46.0% yield) was obtained as yellow oil. LCMS (ESI) m / z = 512.3 (M+1). Step 7: Synthesis of methyl 2-(6-chloro-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4- yl)acetateMTX-04725

[0329] A solution of tert-butyl 4-[2-tert-butoxy-1-(6-chloro-5-fluoro-3,3-dimethyl-chroman-7- yl)-2-oxo-ethyl]piperidine-1-carboxylate (410 mg, 800.70 umol) in HCl / MeOH (4 M, 20 mL) was allowed to stir at 25 °C for 12 h. MeOH was distilled out under vacuum. The mixture was adjusted to pH = 7 with alkaline resin, the mixture was filtered and the filtrate was concentrated to give 2-(6- chloro-5-fluoro-3,3-dimethyl-chroman-7-yl)-2-(4-piperidyl)acetate (400 mg, crude) as yellow oil. LCMS (ESI) m / z = 370.2 (M+1).

[0330] Compounds in the following table were prepared from the starting materials shown using methods similar to those described in the example above:MTX-04725

[0331] Compounds in the following table were prepared from the starting materials shown using methods similar to those described in steps 4, 5 and 6 of the example above:

[0332] Compounds in the following table were prepared from the appropriate starting materials by a method similar to steps 3, 4, 5 and 6 of the method described in the example above:Preparation of 2-(6-ethyl-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4-yl)acetic acidStep 1: Synthesis of 1-(7-bromo-5-fluoro-3,3-dimethylchroman-6-yl)ethanolMTX-04725

[0333] To a solution of 7-bromo-5-fluoro-3,3-dimethylchroman (3 g, 11.58 mmol) in THF (30 mL) was added LDA (2 M, 23.16 mL) at -70 °C. The reaction mixture was allowed to stir at -70 °C for 0.5 h and then acetaldehyde (5 M, 9.26 mL) was added. The reaction mixture was allowed to stir at -70 °C for 0.5 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate / petroleum ether gradient @ 150 mL / min). 1-(7-bromo-5-fluoro-3,3-dimethylchroman-6- yl)ethanol (1.2 g, 3.96 mmol, 34.2% yield) was obtained as yellow oil. LCMS (ESI) m / z = 303.0 (M+1). Step 2: Synthesis of 7-bromo-6-ethyl-5-fluoro-3,3-dimethylchromane

[0334] To a solution of 1-(7-bromo-5-fluoro-3,3-dimethylchroman-6-yl)ethanol (1 g, 3.30 mmol) in DCM (15 mL) was added Et3SiH (767.10 mg, 6.60 mmol, 1.05 mL) and TFA (2.26 g, 19.79 mmol, 1.47 mL). The reaction mixture was allowed to stir at 40 °C for 12 h. Water (10 mL) was added and the mixture was extracted with DCM (10 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Biotage®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~0% ethyl acetate / petroleum ether gradient @ 150 mL / min) to give 7-bromo-6-ethyl-5-fluoro-3,3-dimethylchromane (0.7 g, 2.44 mmol, 73.9% yield) as yellow oil.1H NMR (400 MHz, CDCl3) = 6.77 (d, J = 1.6 Hz, 1H), 3.60 (s, 2H), 2.62 (dq, J = 2.3, 7.5 Hz, 2H), 2.33 (s, 2H), 1.04 (t, J = 7.5 Hz, 3H), 0.93 (s, 6H). Step 3: Synthesis of tert-butyl 2-(6-ethyl-5-fluoro-3,3-dimethylchroman-7-yl)acetate

[0335] To a solution of 7-bromo-6-ethyl-5-fluoro-3,3-dimethylchroman (650 mg, 2.26 mmol) in THF (15 mL) was added Pd(t-Bu3P)2 (231.35 mg, 452.70 umol) and (2-(tert-butoxy)-2- oxoethyl)zinc(II) bromide (1 M, 9.05 mL). The reaction mixture was allowed to stir at 70 °C for 1.5 h. The reaction mixture was added to water (10 mL) and filtered. The mixture was extracted with ethyl acetate (15 mL x 2). The organic solutions were combined, washed with H2O (10 mL x 2) and brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25g Sepa Flash ® Silica Flash Column, Eluent of 0~20% Petroleum ether / Ethyl acetate gradient @ 120 mL / min). tert-butyl 2-(6-ethyl-5-fluoro-3,3- dimethylchroman-7-yl)acetate (490 mg, 1.52 mmol, 67.1% yield) was obtained as yellow oil.1HMTX-04725 NMR (400 MHz, CDCl3) = 6.54 (s, 1H), 3.73 (s, 2H), 3.52 (s, 2H), 2.61 (dd, J = 1.1, 7.5 Hz, 2H), 2.50 (s, 2H), 1.48 (s, 9H), 1.15 (t, J = 7.5 Hz, 3H), 1.06 (s, 6H). LCMS (ESI) m / z = 267.2 (M-57+1). Step 4: Synthesis of tert-butyl 4-(2-(tert-butoxy)-1-(6-ethyl-5-fluoro-3,3-dimethylchroman-7- yl)-2-oxoethyl)piperidine-1-carboxylate

[0336] To a solution of tert-butyl 2-(6-ethyl-5-fluoro-3,3-dimethylchroman-7-yl)acetate (430 mg, 1.33 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (2.07 g, 6.67 mmol) in DMSO (12 mL) was added t-BuOK (748.28 mg, 6.67 mmol) at 50 °C. The reaction mixture was allowed to stir at 50 °C for 0.5 h. Water (30 mL) was added, the pH of the mixture was adjusted to 3-4 with HCl (6 N), and the mixture was extracted with ethyl acetate (10 mL x 2). The organic solutions were combined, washed with H2O (10 mL x 2) and brine (10 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25g Sepa Flash ® Silica Flash Column, Eluent of 0~15% Petroleum ether / Ethyl acetate gradient @ 120 mL / min). tert-butyl 4-(2-(tert-butoxy)-1-(6-ethyl-5-fluoro-3,3-dimethylchroman-7-yl)-2- oxoethyl)piperidine-1-carboxylate (520 mg, 1.03 mmol, 77.1% yield) was obtained as yellow oil. LCMS (ESI) m / z = 394.2 (M-112+1). Step 5: Synthesis of 2-(6-ethyl-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4-yl)acetic acid

[0337] To a solution of tert-butyl 4-(2-(tert-butoxy)-1-(6-ethyl-5-fluoro-3,3-dimethylchroman-7- yl)-2-oxoethyl)piperidine-1-carboxylate (520 mg, 1.03 mmol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL). The reaction mixture was allowed to stir at 25 °C for 12 h. The mixture was concentrated and MeOH (8 mL) was added. The pH of the mixture was adjusted to 8 with basic resin, then the mixture was filtered. The filtrate was concentrated to give 2-(6-ethyl-5-fluoro-3,3- dimethylchroman-7-yl)-2-(piperidin-4-yl)acetic acid (300 mg, crude) as yellow oil. LCMS (ESI) m / z = 350.3 (M+1).

[0338] Compounds in the following table were prepared from the starting materials shown using methods similar to those described in the example above:MTX-04725Preparation of tert-butyl (R)-4-(1-(6-chloro-2,2-dimethylchroman-7-yl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate and tert-butyl (S)-4-(1-(6-chloro-2,2-dimethylchroman-7-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylateStep 1: Synthesis of 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene

[0339] To a mixture of 1-bromo-2-chloro-5-fluoro-4-methylbenzene (20.0 g, 90.1 mmol) and AIBN (2.9 g, 18.0 mmol) in CCl4(200 mL) was added NBS (17.6 g, 90.1 mmol). The mixture was allowed to stir at 80°C for 4 hours. The reaction was diluted with H2O (50 mL) and extracted with DCM (3 x 100 mL). The organic solutions were combined, removed in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~5%) to give 1-bromo-4- (bromomethyl)-2-chloro-5-fluorobenzene as a colorless oil (17 g). Yield 62%. Step 2: Synthesis of 1-(tert-butyl) 3-methyl 2-(4-bromo-5-chloro-2-fluorobenzyl)malonateMTX-04725

[0340] To a mixture of NaH (2.0 g, 84.1 mmol) in DMF (150 mL) at -78°C, was added tert-butyl methyl malonate (14.8 g, 84.1 mmol) dropwise. The reaction mixture was allowed to stir at -78°C for 2 hours, then 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene (17.0 g, 56.7 mmol) was added and the mixture was allowed to stir at -78°C for 1 hour. The reaction was quenched by the addition of H2O (50 mL) and extracted with EtOAc (3x 100mL). The organic solutions were combined, removed in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 1-(tert-butyl) 3-methyl 2-(4-bromo-5-chloro-2-fluorobenzyl)malonate as a colorless oil (17.9 g). Yield 81% (ESI 395 [M+H] +). Step 3: Synthesis of 2-(4-bromo-5-chloro-2-fluorobenzyl)-3-methoxy-3-oxopropanoic acid

[0341] To a solution of 1-(tert-butyl) 3-methyl 2-(4-bromo-5-chloro-2-fluorobenzyl)malonate (7.85 g, 19.9 mmol) in DCM (20 mL) was added TFA (3.87 g, 39.8 mmol) dropwise. The reaction was allowed to stir at 25°C for 2 hours. The reaction was quenched by the addition of H2O (10 mL) and extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-(4-bromo-5-chloro-2-fluorobenzyl)- 3-methoxy-3-oxopropanoic acid as a pale yellow oil (6.1 g). Yield 91% (ESI 339 [M+H] +). Step 4: Synthesis of methyl 3-(4-bromo-5-chloro-2-fluorophenyl)propanoate

[0342] A mixture of 2-(4-bromo-5-chloro-2-fluorobenzyl)-3-methoxy-3-oxopropanoic acid (6.1 g, 18.1 mmol) and K2CO3(4.9 g, 36.1 mmol) in DMF (50 mL) was allowed to stir at 110°C for 5 hours. The reaction was quenched by the addition of H2O (100 mL) and extracted with EtOAc (100 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give methyl 3-(4-bromo-5-chloro-2–fluorop henyl)propanoate as a pale yellow oil (4.8 g). Yield 90% (ESI 295 [M+H]+). Step 5: Synthesis of 4-(4-bromo-5-chloro-2-fluorophenyl)-2-methylbutan-2-ol

[0343] To a solution of methyl 3-(4-bromo-5-chloro-2–fluorophenyl)propanoate (4.8 g, 16.3 mmol) in THF (60 mL) at -10°C, was added MeMgBr (3 M in THF, 10.8 mL) dropwise. The reaction mixture was allowed to stir at -10 °C under an atmosphere of N2for 1 hour. The reaction was quenched by the addition of NaHCO3(aq) and extracted with EtOAc (2 x 20 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~20%) to give 4-(4-bromo-5-chloro-2-fluorophenyl)-2- methylbutan-2-ol as a colorless oil (2.9 g). Yield 60% (ESI 295 [M+H] +).MTX-04725 Step 6: Synthesis of 7-bromo-6-chloro-2,2-dimethylchromane

[0344] A mixture of 4-(4-bromo-5-chloro-2-fluorophenyl)-2-methylbutan-2-ol (2.9 g, 9.86 mmol) and NaH (788 mg, 19.72 mmol) in DMF (20 mL) was allowed to stir at 125°C for 12 hours. The reaction was quenched by the addition of H2O (10 mL) and extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 7-bromo-6-chloro-2,2-dimethylchromane as a pale brown oil (2.3 g). Yield 85% (ESI 275 [M+H]). Step 7: Synthesis of ethyl 2-(6-chloro-2,2-dimethylchroman-7-yl)acetate

[0345] To a mixture of 7-bromo-6-chloro-2,2-dimethylchromane (1.7 g, 6.20 mmol), Q-phos (284 mg, 0.31 mmol) and Pd2(dba)3(220 mg, 0.31 mmol) in THF (20 mL), was added (2-ethoxy-2- oxoethyl)zinc(II) bromide (1 M in THF, 9.3 mL). The reaction mixture was allowed to stir at 60°C under an atmosphere of N2for 2 hours. The reaction was quenched by the addition of NaHCO3(aq) and extracted with EtOAc (2 x 20 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~15%) to give ethyl 2-(6-chloro-2,2-dimethylchroman-7-yl)acetate as a pale red oil (1.1 g). Yield 68% (ESI 283 [M+H] +). Step 8: Synthesis of tert-butyl (R)-4-(1-(6-chloro-2,2-dimethylchroman-7-yl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate and tert-butyl (S)-4-(1-(6-chloro-2,2-dimethylchroman-7-yl)- 2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0346] To a solution of ethyl 2-(6-chloro-2,2-dimethylchroman-7-yl)acetate (600 mg, 2.13 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (1.3 g, 4.26 mmol) in DMF (10 mL) at 0°C, was added t-BuOK (477 mg, 4.26 mmol). The reaction was allowed to stir at rt for 1 hour. The reaction was quenched by the addition of H2O (10 mL), then extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 10%~20%) to give tert-butyl 4-(1-(6-chloro-2,2-dimethylchroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate as a colorless oil (715 mg). Yield 72% (ESI 466 (M + H)+). The racemic product was separated by Prep Chiral SFC J to give the two isomers: peak 1, arbitrarily assigned as tert-butyl (R)-4-(1-(6- chloro-2,2-dimethylchroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate, (205 mg) and peak 2, arbitrarily assigned as tert-butyl (S)-4-(1-(6-chloro-2,2-dimethylchroman-7-yl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate, (325 mg) each as a colorless oil.MTX-04725 Preparation of methyl 2-(2-(2,2-difluoroethyl)-3-fluoro-5-isopropylphenyl)-2-(piperidin-4-yl)acetateStep 1: Synthesis of 2-bromo-6-fluoro-4-isopropylbenzaldehydeame

[0347] To a solution of 1-bromo-3-fluoro-5-isopropyl-benzene (4 g, 18.43 mmol) in THF (80 mL) was added DMF (5.39 g, 73.71 mmol, 5.67 mL) at -70 °C. The reaction mixture was allowed to stir at -70 °C for 30 min, and then LDA (1 M, 9.21 mL) was added. The reaction mixture was allowed to stir at -70 °C for 0.5 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give 2-bromo-6-fluoro-4-isopropyl-benzaldehyde (6.3 g, 25.71 mmol, 69.75% yield) as white oil.1H NMR (400 MHz, CDCl3) = 10.31 (s, 1H), 7.34 (s, 1H), 6.99 (d, J = 11.5 Hz, 1H), 2.93 (spt, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H). Step 2: Synthesis of 1-bromo-2-(2,2-difluorovinyl)-3-fluoro-5-isopropylbenzene

[0348] To a solution of 2-bromo-6-fluoro-4-isopropyl-benzaldehyde (3.9 g, 15.91 mmol) in ACN (100 mL) at 70 °C, was added PPh3(12.52 g, 47.74 mmol,) and KI (5.28 g, 31.83 mmol) at 70 °C. The reaction mixture was allowed to stir at 70 °C for 30 min, and then methyl 2,2-difluoro-2fluorosulfonyl-acetate (6.11 g, 31.83 mmol, 4.05 mL) was added slowly over a period of 1 h. The reaction mixture was allowed to stir at 70 °C for 4 h. The reaction was quenched by the slow addition of ice water (300 mL), and the mixture was extracted with ethyl acetate (200 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% Anhydrous tetrahydrofuran / Petroleum gradient @ 120 mL / min). 1-bromo-2-(2,2-difluorovinyl)-3-fluoro-5-MTX-04725 isopropyl-benzene (6.8 g, 24.36 mmol, 76.56% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.28 (s, 1H), 7.28-7.27 (m, 1H), 6.94 (dd, J = 1.4, 10.6 Hz, 1H), 5.30-5.17 (m, 1H), 2.88 (spt, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H). Step 3: Synthesis of tert-butyl 2-(2-(2,2-difluorovinyl)-3-fluoro-5-isopropylphenyl)acetate

[0349] To a solution of 1-bromo-2-(2,2-difluorovinyl)-3-fluoro-5-isopropyl-benzene (2 g, 7.17 mmol) in THF (10 mL) was added Pd(t-Bu3P)2(732.44 mg, 1.43 mmol) and bromo-(2-tert-butoxy-2- oxo-ethyl)zinc (1 M, 28.66 mL). The reaction mixture was allowed to stir at 70 °C for 2 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The reaction mixture was filtered and the filter cake was washed with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Petroleum ether / THF gradient @ 120 mL / min). tert-butyl 2- (2-(2,2-difluorovinyl)-3-fluoro-5-isopropylphenyl)acetate (1.63 g, 5.19 mmol, 72.36% yield) was obtained as white oil.1H NMR (400 MHz, CDCl3) = 6.94-6.92 (m, 1H), 6.93 (s, 1H), 6.89 (dd, J = 1.4, 10.8 Hz, 1H), 5.26-5.13 (m, 1H), 3.53 (s, 2H), 2.89 (spt, J = 6.9 Hz, 1H), 1.45-1.43 (m, 9H), 1.24 (d, J = 6.9 Hz, 6H). Step 4: Synthesis of tert-butyl 2-(2-(2,2-difluoroethyl)-3-fluoro-5-isopropylphenyl)acetate

[0350] To a solution of tert-butyl 2-[2-(2,2-difluorovinyl)-3-fluoro-5-isopropyl-phenyl]acetate (1.3 g, 4.14 mmol) in MeOH (10 mL) was added Pd / C (0.5 g, 10% purity). The reaction mixture was allowed to stir at 25 °C under an atmosphere of H2(50 psi) for 12 h. The reaction mixture was filtered through a celite pad and the filter cake was further washed with MeOH (10 mL). The filtrate was concentrated in vacuo. tert-butyl 2-[2-(2,2-difluoroethyl)-3-fluoro-5-isopropyl-phenyl]acetate (1.25 g, 3.95 mmol, 95.54% yield) was obtained as white oil. LCMS (ESI) m / z = 261.2 (M-56+1). Step 5: Synthesis of tert-butyl 4-(2-(tert-butoxy)-1-(2-(2,2-difluoroethyl)-3-fluoro-5- isopropylphenyl)-2-oxoethyl)piperidine-1-carboxylate

[0351] To a mixture of tert-butyl 2-[2-(2,2-difluoroethyl)-3-fluoro-5-isopropyl-phenyl]acetate (600 mg, 1.90 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (2.95 g, 9.48 mmol) in DMSO (10 mL) was added t-BuOK (1.06 g, 9.48 mmol) at 50 °C. The reaction mixture was allowed to stir at 50 °C for 0.5 h. Water (50 mL) was added, the mixture was adjusted to pH = 4 by the addition of aq. HCl (3 M). The mixture was extracted with ethyl acetate (10 mL x 2). The organic solutions were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 20 gMTX-04725 SepaFlash® Silica Flash Column, Eluent of 0~10% Petroleum ether / THF gradient @ 120 mL / min). tert-butyl 4-[2-tert-butoxy-1-[2-(2,2-difluoroethyl)-3-fluoro-5-isopropyl-phenyl]-2-oxo- ethyl]piperidine-1-carboxylate (600 mg, 1.20 mmol, 63.32% yield) was obtained was obtained as yellow oil. LCMS (ESI) m / z = 522.3 (M+23). Step 6: Synthesis of methyl 2-(2-(2,2-difluoroethyl)-3-fluoro-5-isopropylphenyl)-2-(piperidin-4- yl)acetate

[0352] A solution of tert-butyl 4-[2-tert-butoxy-1-[2-(2,2-difluoroethyl)-3-fluoro-5-isopropyl- phenyl]-2-oxo-ethyl]piperidine-1-carboxylate (200 mg, 400.32 umol) in HCl / MeOH (20 mL) was allowed to stir at 25 °C for 16 h. The mixture was concentrated. MeOH (10 mL) was added, and the pH was adjusted to 8 with basic resin. The mixture was filtered and the filtrate was concentrated. Methyl 2-[2-(2,2-difluoroethyl)-3-fluoro-5-isopropyl-phenyl]-2-(4-piperidyl)acetate (391 mg, crude) was obtained as white oil. LCMS (ESI) m / z = 358.2 (M+1) Preparation of methyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4-yl)acetateStep 1: Synthesis of 7-bromo-5-fluoro-3,3-dimethylchromane-6-carbonitrile

[0353] To a solution of 7-bromo-5-fluoro-3,3-dimethylchroman (4.5 g, 17.37 mmol) in THF (45 mL) was added LDA (2 M, 10.42 mL) dropwise at -70 °C under an atmosphere of N2. The reaction was allowed to stir at -70 °C for 0.5 h. Then 4-methylbenzenesulfonyl cyanide (3.78 g, 20.84 mmol) in THF (15 mL) was added. The mixture was allowed to stir at -70 °C at 1 h. The reaction was quenched by the addition of aqueous NH4Cl (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 10 / 1). 7-Bromo-5-fluoro-3,3-dimethylchroman-6-carbonitrile (1.5 g, 5.28 mmol, 30.40% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 6.97 (d, J = 1.5 Hz, 1H), 3.84 (s, 2H), 2.47 (s, 2H), 1.05 (s, 6H). Step 2: Synthesis of tert-butyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)acetateMTX-04725

[0354] A suspension of 7-bromo-5-fluoro-3,3-dimethylchroman-6-carbonitrile (1.1 g, 3.87 mmol), bromo-(2-tert-butoxy-2-oxo-ethyl) zinc (1 M, 15.49 mL) and Pd (t-Bu3P)2(158.29 mg, 309.72 umol) in THF (20 mL) was allowed to stir at 70 °C for 3 h under an atmosphere of N2. The reaction was quenched by the addition of H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic solutions were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 5 / 1). tert-butyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7- yl)acetate (1 g, 3.13 mmol, 80.88% yield) was obtained as brown solid.1H NMR (400 MHz, CDCl3) = 6.65 (s, 1H), 3.81 (s, 2H), 3.67 (s, 2H), 2.50 (s, 2H), 1.48 (s, 9H), 1.05 (s, 6H). Step 3: Synthesis of tert-butyl 4-(2-(tert-butoxy)-1-(6-cyano-5-fluoro-3,3-dimethylchroman-7- yl)-2-oxoethyl)piperidine-1-carboxylate

[0355] To a solution of tert-butyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)acetate (1 g, 3.13 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (4.87 g, 15.66 mmol) in NMP (20 mL) was added t-BuOK (1.76 g, 15.66 mmol) at 50 °C. The reaction was allowed to stir at 50° C for 0.5 h. The reaction mixture was quenched by the addition of H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic solutions were combined, washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 3:1). tert-butyl 4-(2-(tert-butoxy)-1- (6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)-2-oxoethyl)piperidine-1-carboxylate (1 g, 1.99 mmol, 63.54% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCl3) = 6.90 (s, 1H), 3.83 (s, 2H), 3.59 (d, J = 10.4 Hz, 1H), 2.81-2.54 (m, 3H), 2.51 (s, 2H), 2.12-2.06 (m, 1H), 1.83 (br d, J = 12.5 Hz, 1H), 1.45 (s, 9H), 1.42 (s, 9H), 1.36-1.18 (m, 4H), 1.05 (d, J = 4.1 Hz, 6H). Step 4: Synthesis of methyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4- yl)acetate

[0356] A solution of tert-butyl 4-(2-(tert-butoxy)-1-(6-cyano-5-fluoro-3,3-dimethylchroman-7- yl)-2-oxoethyl)piperidine-1-carboxylate (600 mg, 1.19 mmol) in HCl (4M in MeOH, 20 mL) was allowed to stir at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Methyl 2-(6-cyano-5-fluoro-3,3-dimethylchroman-7-yl)-2-(piperidin-4-yl)acetate (700 mg) was obtained as yellow oil.1H NMR (400 MHz, CD3OD) = 6.88 (s, 1H), 3.88 (s, 2H), 3.72-3.68 (m, 3H), 3.42 (br d, J = 8.1 Hz, 2H), 3.09-3.00 (m, 1H), 2.98-2.89 (m, 1H), 2.56-2.50 (m, 2H), 2.46-2.35 (m, 1H), 2.14-2.05 (m, 1H), 1.64-1.41 (m, 4H), 1.04 (s, 6H).MTX-04725 Preparation of methyl 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-[(2R,4R)-2-methyl-4- piperidyl]acetateStep 1: Synthesis of tert-butyl (2R,4S)-4-iodo-2-methyl-piperidine-1-carboxylate

[0357] To a solution of tert-butyl (2R,4R)-4-hydroxy-2-methyl-piperidine-1-carboxylate (2.5 g, 11.61 mmol), PPh3(3.96 g, 15.10 mmol) and imidazole (1.19 g, 17.42 mmol) in DCM (10 mL) was added I2(3.54 g, 13.93 mmol, 2.81 mL) at 0 °C. The mixture was allowed to stir for 12 h at 20 °C. The reaction was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give tert-butyl (2R,4S)-4-iodo-2-methyl- piperidine-1-carboxylate (2 g, 6.15 mmol, 52.96% yield) as a yellow oil. Step 2: Synthesis of tert-butyl (2R,4R)-4-[2-tert-butoxy-1-(3-fluoro-5-isopropyl-2-methoxy- phenyl)-2-oxo-ethyl]-2-methyl-piperidine-1-carboxylate

[0358] To a solution of tert-butyl (2R,4S)-4-iodo-2-methyl-piperidine-1-carboxylate (1.38 g, 4.25 mmol) and tert-butyl 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetate (400 mg, 1.42 mmol) in NMP (20 mL) was added t-BuOK (635.88 mg, 5.67 mmol). The mixture was allowed to stir at 50 °C for 1 h. The reaction was quenched by the slow addition of ice water (20 mL), and the mixture was extracted with ethyl acetate (10 mL x 2). The organic solutions were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum gradient @ 80 mL / min). Tert-butyl (2R,4R)-4-[2-tert-butoxy-1-(3-fluoro-5- isopropyl-2-methoxy-phenyl)-2-oxo-ethyl]-2-methyl-piperidine-1-carboxylate (250 mg, 521.24 umol) was obtained as yellow oil. LCMS (ESI) m / z = 480.3 (M+1). Step 3: Synthesis of methyl 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-[(2R,4R)-2-methyl-4- piperidyl]acetate

[0359] A solution of tert-butyl (2R,4R)-4-[2-tert-butoxy-1-(3-fluoro-5-isopropyl-2-methoxy- phenyl)-2-oxo-ethyl]-2-methyl-piperidine-1-carboxylate (250 mg, 521.24 umol) in HCl / MeOH (4 M, 10 mL) was allowed to stir at 50 °C for 3 h. The reaction was filtered and concentrated. Methyl 2-MTX-04725 (3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-[(2R,4R)-2-methyl-4-piperidyl]acetate (160 mg, 474.18 umol, 90.97% yield) was obtained as yellow oil. LCMS (ESI) m / z = 338.2 (M+1) Preparation of 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-(4-hydroxy-4-piperidyl)acetic acidStep 1: Synthesis of 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetic acid

[0360] To a solution of tert-butyl 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetate (2 g, 7.08 mmol) in DCM (15 mL) was added TFA (5 mL). The mixture was allowed to stir at 20 °C for 12 h. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% tetrahydrofuran / Petroleum ether gradient @ 100 mL / min). 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetic acid (1.4 g, 6.19 mmol, 87.36% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.03-6.77 (m, 2H), 3.92 (d, J = 1.8 Hz, 3H), 3.68 (s, 2H), 2.84 (td, J = 6.9, 13.8 Hz, 1H), 1.22 (d, J = 7.0 Hz, 6H). Step 2: Synthesis of 2-(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)-2-(3-fluoro-5-isopropyl-2- methoxy-phenyl)acetic acid

[0361] To a solution of 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetic acid (1.1 g, 4.86 mmol) in THF (15 mL) was added LDA (1 M, 11.05 mL) dropwise at -78 °C under an atmosphere of N2and the mixture was allowed to stir for 1 h. Then tert-butyl 4-oxopiperidine-1-carboxylate (880.67 mg, 4.42 mmol) in THF (5 mL) was added to the mixture dropwise at -78 °C and the mixture was allowed to stir at -78 °C for 2 h. The reaction was quenched by the slow addition of ice water (30 mL), adjusted to pH = 5, and extracted with ethyl acetate (30 mL x 3). The organic solutions were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). 2-(1- tert-butoxycarbonyl-4-hydroxy-4-piperidyl)-2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)acetic acid (430 mg, 1.01 mmol, 22.86% yield) was obtained as yellow oil. LCMS: (ESI) m / z = 326.2 (M+1). Step 3: Synthesis of 2-(3-fluoro-5-isopropyl-2-methoxy-phenyl)-2-(4-hydroxy-4-piperidyl)acetic acidMTX-04725

[0362] To a solution of 2-(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)-2-(3-fluoro-5- isopropyl-2-methoxy-phenyl)acetic acid (430 mg, 1.01 mmol) in DCM (4 mL) was added TFA (610.73 mg, 5.35 mmol, 396.58 uL). The mixture was allowed to stir at 20 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C1880 x 30 mm x 3 um; mobile phase: A water (TFA 0.1%); B MeCN 15%-45%, 8 min. 2-(3- fluoro-5-isopropyl-2-methoxy-phenyl)-2-(4-hydroxy-4-piperidyl)acetic acid (100 mg, 307.34 umol, 30.43% yield) was obtained as white solid. LCMS: (ESI) m / z = 326.2 (M+1). Preparation of 2-(2-ethyl-3-fluoro-5-isopropyl-phenyl)-2-(4-piperidyl)acetic acidStep 1: Synthesis of 1-bromo-3-fluoro-5-isopropenyl-benzene

[0363] A solution of t-BuOK (22.75 g, 202.73 mmol) and methyl(triphenyl)phosphonium bromide (54.32 g, 152.05 mmol) in THF (220 mL) was allowed to stir at 25 °C for 30 min, then a solution of 1-(3-bromo-5-fluoro-phenyl)ethanone (22 g, 101.37 mmol) in THF (5 mL) was added and the reaction was allowed to stir at 35 °C for 0.5 h. The reaction was quenched by the slow addition of water (300 mL) and the mixture was extracted with ethyl acetate (300 mL x 2). The organic solutions were combined, washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to give 1-bromo-3-fluoro-5-isopropenyl-benzene (18.25 g, 84.86 mmol, 83.72% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDCl3) = 7.40 (s, 1H), 7.16 (td, J = 2.0, 8.0 Hz, 1H), 7.10 (td, J = 1.8, 10.1 Hz, 1H), 5.40 (s, 1H), 5.18 (s, 1H), 2.12 (s, 3H) Step 2: Synthesis of 1-bromo-2-ethyl-3-fluoro-5-isopropenyl-benzene

[0364] To a solution of 1-bromo-3-fluoro-5-isopropenyl-benzene (5 g, 23.25 mmol) in THF (50 mL) was added LDA (2 M, 23.25 mL) at -70 °C. The mixture was allowed to stir 0.5 h under an atmosphere of nitrogen. Then EtI (21.76 g, 139.49 mmol, 11.16 mL) was added. The mixture wasMTX-04725 allowed to stir at -70 °C for 1.5 h. The reaction was quenched by the slow addition of aqueous NH4Cl (100 mL) and the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to give 1-bromo-2-ethyl-3-fluoro-5-isopropenyl-benzene (4.68 g, 19.25 mmol, 82.80% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.43-7.39 (m, 1H), 7.08 (d, J = 9.8 Hz, 1H), 5.40-5.37 (m, 1H), 5.12 (s, 1H), 2.84-2.78 (m, 2H), 2.10 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H). Step 3: Synthesis of tert-butyl 2-(2-ethyl-3-fluoro-5-isopropenyl-phenyl)acetate

[0365] To a solution of 1-bromo-2-ethyl-3-fluoro-5-isopropenyl-benzene (4.5 g, 18.51 mmol) in THF (50 mL) was added palladium tri-tert-butylphosphane (472.97 mg, 925.49 umol) and bromo-(2- tert-butoxy-2-oxo-ethyl)zinc (1 M in THF, 74.04 mL) under an atmosphere of N2. The mixture was allowed to stir at 70 °C for 2 h. The reaction was quenched by the slow addition of water (150 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 2-(2-ethyl-3-fluoro-5-isopropenyl-phenyl)acetate (5 g, 17.96 mmol, 97.04% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.13-7.11 (m, 1H), 7.05 (br d, J = 11.4 Hz, 1H), 5.39- 5.35 (m, 1H), 5.13-5.07 (m, 1H), 3.58 (s, 2H), 2.70 (br s, 2H), 2.14-2.11 (m, 4H), 1.46-1.45 (m, 9H), 1.18 (s, 4H). Step 4: Synthesis of tert-butyl 2-(2-ethyl-3-fluoro-5-isopropyl-phenyl)acetate

[0366] To a solution of tert-butyl 2-(2-ethyl-3-fluoro-5-isopropenyl-phenyl)acetate (5 g, 17.96 mmol) in THF (60 mL) was added Pd / C (500 mg, 2.00 mL, 5% purity) under an atmosphere of N2. The suspension was degassed under vacuum and purged with H23 times. The mixture was allowed to stir under H2(15 psi) at 20 °C for 5 h. The reaction was filtered and concentrated. tert-butyl 2-(2- ethyl-3-fluoro-5-isopropyl-phenyl)acetate (4.7 g, crude) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 6.92-6.86 (m, 1H), 6.81 (br d, J = 11.1 Hz, 1H), 3.55 (s, 2H), 2.85 (td, J = 6.9, 13.9 Hz, 1H), 2.71-2.58 (m, 2H), 1.45 (s, 9H), 1.23 (d, J = 6.8 Hz, 6H), 1.15 (t, J = 7.5 Hz, 3H). Step 5: Synthesis of tert-butyl 4-[2-tert-butoxy-1-(2-ethyl-3-fluoro-5-isopropyl-phenyl)-2-oxo- ethyl] piperidine-1-carboxylateMTX-04725

[0367] To a solution of tert-butyl 4-iodopiperidine-1-carboxylate (4.99 g, 16.05 mmol) and tert- butyl 2-(2-ethyl-3-fluoro-5-isopropyl-phenyl)acetate (1.5 g, 5.35 mmol) in NMP (20 mL) was added t-BuOK (2.40 g, 21.40 mmol). The mixture was allowed to stir at 50 °C for 1 h. The reaction was quenched by the slow addition of NH4Cl (50 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert-butyl 4-[2-tert-butoxy-1-(2-ethyl-3- fluoro-5-isopropyl-phenyl)-2-oxo-ethyl] piperidine-1-carboxylate (2 g, 4.31 mmol, 80.63% yield) as yellow oil. LCMS (ESI) m / z = 464.3 (M+1). Step 6: Synthesis of 2-(2-ethyl-3-fluoro-5-isopropyl-phenyl)-2-(4-piperidyl)acetic acid

[0368] A solution of tert-butyl 4-[2-tert-butoxy-1-(2-ethyl-3-fluoro-5-isopropyl-phenyl)-2-oxo- ethyl]piperidine-1-carboxylate (0.5 g, 1.08 mmol) in TFA (2.5 mL) and DCM (5 mL) was allowed to stir at 50 °C for 16 h. The reaction was concentrated. The crude product was purified by prep-HPLC (column: Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water (TFA 0.1%), B MeCN 5%- 35%, 8 min; Flow Rate 25 mL / min) to give 2-(2-ethyl-3-fluoro-5-isopropyl-phenyl)-2-(4- piperidyl)acetic acid (226.6 mg, 737.15 umol, 23.69% yield) as a yellow oil. LCMS (ESI) m / z =308.2 (M+1). Preparation of tert-butyl (R)-4-(1-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate and tert-butyl (S)-4-(1-(3,3-dimethyl-6-(trifluoromethyl)chroman- 7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylateStep 1: Synthesis of 1-bromo-5-fluoro-4-iodo-2-(trifluoromethyl)benzeneMTX-04725

[0369] To a solution of 4-bromo-2-fluoro-5-(trifluoromethyl)aniline (6.0 g, 23.3 mmol) in ACN (30 mL) was added aq. H2SO4(9M, 26 mL) at 0 °C. The reaction mixture was allowed to stir for 20 min, then a solution of NaNO2(2.4 g, 35 mmol) in H2O (10 mL) was added dropwise and the reaction mixture was allowed to stir at 0 °C for 1 hour. To the reaction mixture was added a solution of KI (11.6 g, 70.0 mmol) in H2O (20 mL) and the reaction mixture was allowed to stir at rt for 1 hour. The reaction was quenched by the addition of H2O (20 mL) and extracted with EtOAc (3 x 50 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give 1-bromo-5-fluoro-4-iodo-2- (trifluoromethyl)benzene as a colorless oil (5.7 g). Yield 67%. Step 2: Synthesis of (4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)methanol

[0370] To a solution of 1-bromo-5-fluoro-4-iodo-2-(trifluoromethyl)benzene (5.7 g, 15.5 mmol) in dry THF (50 mL) was added i-PrMgBr (2M in THF, 19.5 mL, 39 mmol) at -20 °C under an atmosphere of Ar. The reaction mixture was allowed to stir at -20 °C for 1 hour, then DMF (5.7 g, 77.5 mmol) was added and the reaction mixture was allowed to stir at 0 °C for 1 hour. The reaction was quenched by the addition of MeOH (5 mL). NaBH4(868 mg, 31 mmol) was added and the reaction mixture was allowed to stir at rt for 2 hours. The reaction was quenched by the addition of aq. NH4Cl solution and extracted with EtOAc (3 x 40 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~15%) to give (4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)methanol (2.9 g, 10.7 mmol) as a colorless oil. Yield 69% (ESI 255.0 [M+H-18] +). Step 3: Synthesis of 1-bromo-4-(bromomethyl)-5-fluoro-2-(trifluoromethyl)benzene

[0371] To a solution of (4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)methanol (2.9 g, 10.7 mmol) in DCM (20 mL) was added PPh3(3.35 g, 12.8 mmol) and CBr4(4.23 g, 12.8 mmol). The reaction was allowed to stir at rt for 2 hours, quenched by the addition of H2O (20 mL) and extracted with DCM (3 x 20 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give 1-bromo-4- (bromomethyl)-5-fluoro-2-(trifluoromethyl)benzene as a colorless oil (2.5 g). Yield 70%. Step 4: Synthesis of ethyl 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2- dimethylpropanoate

[0372] To a solution of ethyl isobutyrate (1.38 g, 11.9 mmol) in dry THF (30 mL) was added LDA (2M in THF, 6.0 mL, 12.0 mmol) at -78 °C under an atmosphere of Ar. The reaction mixture was allowed to stir at -78 °C for 0.5 hour, and then a solution of 1-bromo-4-(bromomethyl)-5-fluoro-MTX-04725 2-(trifluoromethyl)-benzene (2.5 g, 7.46 mmol) in THF (10 mL) was added. The reaction mixture was allowed to stir at -78 °C for 1 hour. The reaction was quenched by the addition of aq. NH4Cl solution and extracted with EtOAc (3 x 30 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give ethyl 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate as a colorless oil (1.6 g). Yield 58% (ESI 371 [M+H] +). Step 5: Synthesis of 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

[0373] To a solution of ethyl 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2- dimethylpropanoate (1.6 g, 4.32 mmol) in THF (20 mL) was added LiBH4(2M in THF, 4.3 mL, 8.6 mmol) at 0 °C. The reaction mixture was allowed to stir at rt for 5 hours, quenched by the addition of aq. NH4Cl and extracted with EtOAc (3 x 30 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~15%) to give 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol as a colorless oil (1.2 g). Yield 85% (ESI 329 [M+H] +). Step 6: Synthesis of 7-bromo-3,3-dimethyl-6-(trifluoromethyl)chromane

[0374] A mixture of 3-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (1.2 g, 3.66 mmol) and Cs2CO3 (2.38 g, 7.32 mmol) in DMF (20 mL) was allowed to stir at 110°C for 18 hours. The reaction was quenched by the addition of H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give 7-bromo-3,3-dimethyl-6- (trifluoromethyl)-chromane as a colorless oil (810 mg). Yield 72%. Step 7: Synthesis of ethyl 2-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)acetate

[0375] To a mixture of 7-bromo-3,3-dimethyl-6-(trifluoromethyl)chromane (810 mg, 2.63 mmol), Q-phos (56 mg, 0.08 mmol) and Pd2(dba)3(73 mg, 0.08 mmol) in THF (10 mL), was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 7 mL). The reaction mixture was allowed to stir at 60 °C under an atmosphere of N2for 1 hour, quenched by the addition of aq. NaHCO3and extracted with EtOAc (3 x 20 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give ethyl 2- (3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)acetate as a colorless oil (689 mg). Yield 83% (ESI 339.1 [M+Na] +).MTX-04725 Step 8: Synthesis of tert-butyl (R)-4-(1-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate and tert-butyl (S)-4-(1-(3,3-dimethyl-6- (trifluoromethyl)chroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0376] To a solution of ethyl 2-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)acetate (689 mg, 2.18 mmol) and tert-butyl 4-iodoazepane-1-carboxylate (1.14 g, 4.36 mmol) in dry DMF (10 mL) at 0 °C, was added t-BuOK (488 mg, 4.36 mmol). The reaction was allowed to stir at rt for 2 hours, quenched by the addition of H2O (10 mL) and extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 5%~10%) to give tert- butyl 4-(1-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1- carboxylate as a colorless oil (610 mg). Yield 56 % (ESI 500 (M + H) +). The racemic product was separated by Prep Chiral SFC J to give the two isomers: peak 1, arbitrarily assigned as tert-butyl (R)- 4-(1-(3,3-dimethyl-6-(trifluoromethyl)chroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (240 mg), and peak 2, arbitrarily assigned as tert-butyl (S)-4-(1-(3,3-dimethyl-6- (trifluoromethyl)chroman-7-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (255 mg), each as a colorless oil. Preparation of methyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)-2-(piperidin-4- yl)acetateStep 1: Synthesis of 1-(3-bromo-5-fluoro-4-methoxyphenyl)cyclohexanol

[0377] To a solution of 1-bromo-3-fluoro-5-iodo-2-methoxybenzene (2.5 g, 7.55 mmol) in THF (60 mL) was added i-PrMgCl (2 M, 4.16 mL) at 0 °C. The mixture was allowed to stir at 0 °C for 0.5 h, and then cyclohexanone (1.85 g, 18.89 mmol, 1.96 mL) was added at 0 °C. The reaction was allowed to stir at 25 °C for 11.5 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, concentrated and purified byMTX-04725 column chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 1-(3-bromo-5-fluoro-4- methoxyphenyl)cyclohexanol (2.1 g, 6.93 mmol, 45.8% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 7.37 (t, J = 1.8 Hz, 1H), 7.14 (dd, J = 2.1, 12.5 Hz, 1H), 3.87 (d, J = 1.1 Hz, 3H), 2.27 (t, J = 6.6 Hz, 2H), 1.84-1.75 (m, 2H), 1.61 (td, J = 3.4, 13.6 Hz, 6H). LCMS (ESI) m / z = 179.2 (M+1). Step 2: Synthesis of 1-bromo-3-fluoro-2-methoxy-5-(2-methoxybutan-2-yl)benzene

[0378] To a solution of NaH (2.08 g, 51.95 mmol, 60% purity) in DMF (70 mL) was added 1-(3- bromo-5-fluoro-4-methoxyphenyl)cyclohexanol (6.3 g, 20.78 mmol) in DMF (10 mL) at 0 °C. The reaction was allowed to stir for 0.5 h, then MeI (8.85 g, 62.34 mmol, 3.88 mL) was added to the mixture at 0 °C and the reaction was allowed to stir at 25 °C for 1 h. The reaction mixture was quenched by the addition of H2O (50 mL) at 0 °C and the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Biotage®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ethergradient @120 mL / min). 1-bromo-3-fluoro-2-methoxy-5-(2-methoxybutan- 2-yl)benzene (4 g, 12.61 mmol, 60.7% yield) was obtained as yellow oil. LCMS (ESI) m / z = 318.3 (M+1). Step 3: Synthesis of methyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)acetate

[0379] To a solution of 1-bromo-3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)benzene (2 g, 6.31 mmol) and Pd(t-Bu3P)2(644.47 mg, 1.26 mmol) in THF (20 mL) was added bromo-(2- methoxy-2-oxo-ethyl)zinc (1 M, 37.83 mL), the reaction was allowed to stir at 65 °C for 2 h. The reaction mixture was added to water (30 mL) and filtered. The filtrate was extracted with ethyl acetate (30 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Biotage®; 40g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @120 mL / min). Methyl 2-(3-fluoro-2-methoxy- 5-(1-methoxycyclohexyl)phenyl)acetate (1.1 g, 3.54 mmol, 56.2% yield) was obtained as yellow oil. LCMS (ESI) m / z = 279.1 (M-74+1). Step 4: Synthesis of benzyl 4-(1-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)-2- methoxy-2-oxoethyl)piperidine-1-carboxylateMTX-04725

[0380] To a solution of methyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)acetate (500 mg, 1.61 mmol) and benzyl 4-iodopiperidine-1-carboxylate (2.78 g, 8.06 mmol) in DMF (10 mL) was added t-BuOK (903.89 mg, 8.06 mmol). The mixture was allowed to stir at 25 °C for 2 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The organic solutions were combined, washed with H2O (20 mL x 2) and brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Biotage®; 40g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @120 mL / min). Benzyl 4-(1-(3-fluoro-2-methoxy-5-(1- methoxycyclohexyl)phenyl)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.1 g, 2.08 mmol, 64.70% yield) was obtained as yellow oil. LCMS (ESI) m / z = 496.3 (M-32+1). Step 5: Synthesis of methyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)-2- (piperidin-4-yl)acetate

[0381] To a solution of benzyl 4-(1-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)-2- methoxy-2-oxoethyl)piperidine-1-carboxylate (0.7 g, 1.33 mmol) in t-BuOH (30 mL) was added Pd / C (0.82 g, 1.33 mmol, 10% purity), the reaction mixture was allowed to stir at 40 °C under H2(50 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated. Methyl 2-(3- fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)-2-(piperidin-4-yl)acetate (500 mg, crude) was obtained as yellow oil. LCMS (ESI) m / z = 394.3 (M+1).

[0382] Compounds in the following table were prepared from the starting materials shown by methods similar to those described in Steps 4 and 5 of the example above:MTX-04725 Preparation of 2-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-(4- piperidyl)acetic acidStep 1: Synthesis of 2-bromo-6-fluoro-4-isopropyl-benzaldehyde

[0383] To a solution of 1-bromo-3-fluoro-5-isopropyl-benzene (10 g, 46.08 mmol) in THF (100 mL) was added LDA (2 M, 46.08 mL) dropwise at -70 °C under an atmosphere of nitrogen. The reaction was allowed to stir at -70 °C for 0.5 h. Then DMF (6.72 g, 92.02 mmol) in THF (10 mL) was added. The mixture was allowed to stir at -70 °C at 1 h. The reaction was quenched by the slow addition of aq.NH4Cl (200 mL), then the mixture was extracted with EtOAc (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 10 / 1). 2-bromo-6-fluoro-4-isopropyl-benzaldehyde (4.2 g, 17.14 mmol, 37.20% yield) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) = 10.31 (s, 1H), 7.37-7.33 (m, 1H), 7.03-6.97 (m, 1H), 2.97-2.89 (m, 1H), 1.28-1.26 (m, 6H). Step 2: Synthesis of 2-bromo-6-fluoro-4-isopropyl-benzaldehyde oxime

[0384] A mixture of 2-bromo-6-fluoro-4-isopropyl-benzaldehyde (4.2 g, 17.14 mmol), TEA (2.77 g, 27.42 mmol, 3.82 mL) and NH2OH.HCl (1.79 g, 25.71 mmol) in EtOH (30 mL) was degassed and purged with N23 times, and then the mixture was allowed to stir at 80 °C for 2 h under an atmosphere of N2. The reaction mixture was quenched by the addition of H2O (100 mL), and the mixture was extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with PE:EtOAc = 5:1 (5 mL) at 20oC for 0.5 h, filtered and the solid was dried. 2-bromo-6-fluoro-4-isopropyl-benzaldehyde oxime (2 g, 7.69 mmol, 44.87% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) = 9.02 (s, 1H), 8.41 (s, 1H), 7.31 (s, 1H), 6.98 (d, J = 11.8 Hz, 1H), 2.97-2.79 (m, 1H), 1.29-1.23 (m, 6H). Step 3: Synthesis of 2-bromo-6-fluoro-N-hydroxy-4-isopropyl-benzamidineMTX-04725

[0385] A solution of NCS (1.39 g, 10.38 mmol) in DMF (10 ml) was added slowly to a solution of 2-bromo-6-fluoro-4-isopropyl-benzaldehyde oxime (1.80 g, 6.92 mmol) in DMF (50 mL) at 50 °C. After completion of the addition, the reaction mixture was allowed to stir for 0.5 h at 50 °C. NH3.H2O (2.86 g, 20.37 mmol, 3.14 mL, 25% purity) was added dropwise to the solution of 2- bromo-6-fluoro-N-hydroxy-4-isopropyl-benzimidoyl chloride (2 g, 6.79 mmol) in THF (20 mL) at 5 °C. The mixture was allowed to stir at 5 °C for 0.5 h. The reaction mixture was quenched by the addition of H2O (200 mL) and extracted with ethyl acetate (150 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-bromo-6-fluoro-N-hydroxy-4-isopropyl-benzamidine (2 g, crude) as brown oil. LCMS (ESI) m / z = 275.0 (M+1). Step 4: Synthesis of 3-(2-bromo-6-fluoro-4-isopropyl-phenyl)-5-methyl-1,2,4-oxadiazole

[0386] A mixture of 2-bromo-6-fluoro-N-hydroxy-4-isopropyl-benzamidine (1.8 g, 6.54 mmol) and 1,1-dimethoxy-N,N-dimethyl-ethanamine (1.31 g, 9.81 mmol, 1.43 mL) in i-PrOH (50 mL) was degassed and purged with N23 times, and then the mixture was allowed to stir at 25 °C for 0.5 h under an atmosphere of nitrogen. The reaction mixture was quenched by the addition of H2O (150 mL), filtered and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 5 / 1). 3-(2-bromo-6-fluoro-4-isopropyl-phenyl)-5-methyl-1,2,4-oxadiazole (1.8 g, 6.02 mmol, 91.97% yield) was obtained as colorless oil. 1H NMR (400 MHz, CDCl3) = 7.37 (s, 1H), 7.05-7.00 (m, 1H), 2.94 (spt, J = 6.9 Hz, 1H), 2.74-2.68 (m, 3H), 1.28 (d, J = 6.9 Hz, 6H). Step 5: Synthesis of 2-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]acetate

[0387] A mixture of 3-(2-bromo-6-fluoro-4-isopropyl-phenyl)-5-methyl-1,2,4-oxadiazole (1.8 g, 6.02 mmol), bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1 M in THF, 24.07 mL) and Pd(t-Bu3P)2 (1.54 g, 3.01 mmol) in THF (30 mL) was degassed and purged with N23 times, and then the mixture was allowed to stir at 70 °C for 8 h under an atmosphere of N2. The reaction was quenched by the addition of H2O (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 5 / 1). 2-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]acetate (1.1 g, 3.29 mmol, 54.67% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 279.2 (M+1-56).MTX-04725 Step 6: Synthesis of tert-butyl 4-[2-tert-butoxy-1-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl]-2-oxo-ethyl]piperidine-1-carboxylate

[0388] t-BuOK (838.94 mg, 7.48 mmol) was added to a solution of tert-butyl 2-[3-fluoro-5- isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]acetate (500 mg, 1.50 mmol) and tert-butyl 4- iodopiperidine-1-carboxylate (2.33 g, 7.48 mmol) in DMSO (5 mL) at 50 °C. The mixture was allowed to stir for 0.5 h at 50 °C. The reaction mixture was quenched by the addition of H2O (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 to 3 / 1). tert-butyl 4-[2-tert-butoxy-1-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo- ethyl]piperidine-1-carboxylate (600 mg, 1.10 mmol, 73.64% yield, 95% purity) was obtained as a yellow oil. LCMS (ESI) m / z = 362.1 (M-156+1). Step 7: Synthesis of 2-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-(4- piperidyl)acetic acid

[0389] A mixture of 2-(1-tert-butoxycarbonyl-4-piperidyl)-2-[3-fluoro-5-isopropyl-2-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl]acetic acid (300 mg, 650.02 umol) in formic acid (29.92 mg, 650.02 umol, 24.52 uL) was degassed and purged with N23 times, and then the mixture was allowed to stir at 25 °C for 16 h under an atmosphere of N2. The reaction mixture was concentrated under reduced pressure. 2-[3-fluoro-5-isopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-(4-piperidyl)acetic acid (200 mg, 553.39 umol, 85.13% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 362.2 (M+1). Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3-isopropyl-6- methoxyphenyl)acetic acid and chiral separation of isomersMTX-04725 Step 1: Synthesis of 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene

[0390] A mixture of 1-bromo-2,5-difluoro-4-methoxybenzene (2.50 g, 11.26 mmol), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.27 g, 13.51 mmol), Pd(dppf)Cl2(552 mg, 0.56 mmol) and K3PO4(7.16 g, 33.78 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was allowed to stir at 70°C under an atmosphere of Ar for 2 hours. The reaction was diluted with H2O (100 mL) and extracted with EtOAc (200 mL × 2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 1,4-difluoro-2-methoxy-5-(prop-1-en-2- yl)benzene as a colorless oil (1.95 g, 94% yield). ESI 185 [M+H] +. Step 2: Synthesis of 2-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane

[0391] To a solution of 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (1.95 g, 10.60 mmol) in THF (100 mL) at -78°C, was added LDA ( 2 M in THF, 8 mL) dropwise. The reaction was allowed to stir at -78°C for 30 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.96 g, 15.90 mmol) was added and the mixture was allowed to stir at -78°C for 1 hour. The reaction was quenched by the addition of H2O (100 mL) and extracted with EtOAc (200 mL × 3). The organic solutions were combined, washed with sat. NaHCO3solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 2-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane as a pale brown oil (1.2 g). Yield 38% (ESI 311 [M+H]+). Step 3: Synthesis of tert-butyl 4-(1-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-2-ethoxy- 2-oxoethylidene)piperidine-1-carboxylate

[0392] To a solution of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (5 g, 18.59 mmol) in DCM (100 mL) at 0°C, was added Br2(5.58 g, 35.32 mmol) dropwise. The reaction was allowed to stir at 0°C for 4 hours. The reaction was quenched by the addition of H2O (80 mL) and extracted with DCM (60 mL × 3). The organic solutions were combined, washed with sat. NaHCO3solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF (100 mL) at 0°C, t-BuOK (2.29 g, 20.45 mmol) was added and the reaction mixture was allowed to stir at 0°C for 0.5 h. The reaction was quenched by the addition of H2O (80 mL) and extracted with DCM (60 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 10%~20%) to give tert-butyl 4-(1-bromo-2-ethoxy-2-MTX-04725 oxoethylidene)piperidine-1-carboxylate as a colorless oil (2.6 g). Yield 41% (ESI 348 [M+H] +). A mixture of 2-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.2 g, 3.87 mmol), tert-butyl 4-(1-bromo-2-ethoxy-2-oxoethylidene)piperidine-1- carboxylate (2.7 g, 7.74 mmol), S-Phos-Pd-G2 (137 mg, 0.19 mmol) and K3PO4 (2.5 g, 11.61 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was allowed to stir at 70°C under an atmosphere of Ar for 2 hours. The reaction was diluted with H2O (40 mL) and extracted with EtOAc (60 mL × 2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~20%) to give tert-butyl 4-(1-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-2-ethoxy-2- oxoethylidene)piperidine-1-carboxylate as a colorless oil (477 mg, 28% yield). ESI 452 [M+H] +. Step 4: Synthesis of tert-butyl 4-(1-(2,5-difluoro-3-isopropyl-6-methoxyphenyl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate

[0393] To a mixture of tert-butyl 4-(1-(2,5-difluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)-2- ethoxy-2-oxoethylidene)piperidine-1-carboxylate (477 mg, 1.06 mmol) and NiCl2(548 mg, 4.24 mmol) in EtOH (50 mL) at 0°C, was added NaBH4(160 mg, 4.24 mmol). The reaction was allowed to stir at 25°C for 8 hours. The reaction was quenched by the addition of H2O (10 mL) and extracted with EtOAc (60 mL × 3). The organic solutions were combined, washed with sat. NaHCO3solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give tert-butyl 4-(1-(2,5-difluoro-3-isopropyl-6- methoxyphenyl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate as a pale brown oil (306 mg, 64% yield). ESI 456 (M+H) +. Step 5: Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3-isopropyl-6- methoxyphenyl)acetic acid and chiral separation of isomers

[0394] To a solution of tert-butyl 4-(1-(2,5-difluoro-3-isopropyl-6-methoxyphenyl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate (306 mg, 0.67 mmol) in MeOH (5 mL) was added LiOH aqueous solution (2N, 5 mL). The mixture was allowed to stir at room temperature for 16 hours. The mixture was concentrated in vacuo, neutralized with 1 N HCl aqueous solution and purified by Prep-HPLC Method B to give 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3-isopropyl-6- methoxyphenyl)acetic acid as a white solid (277 mg). Yield 96% (ESI 428 (M+H) +). The racemic product was separated by Prep chiral SFC Method G to give the two isomers: Peak 1, arbitrarily assigned as (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3-isopropyl-6- methoxyphenyl)acetic acid (110 mg), and Peak 2, arbitrarily assigned as (R)-2-(1-(tert-MTX-04725 butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3-isopropyl-6-methoxyphenyl)acetic acid (140 mg) as white solids. Preparation of (S)-2-(2,5-difluoro-3-isopropyl-6-methoxyphenyl)-2-(piperidin-4-yl)acetic acid

[0395] To a solution of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3- isopropyl-6-methoxyphenyl)acetic acid (110 mg, 0.26 mmol) in MeOH (5 mL) at 0°C, was added SOCl2(2 mL) dropwise. The reaction was allowed to stir at 25°C for 2 hours, then quenched by the addition of H2O (10 mL) and extracted with EtOAc (60 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give (S)-2- (2,5-difluoro-3-isopropyl-6-methoxyphenyl)-2-(piperidin-4-yl)acetic acid as a pale brown oil (81 mg, 95% yield). ESI 328 (M+H) +.

[0396] By a similar method, (R)-2-(2,5-difluoro-3-isopropyl-6-methoxyphenyl)-2-(piperidin-4- yl)acetic acid was prepared from (R)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2,5-difluoro-3- isopropyl-6-methoxyphenyl)acetic acid (Peak2).

[0397] By a similar method, (R)-2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6- yl)-2-(piperidin-4-yl)acetic acid was prepared from (R)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2- (5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid (P1). Yield 95% (ESI 356.1 M+H) +).

[0398] By a similar method, (S)-2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)- 2-(piperidin-4-yl)acetic acid was prepared from (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5- chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid (P2).

[0399] By a similar method ethyl (S)-2-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran- 5-yl)-2-(piperidin-4-yl)acetate was prepared from (S)-4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (P1) as a white solid (200 mg). Yield 82% (ESI 370 (M+H) +).MTX-04725

[0400] By a similar method, ethyl (R)-2-(6-chloro-7-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)-2-(piperidin-4-yl)acetate was prepared from (R)-4-(1-(6-chloro-7-fluoro- 2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (P2). Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2-chloro-3-fluoro-5- isopropylphenyl)acetic acidStep 1: Synthesis of 2-fluoro-4-(prop-1-en-2-yl)aniline

[0401] A mixture of 4-bromo-2-fluoroaniline (10.0 g, 52.91 mmol), 4,4,5,5-tetramethyl-2-(prop- 1-en-2-yl)-1,3,2-dioxaborolane (9.78 g, 58.20 mmol), Pd(dppf)Cl2(2.14 g, 2.64 mmol) and Cs2CO3(43.12 g, 0.13 mol) in 1,4-dioxane (100 mL) and H2O (10 mL) was allowed to stir at 80°C under an atmosphere of Ar overnight. The reaction was quenched by the addition of water (50 mL), then extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with bine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (pet ether: EtOAc 10:1) to give 2-fluoro-4-(prop-1-en-2-yl)aniline as a yellow oil (6.75 g). Yield 84 % (ESI 152 (M+H) +). Step 2: Synthesis of 2-fluoro-4-isopropylaniline

[0402] A mixture of 2-fluoro-4-(prop-1-en-2-yl)aniline (6.75 g, 44.70 mmol) and Pd / C (20wt%, 675 mg) in EtOH (50 mL) was allowed to stir under an atmosphere of H2at 40°C for 4 hours. The solid was removed by filtration and the filtrate was concentrated in vacuo to give 2-fluoro-4- isopropylaniline as a yellow oil (6.45 g). Yield 96% (ESI 154 (M+H) +). Step 3: Synthesis of 2-bromo-6-fluoro-4-isopropylaniline

[0403] A mixture of 2-fluoro-4-isopropylaniline (6.45 g, 41.88 mmol) and NBS (7.83 g, 43.97 mmol) in AcOH (50 ml) was allowed to stir at 0°C for 2 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed withMTX-04725 bine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (pet ether: EtOAc 10:1) to give 2-bromo-6-fluoro-4-isopropylaniline as a colorless oil (6.52 g). Yield 67% (ESI 232 (M+H) +). Step 4: Synthesis of 1-bromo-2-chloro-3-fluoro-5-isopropylbenzene

[0404] To a solution of 2-bromo-6-fluoro-4-isopropylaniline (6.52 g, 28.23 mmol) and CuCl2(6.52 g, 56.45 mmol) in MeCN (50 mL) was added t-BuONO (5.81 g, 56.45 mmol) at 0°C under an atmosphere of Ar. The reaction was allowed to stir at 0 °C for 2 hours, then diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (pet ether) to give 1-bromo-2-chloro-3-fluoro-5-isopropylbenzene as a colorless oil (2.65 g). Yield 37%. Step 5: Synthesis of ethyl 2-(2-chloro-3-fluoro-5-isopropylphenyl)acetate

[0405] To a mixture of 1-bromo-2-chloro-3-fluoro-5-isopropylbenzene (2.65 g, 10.55 mmol), Pd2(dba)3(480 mg, 0.53 mmol) and Q-phos (390 mg, 0.53 mmol) in THF (10 mL) was added (2- ethoxy-2-oxoethyl)zinc(II) bromide solution (1 M in THF, 26.4 mL, 26.4 mmol) at rt under an atmosphere of Ar. The reaction was allowed to stir at 50°C for 1 hour, then quenched by the addition of NaHCO3 solution and the solid was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (pet ether: EtOAc 10:1) to give ethyl 2-(2- chloro-3-fluoro-5-isopropylphenyl)acetate as a pale red oil (2.26 g). Yield 83% (ESI 259 (M+H) +). Step 6: Synthesis of tert-butyl 4-(1-(2-chloro-3-fluoro-5-isopropylphenyl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate

[0406] To a solution of ethyl 2-(2-chloro-3-fluoro-5-isopropylphenyl)acetate (2.26 g, 8.73 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (5.43 g, 17.45 mmol) in DMF (20 mL) was added t-BuOK (1.95 g, 17.45 mmol) at 0°C under an atmosphere of Ar. The reaction was allowed to stir at 0 °C for 1 hour, then diluted with aqueous water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (pet ether: EtOAc 5:1) to give tert-butyl 4-(1-(2-chloro-3-fluoro-5-isopropylphenyl)-2-ethoxy-2-oxoethyl)piperidine-1- carboxylate as colorless oil (2.05 g). Yield 53% (ESI 464 (M+H) +). Step 7: Synthesis and chiral separation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2- chloro-3-fluoro-5-isopropylphenyl)acetic acidMTX-04725

[0407] LiOH monohydrate (543 mg, 12.90 mmol) was added to a mixture of tert-butyl 4-(1-(2- chloro-3-fluoro-5-isopropylphenyl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (600 mg, 1.29 mmol) in 4 mL of MeOH and 1 mL of H2O. The mixture was allowed to stir at room temperature for 16 hours. The mixture was concentrated in vacuo, neutralized with 1 N HCl aqueous solution and extracted with EtOAc (3 × 20 mL). The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was seperated by Prep Chiral SFC Method G to give the desired two isomers Peak 1, arbitrarily assigned as (S)-2-(1-(tert- butoxycarbonyl)piperidin-4-yl)-2-(2-chloro-3-fluoro-5-isopropylphenyl)acetic acid, (190 mg) and Peak 2, arbitrarily assigned as (R)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2-chloro-3-fluoro-5- isopropylphenyl)acetic acid, (200 mg) as white solids. Preparation of (S)-2-(2-chloro-3-fluoro-5-isopropylphenyl)-2-(piperidin-4-yl)acetic acid

[0408] A mixture of (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(2-chloro-3-fluoro-5- isopropylphenyl)acetic acid (190 mg, 0.46 mmol) in 4N HCl / dioxane (5 mL) was allowed to stir at rt for 5 hours. The mixture was concentrated in vacuo to give (S)-2-(2-chloro-3-fluoro-5- isopropylphenyl)-2-(piperidin-4-yl)acetic acid as a white solid (140 mg). Yield 97% (ESI 314 (M+H) +).

[0409] Compounds in the following table were prepared from the starting materials shown by methods similar to that described in the example above:MTX-04725Preparation of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4- (trimethylsilyl)phenyl)-2-oxoethyl)piperidine-1-carboxylateStep 1: Synthesis of 4-(4-bromo-2,5-difluorophenoxy)tetrahydro-2H-pyranMTX-04725

[0410] A mixture of 4-bromo-2,5-difluorophenol (10.0 g, 48.08 mmol), 4-bromotetrahydro-2H- pyran(10.25 g, 62.51 mmol) and Cs2CO3(31.25 g, 96.16 mmol) in DMF (100 mL) was allowed to stir at 90 °C for 16 hours. The reaction was quenched by the addition of H2O (60 mL) and extracted with EtOAc (3 x 60 mL). The organic solutions were combined, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 4-(4-bromo-2,5- difluorophenoxy)tetrahydro-2H-pyran as a red oil (4.3 g). Yield 31% (ESI 293[M+H] +). Step 2: Synthesis of 4-(2,5-difluoro-4-vinylphenoxy)tetrahydro-2H-pyran

[0411] A mixture of 4-(4-bromo-2,5-difluorophenoxy)tetrahydro-2H-pyran (4.3 g, 14.73 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.5 g, 29.45 mmol), Pd(dppf)Cl2(492 mg, 0.74 mmol) and K3PO4(9.37 g, 44.19 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was allowed to stir at 70°C under an atmosphere of Ar for 2 hours. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (100 mL × 2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~20%) to give 4-(2,5-difluoro-4-vinylphenoxy)tetrahydro- 2H-pyran as a colorless oil (3.1 g). Yield 89% (ESI 241 [M+H] +). Step 3: Synthesis of 4-(4-ethyl-2,5-difluorophenoxy)tetrahydro-2H-pyran

[0412] A mixture of 4-(2,5-difluoro-4-vinylphenoxy)tetrahydro-2H-pyran (3.1 g, 12.92 mmol) and Pd / C (10 wt%, 320 mg) in MeOH (30 mL) was allowed to stir under an atmosphere of H2at rt for 16 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give 4-(4-ethyl-2,5- difluorophenoxy)tetrahydro-2H-pyran as a pale brown oil (2.98 g). Yield 95%(ESI 243 [M+H]). Step 4: Synthesis of (3-ethyl-2,5-difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)- trimethylsilane

[0413] To a solution of 4-(4-ethyl-2,5-difluorophenoxy)tetrahydro-2H-pyran (2.98 g, 12.31 mmol) in THF (50 mL) at -78°C, was added LDA (2.0 M in THF / hexanes, 12 mL, 24 mmol) dropwise. The reaction was allowed to stir at -78°C for 30 min, and then TMSCl (2 g, 18.47 mmol) was added dropwise and the reaction mixture was allowed to stir at -78°C for 1 hour. The reaction was quenched by the addition of H2O (50 mL) and extracted with EtOAc (100 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give (3- ethyl-2,5-difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)trimethylsilane as a pale brown oil (0.95 g). Yield 25% (ESI 315 [M+H])MTX-04725 Step 5: Synthesis of (3-ethyl-2,5-difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane

[0414] To a solution of (3-ethyl-2,5-difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)- trimethylsilane (950 mg, 3.03 mmol) in THF (20 mL) at -78°C, was added lithium diisopropylamide solution 2.0 M in THF / hexanes (3 mL, 6.0 mmol) dropwise. The reaction mixture was allowed to stir at -78°C for 30 min, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 5.91 mmol) was added dropwise. The reaction was allowed to stir at rt for 4 hours, quenched by the addition of H2O (30 mL), and extracted with EtOAc (50 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography EtOAc / pet ether = 0%~20%) to give (3-ethyl-2,5- difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)trimethylsilane as a pale brown oil (910 mg). Yield 68%(ESI 441 [M+H]) Step 6: Synthesis of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4- yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethylidene)piperidine-1-carboxylate

[0415] A mixture of (3-ethyl-2,5-difluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (2.0 g, 4.55 mmol), tert-butyl 4-(1- bromo-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (2.05 g, 5.92 mmol), Sphos-Pd-G2 (166 mg, 0.23 mmol) and K3PO4(2.9 g, 13.65 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was allowed to stir at 80°C under an atmosphere of Ar for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~20%) to give tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6- difluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethylidene)piperidine-1- carboxylate as a colorless oil (526 mg). Yield 21% (ESI 582 [M+H] +). Step 7: Synthesis of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4- yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethyl)piperidine-1-carboxylate

[0416] To a mixture of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4- yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethylidene)piperidine-1-carboxylate (526 mg, 0.91 mmol) and NiCl2(236 mg, 1.82 mmol) in EtOH (20 mL) at 0°C was added NaBH4(140 mg, 3.64 mmol). The reaction was allowed to stir at rt for 8 hours, quenched by the addition of H2O (20 mL) and extracted with EtOAc (60 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gelMTX-04725 chromatography (EtOAc / pet ether = 0%~10%) to give tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6- difluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethyl)piperidine-1- carboxylate as a pale brown oil (506 mg). Yield 96% (ESI 584 (M+H) +). Step 8: Synthesis of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)-2-oxoethyl)piperidine-1-carboxylate

[0417] To a solution of tert-butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran- 4-yl)oxy)-4-(trimethylsilyl)phenyl)-2-oxoethyl)piperidine-1-carboxylate (506 mg, 0.87 mmol) in THF (20 mL) was added TBAF (1M in THF, 10 mL). The reaction was allowed to stir at rt for 2 hours, quenched by the addition of H2O (10 mL) and extracted with EtOAc (60 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~10%) to give tert- butyl 4-(2-ethoxy-1-(2-ethyl-3,6-difluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-2- oxoethyl)piperidine-1-carboxylate as a pale brown oil (385 mg). Yield 87% (ESI 512 (M+H) +). Preparation of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-4-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-6-yl)acetic acidStep 1: Synthesis of methyl 2-(4-bromo-2,6-difluorophenyl)acetate

[0418] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (3.01 g, 12.0 mmol) in MeOH (25 mL) was added conc. H2SO4(3 mL) slowly. The reaction mixture was allowed to stir at reflux for 2 hours, then concentrated in vacuo. The mixture was adjusted with sat.NaHCO3solution to pH=7-8 and extracted with EtOAc (20 mL x2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give methyl 2-(4-bromo-2,6- difluorophenyl)acetate as an yellow oil (3.12 g). Yield 98% (ESI 265 / 267 (M+H).MTX-04725 Step 2: Synthesis of 1-(4-bromo-2,6-difluorophenyl)-2-methylpropan-2-ol

[0419] To a solution of methyl 2-(4-bromo-2,6-difluorophenyl)acetate (1.59 g, 6.0 mml) in THF (10 mL) at 0 °C, was added MeMgBr (3M in THF, 6 mL) dropwise. The reaction was allowed to stir at rt for 6 hours, then MeMgBr (3M in THF, 3 mL) was added and the reaction was allowed to stir at rt overnight. The reaction was quenched by the addition of sat. NH4Cl solution and extracted with EtOAc (30 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give 1-(4-bromo-2,6-difluorophenyl)-2-methylpropan-2-ol as a colorless oil (885 mg). Yield 55% (ESI 246.9 (M+H) +).1H NMR (400 MHz, CDCl3) 7.10-7.08 (m, 2H), 2.84 (s, 2H), 1.28 (s, 6H). Step 3: Synthesis of 6-bromo-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran

[0420] A mixture of 1-(4-bromo-2,6-difluorophenyl)-2-methylpropan-2-ol (885 mg, 3.34 mmol) and Cs2CO3(2.18 g, 6.68 mmol) in MeCN (12mL) was subjected to microwave irradiation at 110°C for 4 hours. The reaction was diluted with water (10 mL) and EtOAc (25 mL). The organic solution was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give 6-bromo-4-fluoro- 2,2-dimethyl-2,3-dihydrobenzofuran as a white solid (516 mg). Yield 63%.1H NMR (400 MHz, CDCl3) 6.73-6.70 (m, 2H), 2.98 (s, 2H), 1.50 (s, 6H). Step 4: Synthesis of 6-bromo-5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran

[0421] To a mixture of 6-bromo-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (515 mg, 2.1 mmol) in THF (10 mL) at -78°C, was added LDA (2.0 M in THF / hexanes, 1.4 mL, 2.8 mmol) dropwise. The reaction was allowed to stir at -78°C for 60 min, then perchloroethane (696 mg, 2.94 mmol) in THF (5 mL) was added and the reaction was allowed to stir at -78°C for 60 min. The reaction was quenched by the addition of sat. NH4Cl solution and extracted with EtOAc (30 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give 6-bromo-5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran as a white solid (366 mg). Yield 62%.1H NMR (400 MHz, CDCl3) 6.84 (s, 1H), 3.03 (s, 2H), 1.50 (s, 6H). Step 5: Synthesis of ethyl 2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetate

[0422] To a mixture of 6-bromo-5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (560 mg, 2.0 mmol), Pd2(dba)3(55 mg, 0.06 mmol) and Q-phos (43 mg, 0.06 mmol) in THF (4 mL) wasMTX-04725 added (2-ethoxy-2-oxoethyl)zinc(II) bromide solution 1M in THF (6 mL, 6 mmol). The reaction was allowed to stir at 60°C for 1 hour. The mixture was quenched by the addition of sat. NaHCO3solution and the solid was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~15%) to give ethyl 2-(5- chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetate as a pale red oil (384 mg). Yield 67% (ESI 287.1 (M+H)+).1H NMR (400 MHz, CDCl3) 6.49 (s,1H), 4.20 (d, J= 7.2Hz, 2H), 3.71 (s, 2H), 3.06 (s, 2H), 1.50 (s, 6H), 1.28 (t, J= 7.2Hz, 3H). Step 6: Synthesis of tert-butyl 4-(1-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6- yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0423] To a solution of ethyl 2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6- yl)acetate (382 mg, 1.33 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (828 mg, 2.66 mmol) in DMF (5 mL) at 5°C, was slowly added t-BuOK (298 mg, 2.66 mmol). The reaction was allowed to stir at rt for 18 hours, then quenched by the addition of water (6 mL) and extracted with EtOAc (10 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~20%) to give tert-butyl 4-(1-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate as a colorless oil (481 mg). Yield 77% (ESI 428.1 (M+H-t-Bu) +). Step 7: Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-4-fluoro-2,2- dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid

[0424] To a solution of tert-butyl 4-(1-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran- 6-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (481 mg, 1.02 mmol) in MeOH (4 mL) and THF (2 mL) was added aqueous LiOH solution (2M, 2.5 mL), and the mixture was allowed to stir at 60°C for 2 hours. Solvent was removed in vacuo, the residue was adjusted to pH=6~7 with 2M HCl and the residue was extracted with DCM (10 mL x2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(1-(tert-butoxycarbonyl)piperidin- 4-yl)-2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid as a white solid (447 mg).98% yield (ESI 386.1 (M+H- t-Bu ) +). The racemic product was separated by Prep chiral SFC B to give the desired two isomers peak 1, arbitrarily assigned as (R)-2-(1-(tert- butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid (332 mg) and peak 2, arbitrarily assigned as (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5- chloro-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)acetic acid (351 mg), as white solids.MTX-04725

[0425] Compounds in the following table were prepared from the starting materials shown by methods similar to those described in Steps 4 through 7 of the example above:Preparation of ethyl (S)-2-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperidin-4- yl)acetate and ethyl (R)-2-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperidin-4- yl)acetateStep 1: Synthesis of tert -butyl (S)-4-(1-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 2-ethoxy-2-oxoethyl)piperidine-1-carboxylate and tert -butyl (R)-4-(1-(7-chloro-8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0426] Racemic tert-butyl 4-(1-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate (476 mg) was separated by Prep Chiral SFC Method C to give the two isomers: peak 1, arbitrarily assigned as tert -butyl (S)-4-(1-(7-chloro-8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (180 mg), and peak 2, arbitrarily assigned as tert -butyl (R)-4-(1-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (209 mg), each as white solids. Step 2: Synthesis of ethyl (S)-2-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2- (piperidin-4-yl)acetate

[0427] To a solution of tert-butyl (S)-4-(1-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6- yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (107 mg, 0.23 mmol) in DCM (2 mL) was added HCl (4 M in 1,4-dioxane, 2 mL). The reaction was allowed to stir at room temperature for 1 hour. The mixture was concentrated in vacuo, the residue was dissolved in water (10 mL), basified withMTX-04725 saturated NaHCO3aqueous solution and extracted with EtOAc (10 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl (S)-2-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(piperidin-4-yl)acetate as a colorless oil (85 mg). Yield 100% (ESI 358.0 [M+H]+).

[0428] Using a similar method, ethyl (R)-2-(7-chloro-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-2-(piperidin-4-yl)acetate was prepared from tert-butyl (R)-4-(1-(7-chloro-8-fluoro-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate. Preparation of isomers of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-chloro-5- fluorospiro[chroman-3,3'-oxetane]-7-yl)acetic acidStep 2: Synthesis of isomers of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-chloro-5- fluorospiro[chroman-3,3'-oxetane]-7-yl)acetic acid

[0429] To a solution of tert-butyl 4-(1-(6-chloro-5-fluorospiro[chroman-3,3'-oxetane]-7-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate (657 mg, 1.32 mmol) in MeOH (5 mL) and THF (5 mL) was added aq. LiOH (2M, 3.3 mL) and the mixture was allowed to stir at 60°C for 4 hours. Solvent was removed in vacuo, the residue was adjusted to pH=6~7 with 2M HCl and extracted with DCM (10 mL x2). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-chloro-5- fluorospiro[chroman-3,3'-oxetane]-7-yl)acetic acid as a white solid (564 mg). Yield 91% (ESI 414.0 (M+H- t-Bu ) +). The racemic product was separated by Prep Chiral SFC J to give the two isomers Peak 1 (252 mg) and Peak 2 (261 mg) as white solids.

[0430] Compounds in the following table were prepared from the starting materials shown by a method similar to that described in the example above:MTX-04725Preparation of (R)-2-(6-chloro-5-fluorospiro[chroman-3,3'-oxetane] 7-yl)-2-(piperidin-4-yl)acetic acid

[0431] A solution of (R)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-chloro-5- fluorospiro[chroman-3,3'-oxetane]-7-yl)acetic acid (282 mg, 0.60 mmol) in DCM (2 mL) and TFA (0.5 mL) was allowed to stir at rt for 0.5 hour. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM: MeOH 20:1~5:1) to give (R)-2-(6- chloro-5-fluorospiro[chroman-3,3'-oxetane]-7-yl)-2-(piperidin-4-yl)acetic acid as a yellow solid (215 mg). Yield 97% (ESI 370.0(M+H) +).

[0432] By a similar method, (S)-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-chloro-5- fluorospiro[chroman-3,3'-oxetane]-7-yl)acetic acid was prepared.MTX-04725 Preparation of tert-butyl (S)-4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate and tert-butyl (R)-4-(1-(6-chloro-7-fluoro-2,2-dimethyl- 2,3-dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylateStep 1: Synthesis of 1-chloro-2-fluoro-3-((2-methylallyl)oxy)benzene

[0433] A mixture of 3-chloro-2-fluorophenol (1.0 g, 6.82 mmol), 3-bromo-2-methylprop-1-ene (1.38 g, 10.24 mmol) and K2CO3(2.83 g, 20.46 mmol) in MeCN (50 mL) was allowed to stir at 70°C for 5 hours, then diluted with water (80 mL) and extracted with EtOAc (40 mL x3). The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give 1-chloro-2-fluoro-3-((2- methylallyl)oxy)benzene as a white solid (1.3 g). Yield 95%. Step 2: Synthesis of 3-chloro-2-fluoro-6-(2-methylallyl)phenol

[0434] A mixture of 1-chloro-2-fluoro-3-((2-methylallyl)oxy)benzene (1.0 g, 4.98 mmol) and N,N-diethylaniline (10 mL) was allowed to stir at 190°C for 3 hours, then diluted with water (40 mL) and extracted with EtOAc (40 mL x3). The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0~20%) to give 3-chloro-2-fluoro-6-(2-methylallyl)phenol as a white solid (710 mg). Yield 71% (ESI 201 (M+H) +). Step 3: Synthesis of 6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran

[0435] A mixture of 3-chloro-2-fluoro-6-(2-methylallyl)phenol (2.19 g, 10.92 mmol) and trifluoride-diethyl ether complex (1.86 g, 13.10 mmol) in toluene (20 mL) was allowed to stir at 75°C for 2 hours, then diluted with water (50 mL) and extracted with EtOAc (40 mL x3). The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residueMTX-04725 was purified by silica gel chromatography (EtOAc / pet ether = 0~5%) to give 6-chloro-7-fluoro-2,2- dimethyl-2,3-dihydrobenzofuran as a white solid (1.63 g). Yield 74% (ESI 201 (M+H) +). Step 4: Synthesis of 5-bromo-6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran

[0436] A solution of 6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (1.48 g, 7.38 mmol) and NBS (1.32 g, 7.38 mmol) in MeCN (20 mL) was allowed to stir at rt for 2 hours. The reaction was quenched by the addition of H2O (20 mL) and the mixture was extracted with EtOAc (50 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~15%) to give 5-bromo-6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran as a colorless oil (1.83 g). Yield 89% (ESI 279 [M+H]). Step 5: Synthesis of ethyl 2-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)acetate

[0437] To a mixture of 5-bromo-6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (1.31 g, 4.7 mmol), Pd2(dba)3(86 mg, 0.09 mmol) and Q-phos (66 mg, 0.09 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide solution 1M in THF (14 mL, 14.0 mmol) at rt under an atmosphere of argon. The reaction was allowed to stir at 60°C for 1 hour. The reaction was quenched by the addition of sat. aq. NaHCO3solution (10 mL) and the solid was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / pet ether = 0~10%) to give ethyl 2-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran- 5-yl)acetate as a pale red oil (1.10 g). Yield 82% (ESI 287 (M+H)+). Step 6: Synthesis of give tert-butyl 4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0438] To a solution of ethyl 2-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5- yl)acetate (1.42 g, 4.95 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (2.77 g, 8.91 mmol) inDMF (20.0 mL) at 0 , was added t-BuOK (998 mg, 8.91 mmol). The reaction was allowed to stir atrt for 2 hours, then quenched by the addition of H2O (20 mL) and extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether = 0%~15%) to give tert-butyl 4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2- ethoxy-2-oxoethyl)piperidine-1-carboxylate as a colorless oil (1.81 g). Yield 78% (ESI 470 (M + H) +).MTX-04725 Step 7: Synthesis and Separation of tert-butyl (S)-4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate and tert-butyl (R)-4-(1- (6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1- carboxylate

[0439] The racemic compound tert-butyl 4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (930 mg) was separated by Prep Chiral SFC Method G to give the two isomers Peak 1 (310 mg), arbitrarily assigned as tert- butyl (S)-4-(1-(6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate, and Peak 2 (150 mg), arbitrarily assigned as tert-butyl (R)-4-(1- (6-chloro-7-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-ethoxy-2-oxoethyl)piperidine-1- carboxylate, each as white solids. Preparation of (racemic mixture of diastereomers of) tert-butyl 4-(2-ethoxy-1-(3-fluoro-5-isopropyl- 2-methoxyphenyl)-2-oxoethyl)-2-(methoxymethyl)piperidine-1-carboxylateStep 1: Synthesis of tert-butyl 4-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate

[0440] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 g, 10.0 mmol) and imodazole (1.36 g, 20.0 mmol) in DMF (20 mL) at rt, was added TBSCl (2.25 g, 15.0 mmol). The mixture was allowed to stir at rt for 12 hours. The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and brine. The organic solutions were combined, dried over sodium sulfate, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether=5%~15%) to give tert-butyl 4-((tert-butyldimethylsilyl)oxy)piperidine-1- carboxylate as a colorless oil (3.1 g). Yield 98% (ESI 260 [M+H-t-Bu] +). Step 2: Synthesis of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-formylpiperidine-1- carboxylateMTX-04725

[0441] To a solution of tert-butyl 4-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) in THF (15 mL) at -78°C under an atmosphere of argon, was added s-BuLi (1 M in n- hexane, 3.8 mL, 3.8 mmol) dropwise. The reaction mixture was allowed to stir at -78°C for 30 mins, and then DMF (2.3 g, 32 mmol) was added in portions and the reaction mixture was allowed to stir at -78°C for 30 min. The reaction was quenched by the addition of sat. aq. NH4Cl solution (10 mL). The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL). The organic solutions were combined, dried over sodium sulfate, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether =5%~20%) to give tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-formylpiperidine-1-carboxylate as a colorless oil (0.45 g). Yield 41% (ESI 288 [M+H-tBu] +). Step 3: Synthesis of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1- carboxylate

[0177] To a solution of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-formylpiperidine-1- carboxylate (450 mg, 1.3 mmol) in MeOH (15 mL) at 0°C, was added NaBH4(0.1 g, 2.6mmol) in portions. The reaction was allowed to stir at rt for 30 min, quenched by the addition of H2O (20 mL) and extracted with EtOAc (20 mL x3). The organic solutions were combined, dried over sodium sulfate, filtered, concentrated in vacuo to give tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2- (hydroxymethyl)piperidine-1-carboxylate as a colorless oil (440 mg). Yield 97% (ESI 290 [M+H-t- Bu] +). Step 4: Synthesis of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)piperidine-1- carboxylate

[0177] To a solution of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine- 1-carboxylate (5.15 g, 14.9 mmol) in DMF (30 mL) at 0°C, was added NaH (60%, 894 mg, 22.4 mmol) in portions. The reaction was allowed to stir at 0°C for 30 min, then CH3I (4.23 g, 29.8 mmol) was added and the reaction mixture was allowed to stir at rt overnight. The reaction was quenched by the addition of H2O (20 mL) and extracted with EtOAc (20 mL x3). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether =5%~15%) to give tert-butyl 4-(tert- butyldimethylsilyloxy)-2-(methoxymethyl)piperidine-1-carboxylate (4.55 g) as a colorless oil. Yield 85% (ESI 304 [M+H-t-Bu] +). Step 5: Synthesis of tert-butyl 4-hydroxy-2-(methoxymethyl)piperidine-1-carboxylateMTX-04725

[0177] A solution of tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(methoxymethyl)piperidine-1- carboxylate (3.47 g, 9.65 mmol) in TBAF (1M in THF, 40 mL) was allowed to stir at rt for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / pet ether =5%~30%) to give tert-butyl 4-hydroxy-2-(methoxymethyl)piperidine-1- carboxylate as a colorless oil (2.31g). Yield 97% (ESI 268.0 (M+Na)+). Step 6: Synthesis of tert-butyl 4-iodo-2-(methoxymethyl)piperidine-1-carboxylate

[0177] To a solution of tert-butyl 4-hydroxy-2-(methoxymethyl)piperidine-1-carboxylate (980 mg, 4.0 mmol), imidazole (408 mg, 6.0 mmol) and PPh3(1.57 g, 6.0 mmol) in DCM (20 mL) at 0°C, was added I2 (1.07 g, 4.2 mmol) slowly. The reaction mixture was allowed to stir at rt for 18 hours, quenched by the addition of water (10 mL) and extracted with DCM (10 mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / pet ether =5%~20%) to give tert- butyl 4-iodo-2-(methoxymethyl)piperidine-1-carboxylate as an yellow oil (1.02 g). Yield 72% (ESI 378.0 (M+Na)+). Step 7: Synthesis of tert-butyl 4-(2-ethoxy-1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- oxoethyl)-2-(methoxymethyl)piperidine-1-carboxylate

[0177] To a solution of ethyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetate (1.22 g, 4.8 mmol) and tert-butyl 4-iodo-2-(methoxymethyl)piperidine-1-carboxylate (1.07 g, 3.0 mmol) in DMF (20 mL) at 0°C, was added t-BuOK (608 mg,7.2 mmol). The reaction was allowed to stir at rt for 18 hours, quenched by the addition of water (20 mL) and extracted with EtOAc (20mL x3). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC B (30-65% MeCN) to give two isomers of tert-butyl 4-(2- ethoxy-1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-oxoethyl)-2-(methoxymethyl)piperidine-1- carboxylate Peak 1 (241 mg) and P2 (232 mg). Yield 33% (ESI 382.2 (M+H-t-Bu) +). Preparation of 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(2-(methoxymethyl)piperidin-4-yl)acetic acidMTX-04725 Step 1: Synthesis of 2-(1-(tert-butoxycarbonyl)-2-(methoxymethyl)piperidin-4-yl)-2-(3-fluoro-5- isopropyl-2-methoxyphenyl)acetic acid

[0442] To a solution tert-butyl 4-(2-ethoxy-1-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2- oxoethyl)-2-(methoxymethyl)piperidine-1-carboxylate (isomer P2, 241 mg, 0.5 mmol) in MeOH (4 mL) and THF (2 mL) was added aq. LiOH (2M, 2 mL), and the mixture was allowed to stir at 60°C for 6 hours. Solvent was removed in vacuo, the residue was adjusted to pH=6~7 with 2M HCl and purified by Prep-HPLC Method A (30-65% MeCN) to give 2-(1-(tert-butoxycarbonyl)-2- (methoxymethyl)piperidin-4-yl)-2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetic acid as two isomers P2-P1 (63 mg) and P2-P2 (155 mg). Yield 78% (ESI 354.3 (M+H- Boc ) +). Step 2: Synthesis of 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)-2-(2-(methoxymethyl)piperidi...

Claims

MTX-04725 WE CLAIM:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:L is C4-6-alkyl optionally substituted with 1 to 6 R4; each of R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H, C1-4alkyl, halogen, C1-4alkyloxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyloxy, C1-4- alkyloxy-C1-4alkyloxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, R2is H, or C1-4alkyl optionally substituted with 1 to 4 R5; R3ais halogen, C1-4alkyloxy, C3-5cycloalkoxy, cyano, or C1-4alkyl optionally substituted with one or more halogen; R3bis H, halogen, CF3or CN; R3cis H, halogen, CN, or C1-4alkyl; andMTX-04725 R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, 5-6 member heteroaryl, C6aryl, -O- (C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), -O-(5-6 member heteroaryl), -O-(C6aryl), - CH2-(C3-6cycloalkyl), -CH2- (4-6-membered heterocycloalkyl), -CH2- (5-6 member heteroaryl), or - CH2-(C6 aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6; R3eis H, halogen or C1-4alkyl optionally substituted with one or more halogen; or R3aand R3b, R3band R3c, R3cand R3d, or R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8; each R4is independently H, halogen, C1-4alkyloxy or C1-4alkyl optionally substituted with one or more halogen, or two geminal R4groups together can form a spiro-cyclopropyl; each R5is independently halogen or C1-4alkyl optionally substituted with halogen; each R6is independently C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, C1-4alkyloxy, C3-6cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, oxo, 5-6-membered heteroaryl, or NRaRb; each R7is independently C1-4alkyl optionally substituted with one or more F, C1-4alkoxy or F; each R8is independently halogen, C1-4alkyl, C3-6cycloalkyl, or two geminal R8groups together can form a spiro-C3-6cycloalkyl or together can form a spirocyclic 3-6 member heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; each of Raand Rbis independently hydrogen, or C1-4alkyl optionally substituted with one or more halogen; a and b are each independently 0 or 1 provided a+b is 1 or 2; and m is 0, 1 or 2.

2. The compound of Claim 1, wherein each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H.

3. The compound of any one of Claims 1 or 2, wherein each of R1band R1b1is independently H, methoxy, or methyl optionally substituted with one or more F.

4. The compound of any one of Claims 1-3, wherein L is C5-alkyl optionally substituted with 1 to 6 R4.MTX-04725 5. The compound of Claim 4, wherein L is, wherein R4a1, R4a2, R4b1, and R4b2are each independently H, halogen or C1-4alkyl optionally substituted with one or more halogen.

6. The compound of Claim 5, wherein R4a1, R4a2, R4b1, and R4b2are each independently H, F or methyl optionally substituted with one or more F.

7. The compound of Claim 6, wherein R4a1and R4a2are each H.

8. The compound of Claim 7, wherein R4b1is H or F.

9. The compound of Claim 8, wherein R4b2is F.

10. The compound of Claim 9, wherein R4b1is H.

11. The compound of Claim 9, wherein R4b1is F.

12. The compound of Claim 6, wherein R4b1and R4b2are each H.

13. The compound of Claim 12, wherein R4a1is H or F.

14. The compound of Claim 13, wherein R4a2is F.

15. The compound of Claim 14, wherein R4a1is H.

16. The compound of Claim 14, wherein R4a1is F.

17. The compound of any one of claims 1-16, wherein m is 0.

18. The compound of any one of Claims 1-Error! Reference source not found., wherein R3ais halogen, C1-4alkyloxy, or C1-4alkyl wherein the alkyl or alkyloxy are each optionally substituted with one or more halogen.

19. The compound of claim 17, wherein R3ais Cl, F, cyano, OMe, C1-4alkyl optionally substituted with one or more F.

20. The compound of claim 17, wherein R3ais OMe.

21. The compound of claim 17, wherein R3ais Cl.

22. The compound of claim 17, wherein R3ais -CN.

23. The compound of claim 17, wherein R3ais ethyl.

24. The compound of claim 17, wherein R3ais methyl.

25. The compound of claim 17 wherein R3ais OCHF2.

26. The compound of claim 17, wherein R3ais OCF3.

27. The compound of any one of Claims 1-26, wherein R3bis halogen.

28. The compound of any one of Claims 1-26, wherein R3bis F.MTX-04725 29. The compound of any one of Claims 1-28, wherein R3cis H.

30. The compound of any one of Claims 1-29, wherein R3dis C1-4alkyl, C3-6cycloalkyl, 4-6- membered heterocycloalkyl, -O-(C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), 5-6 member heteroaryl, or C6aryl, wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6.

31. The compound of any one of Claims 1-29, wherein R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, -O-(C3-6cycloalkyl), -O-(4-6-membered heterocycloalkyl), 5-6 member heteroaryl, C6aryl, -O-(5-6 member heteroaryl), or -O-(C6aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6.

32. The compound of any one of Claims 1-29, wherein R3dis 4-6-membered heterocycloalkyl, optionally substituted with 1 to 4 R6.

33. The compound of claim 32, wherein R3dis a 4-6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, O and S optionally substituted with 1 to 4 R6.

34. The compound of claim 32, wherein R3dis a 4-6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, and O optionally substituted with 1 to 4 R6.

35. The compound of claim 32, wherein R3dis a 4-6-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6.

36. The compound of Claim 32, wherein R3dis a 6-membered heterocycloalkyl comprising one or two O heteroatoms, and optionally substituted with 1 to 4 R6.

37. The compound of Claim 32, wherein R3dis a tetrahydropyran optionally substituted with 1 to 4 R6.

38. The compound of claim 37, wherein is R3dis.

39. The compound of Claim 32, wherein R3dis a morpholino optionally substituted with 1 to 4 R6.

40. The compound of claim 39, wherein is R3dis.

41. The compound of Claim 32, wherein R3dis a tetrahydrofuran optionally substituted with 1 to 4 R6.

42. The compound of claim 41, wherein is R3dis.MTX-04725 43. The compound of Claim 32, wherein R3dis an oxetane optionally substituted with 1 to 4 R6.

44. The compound of claim 43, wherein is R3dis.

45. The compound of Claim 32, wherein R3dis a thietane optionally substituted with 1 to 4 R6.

46. The compound of Claim 45, wherein R3dis47. The compound of any one of Claims 1-29, wherein R3dis -O-(C3-6cycloalkyl) optionally substituted with 1 to 4 R6.

48. The compound of claim 47, wherein R3dis -O-(6-member heterocyclyl) optionally substituted with 1 to 4 R6.

49. The compound of claim 47, wherein R3dis -O-(tetrahydropyran) optionally substituted with 1 to 4 R6.

50. The compound of any one of Claims 1-29, wherein R3dis -O-(5-6-membered heteroaryl) optionally substituted with 1 to 4 R6.

51. The compound of any one of Claims 1-29, wherein R3dis 5-6 membered heteroaryl optionally substituted with 1 to 4 R6.

52. The compound of claim 51, wherein R3dis 5-member heteroaryl optionally substituted with 1 to 4 R6.

53. The compound of claim 52, wherein R3dis an imidazole.

54. The compound of claim 53, wherein R3dis55. The compound of claim 51, wherein R3dis a 6- member heteroaryl optionally substituted with 1 to 4 R6.

56. The compound of claim 51, wherein R3dis pyridinyl.

57. The compound of claim58. The compound of any one of Claims 1-29, wherein R3dis phenyl or benzyl optionally substituted with 1 to 4 R6.

59. The compound of any one of Claims 1-29, wherein R3dis unsubstituted phenyl.

60. The compound of any one of Claims 1-29, wherein R3dis C3-5cycloalkyl.

61. The compound of claim 60, wherein R3dis cyclopropyl.

62. The compound of claim 60, wherein R3dis cyclobutyl.MTX-04725 63. The compound of claim 60, wherein R3dis cyclohexyl.

64. The compound of any one of Claims 1-29, wherein R3dis -O-(phenyl) optionally substituted with 1 to 4 R6.

65. The compound of any one of Claims 1-29, wherein R3dis anisolyl.

66. The compound of any one of Claims 1-29, wherein R3dis unsubstituted phenyl.

67. The compound of any one of Claims 1-29, wherein R3dis oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, pyrrolidinone, piperazinyl-C1-4alkyl, C1-4alkoxyl, -O- (tetrahydro-2H-pyranyl) or anisolyl.

68. The compound of any one of Claims 1-29, wherein R3dis C1-4alkyl, optionally substituted with 1 to 4 R6.

69. The compound of claim 68, wherein R3dis iso-propyl.

70. The compound of any one of Claims 1-29, wherein R3dis –O-(C1-4alkyl), optionally substituted with 1 to 4 R6.

71. The compound of claim 70, wherein R3dis -O-CH(CH3)(CH3).

72. The compound of any one of claims 1-71, wherein R6is oxo.

73. The compound of any one of claims 1-71, wherein R6is C1-4alkyl optionally substituted with one or more halogen.

74. The compound of any one of claims 1-71, wherein R6is C1-4alkyl optionally substituted with one or more F.

75. The compound of any one of claims 1-71, wherein R6is methyl.

76. The compound of any one of claims 1-71, wherein R6is halogen.

77. The compound of any one of claims 1-71, wherein R6is F.

78. The compound of any one of claims 1-17 or 29-77, wherein R3aand R3b, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8.

79. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.MTX-04725 80. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

81. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they areattached, form wherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

82. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

83. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

84. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8.

85. The compound of claim 84, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

86. The compound of claim 84, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.MTX-04725 87. The compound of claim 84, wherein R3aand R3b, together with the atoms to which they areattached, form wherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

88. The compound of any one of claims 1-26 or 30-77, wherein R3band R3c, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8.

89. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.

90. The compound of claim 88, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

91. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

92. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.MTX-04725 93. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

94. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8.

95. The compound of claim 94, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

96. The compound of claim 94, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

97. The compound of claim 94, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

98. The compound of any one of claims 1-28 or 72-77, wherein R3cand R3d, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8.

99. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.MTX-04725 100. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. . The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

102. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

103. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d.

105. The compound of claim 98, wherein R3band R3c, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8.MTX-04725 106. The compound of claim 105, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

107. The compound of claim 105, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

108. The compound of claim 105, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

109. The compound of claim 105, wherein R3cand R3d, together with the atoms to which110. The compound of claim 105, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d.

111. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d.MTX-04725 112. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d.

113. The compound of any one of claims 1-29, wherein R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8.

114. The compound of claim 113, wherein R3dand R3e, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.

115. The compound of claim 114, wherein R3dand R3e, together with the atoms to which they are attached, form wherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

116. The compound of claim 114, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

117. The compound of claim 114, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

118. The compound of claim 114, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.MTX-04725 119. The compound of claim 113, wherein R3dand R3e, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8.

120. The compound of claim 119, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. laim 119, wherein R3dand R3e, together with the atoms to whichthey are attached, form wherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. The compound of claim 119, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, form a morpholin optionally substituted by from 1 to 4 R8. The compound of claim 123, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

125. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, form a morpholin optionally substituted by from 1 to 4 R8.

126. The compound of claim 125, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.MTX-04725 127. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, form a morpholine optionally substituted by from 1 to 4 R8.

128. The compound of claim 127, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

129. The compound of claim 127, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d. The compound of claim 113, wherein R3dand R3e, together with the atoms to which they are attached, form a morpholin optionally substituted by from 1 to 4 R8.

131. The compound of claim 130, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

132. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8.

133. The compound of claim 132, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

134. The compound of claim 132, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.MTX-04725 135. The compound of claim 132, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

136. The compound of claim 88, wherein R3band R3c, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8.

137. The compound of claim 136, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

138. The compound of claim 136, wherein R3band R3c, together with the atoms to which they are attached, formwherein * denotes a bond to R3band ** denotes a bond to R3c, optionally substituted with from 1 to 4 R8.

139. The compound of claim 136, wherein R3band R3c, together with the atoms to which denotes a bondto R3c, optionally substituted with from 1 to 4 R8.

140. The compound of claim 98, wherein R3cand R3d, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8.

141. The compound of claim 140, wherein R3cand R3d, together with the atoms to which they are attached, form wherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.MTX-04725 142. The compound of claim 140, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

143. The compound of claim 140, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

144. The compound of claim 113, wherein R3dand R3e, together with the atoms to which they are attached, form a pyrrolidine optionally substituted by from 1 to 4 R8.

145. The compound of claim 130, wherein R3dand R3e, together with the atoms to which they are attached, formdenotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

146. The compound of claim 130, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.

147. The compound of claim 130, wherein R3dand R3e, together with the atoms to which they are attached, formwherein * denotes a bond to R3dand ** denotes a bond to R3e, optionally substituted with from 1 to 4 R8.MTX-04725 148. The compound of claim 140, wherein R3cand R3d, together with the atoms to which they are attached, formwherein * denotes a bond to R3cand ** denotes a bond to R3d.

149. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

150. The compound of claim 78, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

151. The compound of any one of Claims 1-150, wherein R3eis H.

152. The compound of any one of Claims 1-150, wherein R3eis halogen.

153. The compound of any one of Claims 1-150, wherein R3eis F. d of any one of claims 1-153, wherein the Q ring id of any one of claims 1-153, wherein the Q ring is156. The compound of any one of claims 1-153, wherein the Q ring isMTX-04725 157. The compound of any one of claims 1-156, wherein R2is H.

158. The compound of any one of claims 1-156, wherein R2is methyl optionally substituted with one or more F.

159. The compound of any one of claims 1-156, wherein R2is methyl.

160. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:each of R1a, R1a1, R1a2, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H; each of R1band R1b1is independently H, methyl or methoxy; R2is H; R3ais halogen, C1-4alkyloxy, cyano, or C1-4alkyl optionally substituted with one or more halogen; R3bis halogen; R3cis H; and R3dis C3-6cycloalkyl, 4-6-membered heterocycloalkyl, -O-(C3-6cycloalkyl), -O-(4-6- membered heterocycloalkyl), 5-6 member heteroaryl, C6aryl, -O-(5-6 member heteroaryl), or -O-(C6aryl), wherein each cycloalkyl, heterocycloalkyl, aryl or heteraryl is optionally substituted with 1 to 4 R6; orMTX-04725 R3aand R3b, R3band R3c, R3cand R3d, or R3dand R3e, together with the atoms to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from 1 to 4 R8; R3eis H, or halogen; R4a1, R4a2, R4b1, and R4b2are each independently H, F or methyl optionally substituted with one or more F; each R6is independently halogen, C1-4alkyl optionally substituted with halogen, hydroxyl or oxo; each R8is independently halogen, C1-4alkyl optionally substituted with halogen, hydroxyl or oxo; each of Ra and Rb is independently hydrogen, or C1-4alkyl optionally substituted with one or more halogen; and m is 0.

161. The compound of claim 160, wherein each of R1band R1b1is independently H.

162. The compound of any one of Claims 160-161, wherein R3ais Cl, methoxy, ethyl, - CN or methyl optionally substituted with one or more F.

163. The compound of any one of Claims 160-162, wherein R3bis F.

164. The compound of any one of Claims 160-163, wherein R3eis H or F.

165. The compound of any one of Claims 160-164, wherein R3eis H.

166. The compound of any one of Claims 160-164, wherein R3eis F.

167. The compound of any one of Claims 160-166, wherein R3dis C1-4alkyl.

168. The compound of any one of Claims 160-166, wherein R3dis isopropyl.

169. The compound of any one of Claims 160-166, wherein R3dis tetrahydropyran, tetrahydrofuran, morpholino, oxetane, or thietane.

170. The compound of any one of Claims 160-166, wherein R3dis -O-(tetrahydropyran), -O-(tetrahydrofuran), -O-(morpholino), -O-(oxetane), or -O-(thietane).

171. The compound of any one of Claims 160-166, wherein R3dis pyridinyl, -O- (pyridinyl), pyrimidinyl, -O-(pyrimidinyl), phenyl or anisole.

172. The compound of any one of Claims 160-166, wherein R3dis a diazole optionally substituted with one or more R6.MTX-04725 173. The compound of any one of Claims 160-166, wherein R3dis a diazole optionally substituted with one or more methyl, F, Cl or methyl optionally substituted with F.

174. The compound of any one of Claims 160-166, wherein R3dis a diazole optionally substituted with one or more methyl.

175. The compound of any one of claims 160-162, wherein R3aand R3b, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.

176. The compound of any one of claims 160-162, wherein R3aand R3b, together with the atoms to which they are attached, form, ,a bond to R3b, optionally substituted with from 1 to 4 R8.

177. The compound of claim 176, wherein R8is methyl.

178. The compound of any one of claims 160-162, wherein R3aand R3b, together with the atoms to which they are attached, formwherein * denotes a bond to R3aand ** denotes a bond to R3b, optionally substituted with from 1 to 4 R8.

179. The compound of any one of Claims 160-166, wherein R3cand R3d, together with the atoms to which they are attached, form a tetrahydropyran, or tetrahydrofuran, each optionally substituted by from 1 to 4 R8.MTX-04725 180. The compound of claim 179, wherein R3cand R3d, together with the atoms to which they are attached, formdenotes a bond to R3d, optionally substituted with from 1 to 4 R8.

181. The compound of any one of Claims 160-166, wherein R3cand R3d, together with the atoms to which they are attached, form a tetrahydropyran optionally substituted by from 1 to 4 R8.

182. The compound of any one of Claims 160-166, wherein R3cand R3d, together with the atoms to which they are attached, form a tetrahydrofuran optionally substituted by from 1 to 4 R8. The compound of claim 182, wherein R3cand R3d, together with the atoms to whichdenotes a bond to R3cand ** denotes a bond to R3d, optionally substituted with from 1 to 4 R8.

184. The compound of any one of claims 179-183, wherein R8is methyl.MTX-04725 185. The compound of claim 179, wherein R3cand R3d, together with the atoms to which, wherein * denotes a bond to R3cand ** denotes a bond to R3d.

186. The compound of claim 179, wherein R3cand R3d, together with the atoms to whichdenotes a bond to R3d.

187. The compound of any one of Claims 160-174, wherein R3cis H.

188. The compound of any one of Claims 160-187, wherein R3eis H.

189. The compound of any one of Claims 160-188, wherein R4a1is F and R4a2, R4b1, and R4b2are each independently H.

190. The compound of any one of Claims 160-188, wherein R4a1and R4a2are each F, and R4b1, and R4b2are each independently H.

191. The compound of any one of Claims 160-188, wherein R4a1and R4a2are each H, and R4b1, and R4b2are each independently F.

192. The compound of any one of Claims 160-188, wherein R4a1, R4a2, and R4b1, are each independently H, and R4b2 is F.

193. The compound of any one of Claims 160-188, wherein R4a1, R4a2, and R4b1, are each independently H, and R4b2is methyl.

194. The compound of any one of Claims 160-188, wherein R4a1and R4a2are each H, and R4b1, and R4b2are each independently methyl.MTX-04725 195. The compound of any one of claims 160-194, wherein the Q ring is196. The compound of any one of claims 160-194, wherein the Q ring is.

197. The compound of any one of claims 160-194, wherein the Q ring is198. The compound of any one of claims 160-197, wherein each of R1a, R1a1, R1a2, R1b, R1b1, R1b2, R1c, R1c1, R1c2, R1d, R1d1, R1d2, R1e, R1e1, and R1e2is independently H.

199. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (II-A)or a pharmaceutically acceptable salt thereof.MTX-04725 200. The compound of any one of claims 1-198, wherein the compound is is a compound of Formula (II-B)or a pharmaceutically acceptable salt thereof.

201. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (III-A)or a pharmaceutically acceptable salt thereof.

202. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (III-B)MTX-04725or a pharmaceutically acceptable salt thereof.

203. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (IV-A)or a pharmaceutically acceptable salt thereof.

204. The compound of any one of Claims 199-203, wherein R4a1and R4a2are each independently H or F and R4b1and R4b2are each independently H; or R4b1and R4b2are each independently H or F and R4a1and R4a2are each independently H.

205. The compound of claim 204, wherein R3ais Cl, -CN, -OCH3, methyl or ethyl; and R3bis F.

206. The compound of any one of Claims 204-205, wherein R3dis isopropyl.

207. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (V)MTX-04725or a pharmaceutically acceptable salt thereof, wherein R3cand R3dtogether form a tetrahydropyran or tetrahydrofuran optionally substituted with one or two methyl.

208. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (V-A)or a pharmaceutically acceptable salt thereof, wherein R3c and R3d together form a tetrahydropyran or tetrahydrofuran optionally substituted with a methyl, gem-dimethyl or a spirocyclic C3-6cycloalkyl or spirocyclic 3-6 member heterocyclyl ring.

209. The compound of any one of Claims 207-208, wherein R3ais methyl, ethyl, methoxy, Cl or -CN, R3bis H or F and R3eis H.

210. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (VI)MTX-04725pharmaceutically acceptable salt thereof.

211. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (VI-A)pharmaceutically acceptable salt thereof.

212. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (VI-B)MTX-04725pharmaceutically acceptable salt thereof.

213. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (VI-C)pharmaceutically acceptable salt thereof.

214. The compound of any one of claims 1-198, wherein the compound is a compound of Formula (VI-D)MTX-04725pharmaceutically acceptable salt thereof.

215. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 216. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

217. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

218. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 219. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

220. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

221. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 222. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

223. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

224. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

225. The compound of Claim 1, wherein the compound isMTX-04725 226. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

227. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

228. The compound of Claim 1, wherein the compound issalt thereof.

229. The compound of Claim 1, wherein the compound isMTX-04725 230. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

231. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

232. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 233. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

234. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

235. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

236. The compound of Claim 1, wherein the compound isMTX-04725 237. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

238. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

239. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 240. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

241. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

242. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 243. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

244. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

245. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

246. The compound of Claim 1, wherein the compound is sMTX-04725 247. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

248. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

249. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

250. The compound of Claim 1, wherein the compound isMTX-04725 251. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

252. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

253. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

254. The compound of Claim 1, wherein the compound is sMTX-04725 255. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

256. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

257. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

258. The compound of Claim 1, wherein the compound issalt thereof.MTX-04725 259. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

260. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

261. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.MTX-04725 262. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

263. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

264. The compound of Claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

265. The compound of claim 1, wherein the compound ior a pharmaceutically acceptable salt thereof.MTX-04725 266. The compound of claim 1, wherein the compound ior a pharmaceutically acceptable salt thereof.

267. The compound of claim 1, wherein the compound i, or a pharmaceutically acceptable salt thereof.

268. The compound of claim 1, wherein the compound ior a pharmaceutically acceptable salt thereof.

269. The compound of claim 1, wherein the compound i, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound i, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound ior a pharmaceutically acceptable salt thereof.

272. A pharmaceutical composition, comprising a compound of any one of Claims 1-264, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.MTX-04725 273. A method of inhibitingv 8integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-271, or a pharmaceutically acceptable salt thereof.

274. The method of claim 273, wherein the method is for treating a solid tumor in a patient in need thereof.

275. A method of treating solid tumor in a patient, the method comprising administering to the patient in need thereof (a) a therapeutically effective amount of a compound of any one of claims 1-271, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.

276. The method of claim 275, wherein the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.

277. The method of claim 276, wherein the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.

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