Carboxylic acid-containing indanyl compounds for the treatment of neurodegenerative diseases

Abstract

TIFF2024546678000220.tif3552I Provided herein are compounds and compositions thereof for modulating S1P5. In some embodiments, the compounds and compositions are provided for the treatment of neurological disorders.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 286,749, filed December 7, 2021, the disclosure of which is incorporated by reference in its entirety herein for all purposes.

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of said compounds and compositions for treating neurological disorders. [Background technology]

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate) is a bioactive sphingolipid synthesized by intracellular sphingolipid turnover and by the extracellular action of secreted sphingosine kinase. S1P binds to and stimulates members of the endothelial cell differentiation gene family (EDG receptors), which are plasma membrane-localized G protein-coupled receptors. The five members of this family are S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P1 mediates a wide range of cellular responses, including proliferation, cytoskeletal organization and migration, adherens and tight junction assembly, and morphogenesis.

[0004] S1P5 is mainly expressed in the central nervous system. In particular, S1P5 is highly expressed in oligodendrocytes and oligodendrocyte precursor cells (Jaillard, C. et al., J.Neuroscience, 2005, 25(6), 1459-1469; Novgorodov, A. et al., FASEB J., 2007, 21, 1503-1514). Oligodendrocytes are glial cells that bind to the axons of neurons to form myelin. Compounds that bind to S1P5 can regulate the function of S1P5 and may be useful for treating neurodegenerative diseases.

[0005] Thus, in one aspect, there is provided herein compounds that modulate S1P5 for use in the treatment of neurodegenerative diseases. Summary of the Invention

[0006] In some embodiments, compounds and compositions for modulating S1P5 are described herein. In various embodiments, the compounds and compositions may be used for the treatment of neurodegenerative diseases.

[0007] The present embodiments can be more fully understood by reference to the detailed description and examples given by way of illustration of non-limiting embodiments.

[0008] Embodiment 1 is a compound of formula I: [ka] I or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 are each independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 2 are each independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 3a and R3b are independently H, C1-C6 alkyl, halo, or C1-C6 haloalkyl; x is 1 to 5; y is 0 to 3; z is 1 to 5; n is 1, 2, or 3; R 4 are each independently -COH, halo, C1-C6 haloalkyl, or C1-C6 alkyl, or two R 4 The groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C-C cycloalkyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety.

[0009] In embodiment 2, R 1 is each independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, or a pharma- ceutically acceptable salt thereof.

[0010] In a third embodiment, R 1 is each independently F, Cl, I, -CN, -CH3, -CF3, -OCH(CH3)2, or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0011] Embodiment 4 is a compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein x is 1, 2, or 3.

[0012] Embodiment 5 is a compound of the formula: [ka] But the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0013] Embodiment 6 is directed to R 2 is each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0014] Embodiment 7 is R 2 is each independently F or -CH3, or a pharma- ceutically acceptable salt thereof.

[0015] Embodiment 8 is a compound according to any one of embodiments 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein y is 1.

[0016] Embodiment 9 is a compound according to any one of embodiments 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein y is 0.

[0017] Embodiment 10 is a compound of the formula: [ka] But the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0018] Embodiment 11 is directed to R 3a and R 3b is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0019] Embodiment 12 is a compound comprising R 3a and R 3b is independently H or -CH3, or a pharma- ceutically acceptable salt thereof.

[0020] Embodiment 13 is a compound of the formula: [ka] But the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0021] Embodiment 14 is a compound of the formula: [ka] But the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0022] Embodiment 15 is a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

[0023] Embodiment 16 is a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein n is 2.

[0024] Embodiment 17 is a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein n is 3.

[0025] Embodiment 18 is directed to R 4 are each independently -COH, halo, C1-C3 haloalkyl, or C1-C3 alkyl, provided that at least one R 4 The compound according to any one of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein the group is -CO2H.

[0026] Embodiment 19 is a compound having two R 4A compound according to any one of embodiments 1-17, or a pharma- ceutically acceptable salt thereof, wherein the groups, taken together with the carbon atom to which they are attached, form a fused or spiro C3-C5 cycloalkyl, substituted by -CO2H.

[0027] Embodiment 20 is a compound according to any one of embodiments 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein z is 1 to 3.

[0028] Embodiment 21 is a compound of the formula: [ka] But the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0029] Embodiment 22 is a compound selected from the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0030] Embodiment 23 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 22 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0031] Embodiment 24 is a method for modulating sphingosine-1-phosphate receptor 5 (S1P5), comprising contacting S1P5 with an effective amount of a compound according to any one of embodiments 1 to 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 23.

[0032] Embodiment 25 is a method for treating a neurological disorder in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 23.

[0033] Embodiment 26 is the method according to embodiment 25, wherein the neurological disease is Alzheimer's disease or multiple sclerosis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] (Detailed Description) (definition) As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are to be interpreted to specify that the stated features or components are present exactly as stated, but do not exclude the presence or addition of one or more features, components, or groups thereof. In addition, the terms "comprising" and "including" include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the invention.

[0035] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In other embodiments, the term "consisting of" excludes from the ensuing description any other features or components, except those that are not essential to the technical effect to be achieved.

[0036] As used herein, the term "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C." Exceptions to this definition occur only when combinations of elements, features, steps, or acts are, for some reason, mutually exclusive in nature.

[0037] Unless otherwise indicated herein, any concentration range, percentage range, proportion range, or integer range should be understood to include any integer value within the stated range and, where appropriate, fractions thereof (e.g., tenths and hundredths of an integer value). Also, unless otherwise indicated, any numerical range relating to any physical characteristic described herein, such as a polymer subunit, size, or thickness, should be understood to include any integer value within the stated range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0038] An "alkyl" group is a fully saturated, partially saturated or unsaturated, straight or branched chain acyclic hydrocarbon having from 1 to 10 carbon atoms (C1 to C 10alkyl), typically having 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 (C1-C6 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl). In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group that contains one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, CH2C≡C(CH3), and -CH2C≡C(CH2CH3), among others. Alkyl groups can be substituted or unsubstituted.When alkyl groups as described herein are referred to as "substituted," they include, but are not limited to, halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkyla alkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2, which may be substituted with any of the optional substituent(s) as found in the exemplary compounds and embodiments disclosed herein.In some embodiments, when alkyl groups described herein are referred to as "substituted," they may be substituted with any substituent(s) such as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl, as well as any substituent(s) as found in the exemplary compounds and embodiments disclosed herein.

[0039] A "cycloalkyl" group contains 3 to 10 carbon atoms (C 10Cycloalkyl groups are optionally substituted, saturated or partially saturated cyclic alkyl groups having a single ring or multiple fused or bridged rings. In some embodiments, the cycloalkyl groups have 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments the number of ring carbon atoms is 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl groups are saturated cycloalkyl groups. Examples of such saturated cycloalkyl groups include single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl groups are unsaturated cycloalkyl groups. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like, among others. The cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol, and the like.

[0040] An "aryl" group contains 6 to 14 carbon atoms (C 14 Aryl) is an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, an aryl group contains 6 to 14 carbon atoms (C 14 aryl), in other embodiments, the ring portion of said groups may contain 6 to 12 carbon atoms (C 12 aryl), or even 6 to 10 (C6 to C 10The term "aryl group" includes carbon atoms of the aryl group (aryl), which includes, inter alia, phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as aromatic fused alicyclic systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0041] "Halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0042] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1-6 carbon atoms and is substituted with one or more halo groups (C1-C6 haloalkyl), or the haloalkyl group has 1-3 carbon atoms and is substituted with one or more halo groups (C1-C3 haloalkyl). The halo groups may all be the same, or the halo groups may be different. Unless otherwise specified, haloalkyl groups are optionally substituted.

[0043] A "heteroaryl" group is an aromatic ring system having from 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, heteroaryl groups contain from 3 to 6 ring atoms, and in other embodiments, from 6 to 9, or even 6 to 10 ring atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring system is a monocyclic or bicyclic system. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazolyl, Examples of heteroaryl groups include pyridyl groups (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl groups, triazolopyridyl groups, benzotriazolyl groups (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl groups (e.g., benzo[d]oxazolyl), benzothiazolyl groups, benzothiadiazolyl groups, isoxazolopyridyl groups, thianaphthalenyl groups, purinyl groups, xanthinyl groups, adeninyl groups, guaninyl groups, quinolinyl groups, isoquinolinyl groups (e.g., 3,4-dihydroisoquinolin-1-(2H)-onyl), tetrahydroquinolinyl groups, quinoxalinyl groups, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0044] "Heterocyclyl" is a non-aromatic cycloalkyl in which one to four ring carbon atoms are independently replaced by a heteroatom selected from O, S, and N. In some embodiments, the heterocyclyl group contains 3 to 10 ring members, and in other embodiments, the group has 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyl can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclyl ring). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include saturated and partially saturated ring systems. Furthermore, the term "heterocyclyl" is intended to include any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the manner of attachment to the rest of the molecule. The phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono- or more than mono-substituted, and include, but are not limited to, pyridyl or morpholinyl groups substituted at the 2-, 3-, 4-, 5-, or 6-positions with various substituents described below, or di-substituted.

[0045] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0046] A "carboxy" group is a group represented by the formula: --C(O)OH.

[0047] Except for alkyl groups, when groups described herein are referred to as "substituted," those groups may be substituted with any suitable substituent(s). Specific examples of substituents include halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; cycloalkyl (e.g., cyclopropyl, cyclobutyl ... aryl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be a single ring or multiple fused or non-fused rings (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); single ring or multiple fused or non-fused rings aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetraazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy, as well as those found in the exemplary compounds and embodiments disclosed herein.

[0048] Embodiments of the present disclosure are meant to include pharma- ceutically acceptable salts, tautomers, isotopes, and stereoisomers of the compounds provided herein, such as the compounds of Formula I.

[0049] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases, and organic acids and bases. Suitable pharmaceutically acceptable base addition salts for compounds of formula I include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include inorganic and organic acids such as, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Particular non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Thus, specific examples of salts include hydrochloride, formate, and mesylate. Others well known in the art include, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990), or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0050] As used herein, and unless otherwise specified, the terms "stereoisomer" and "stereoisomerically pure" refer to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the other enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All of these isomers, including mixtures, are included in the embodiments disclosed herein.

[0051] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are also included in the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. Examples include Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0052] It should also be noted that the compounds disclosed herein may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0053] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is present, and may vary depending on whether the compound is a solid or in an organic solvent or aqueous solution. For example, in aqueous solution, pyrazole exhibits the isomers shown below, which are referred to as tautomers of each other. [ka]

[0054] As one of ordinary skill in the art would readily appreciate, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formula I are within the scope of the disclosure.

[0055] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 It may be labeled with a radioisotope such as C, or with deuterium ( 2 H), Carbon-13( 13 C), or nitrogen-15 ( 15As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope contained in an atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, binding assay reagents, diagnostic agents, and in vivo imaging agents. As described herein, all isotopic variations of compounds, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopic substitutions of the compounds disclosed herein are provided, e.g., isotopic substitutions are compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., the compound is deuterium-rich in at least one position.

[0056] It is understood that each compound disclosed herein, independently of its stereoisomeric or isotopic composition, can be provided in the form of any of the pharma- ceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound mentioned herein.Furthermore, the isotopic composition is limited to the elements contained in each compound or their salts disclosed herein, but can otherwise vary independently of the choice of pharma-ceutically acceptable salt of each compound.

[0057] It should be noted that in the event of a discrepancy between a depicted structure and the name of that structure, the depicted structure shall be borne more weight.

[0058] "Treatment," as used herein, means alleviating, in whole or in part, a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or slowing or halting further progression or worsening of the symptoms, or alleviating or eradicating the cause(s) of the disorder, disease or condition itself. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof, as described herein.

[0059] "Prevention," as used herein, refers to a method of slowing and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, i.e., protecting a subject from acquiring a disorder, disease, or condition, or reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof, as described herein.

[0060] The term "effective amount," in reference to a compound disclosed herein, means an amount capable of treating or preventing a disorder, symptom or condition, or a symptom thereof, as disclosed herein.

[0061] The term "subject" or "patient" as used herein includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans. In one embodiment, the subject is a human having or at risk for an S1P5-mediated disease, or a symptom thereof.

[0062] Although various features of the invention may be described in the context of a single embodiment, such features may also be provided separately or in any suitable combination. Conversely, although the invention may, for clarity, be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment. (compound)

[0063] In one aspect, provided herein is a compound of formula I: [ka] I or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 are each independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 2 are each independently halo, C1-C6 alkyl, or C1-C6 haloalkyl; R 3a and R 3b are independently H, C1-C6 alkyl, halo, or C1-C6 haloalkyl; x is 1 to 5; y is 0 to 3; z is 1 to 5; n is 1, 2, or 3; R 4 are each independently -COH, halo, C1-C6 haloalkyl, or C1-C6 alkyl, or two R 4 groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C-C cycloalkyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety.

[0064] In some embodiments, R 1 are each independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. 1 are each independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl. 1are each independently F, Cl, I, -CN, methyl, CF3, -OCH(CH3)2, or cyclopropyl.

[0065] In some embodiments, R 1 is halo. In some embodiments, R 1 is F, Cl, Br, or I. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0066] In some embodiments, R 1 is -CN.

[0067] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is isopropyl.

[0068] In some embodiments, R 1 is C1-C6 haloalkyl. In some embodiments, R 1 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 1 is C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 1is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 1 is -CF3.

[0069] In some embodiments, R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R 1 is -OCH(CH3)2.

[0070] In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl.

[0071] In some embodiments, x is 1 to 5. In some embodiments, x is 1 to 3. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5.

[0072] In some embodiments, the formula: [ka] is the expression: [ka] It is.

[0073] In some embodiments, R 2 are each independently halo, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 2 are each independently halo, C1-C3 alkyl, or C1-C3 haloalkyl. 2 are each independently halo or C1-C3 alkyl. In some embodiments, R 2 are each independently F or -CH3.

[0074] In some embodiments, R 2 is halo. In some embodiments, R 2 is F, Cl, Br, or I. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I.

[0075] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl.

[0076] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 2 is C1-C3 haloalkyl. In some embodiments, R 2is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 2 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2 is -CF3.

[0077] In some embodiments, y is 0 to 3. In some embodiments, y is 0. In some embodiments, y is 1 or 2. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3.

[0078] In some embodiments, the formula: [ka] is the expression: [ka] It is.

[0079] In some embodiments, R 3a and R 3b is independently H, C1-C6 alkyl, halo, or C1-C6 haloalkyl. In some embodiments, R 3a and R 3b is independently H, C1-C3 alkyl, halo, or C1-C3 haloalkyl. In some embodiments, R 3a and R 3b is independently H, C-C cycloalkyl, or halo. In some embodiments, R 3a and R 3b are independently H or -CH3.

[0080] In some embodiments, R 3a is H. In some embodiments, R 3a is C1-C6 alkyl. In some embodiments, R 3ais C1-C3 alkyl. In some embodiments, R 3a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3a is methyl or ethyl. In some embodiments, R 3a is methyl. In some embodiments, R 3a is halo. In some embodiments, R 3a is F, Cl, or Br. In some embodiments, R 3a is C1-C6 haloalkyl. In some embodiments, R 3a is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 3a is C1-C3 haloalkyl. In some embodiments, R 3a is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 3a is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 3a is -CF3.

[0081] In some embodiments, R 3b is H. In some embodiments, R 3b is C1-C6 alkyl. In some embodiments, R 3b is C1-C3 alkyl. In some embodiments, R 3b is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3b is methyl or ethyl. In some embodiments, R 3b is methyl. In some embodiments, R 3b is halo. In some embodiments, R 3b is F, Cl, or Br. In some embodiments, R 3b is C1-C6 haloalkyl. In some embodiments, R 3bis a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 3b is C1-C3 haloalkyl. In some embodiments, R 3b is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 3b is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 3b is -CF3.

[0082] In some embodiments, R 3a and R 3b are each H. In some embodiments, R 3a and R 3b is C1-C6 alkyl. In some embodiments, R 3a and R 3b is C1-C3 alkyl. In some embodiments, R 3a and R 3b is methyl, ethyl, n-propyl, or isopropyl. 3a and R 3b Each is methyl. In some embodiments, R 3a and R 3b Each is halo. In some embodiments, R 3a and R 3b are each F, Cl, or Br. In some embodiments, R 3a and R 3b Each is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 3a and R 3b Each is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 3a and R 3bare each -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. 3a and R 3b Each is -CF3. In some embodiments, R 3a and R 3b One of R is H and the other is C1-C6 alkyl. 3a and R 3b One of R is H and the other is C1-C3 alkyl. 3a and R 3b One of R is H and the other is methyl, ethyl, n-propyl, or isopropyl. 3a and R 3b One of R is H and the other is methyl. 3a and R 3b One of R is H and the other is halo. 3a and R 3b One of R is H and the other is F, Cl, or Br. 3a and R 3b One of R is H and the other is a C1-C6 haloalkyl containing 1-13 halogen atoms. 3a and R 3b One of R is H and the other is a C1-C3 haloalkyl containing 1-7 halogen atoms. 3a and R 3b is H and the other is -CF, -CHF, -CHF, -CCl, -CHCl, -CHCl, -CFCl, -CFCl, -CHCF, -CHCHF, or -CHCCl. 3a and R 3b One of R is H and the other is -CF3. 3a and R 3b One of R is C1-C6 alkyl and the other is halo. 3a and R3b One of R is C1-C3 alkyl and the other is halo. 3a and R 3b One of R is methyl, ethyl, n-propyl, or isopropyl, and the other is F, Cl, or Br. 3a and R 3b One of R is methyl and the other is F, Cl, or Br. 3a and R 3b One of R is C1-C6 alkyl and the other is C1-C6 haloalkyl containing 1 to 13 halogen atoms. 3a and R 3b One of R is C1-C3 alkyl and the other is C1-C3 haloalkyl containing 1 to 7 halogen atoms. 3a and R 3b is methyl, ethyl, n-propyl, or isopropyl, and the other is -CF, -CHF, -CHF, -CCl, -CHCl, -CHCl, -CFCl, -CHCF, -CHCHF, or -CHCCl. 3a and R 3b is methyl and the other is -CF, -CHF, -CHF, -CCl, -CHCl, -CHCl, -CFCl, -CFCF, -CHCHF, or -CHCCl. 3a and R 3b One of R is methyl and the other is -CF3. 3a and R 3b One of R is halo and the other is a C1-C6 haloalkyl containing 1-13 halogen atoms. 3a and R 3b One of R is halo and the other is a C1-C3 haloalkyl containing 1-7 halogen atoms. 3a and R 3bis F, Cl, or Br, and the other is -CF, -CHF, -CHF, -CCl, -CHCl, -CHCl, -CFCl, -CFCl, -CHCF, -CHCHF, or -CHCCl. 3a and R 3b One of the is F or Cl and the other is -CF3.

[0083] In some embodiments, the formula: [ka] is the expression: [ka] It is.

[0084] In some embodiments, the formula: [ka] is the expression: [ka] It is.

[0085] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0086] In some embodiments, R 4 are each independently -COH, halo, C1-C6 haloalkyl, or C1-C6 alkyl, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety.

[0087] In some embodiments, R 4 are each independently -COH, halo, C1-C3 haloalkyl, or C1-C3 alkyl, provided that at least one R 4The group is -CO2H or contains a -CO2H moiety. 4 is -COH. In some embodiments, R 4 is halo, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is fluoro, chloro, or bromo, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is C1-C6 haloalkyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is C1-C3 haloalkyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is C1-C6 alkyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is C1-C3 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 is methyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. 4 are each independently -COH or methyl, provided that at least one R 4The group is -CO2H or contains a -CO2H moiety.

[0088] In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C-C cycloalkyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form a fused C3-C5 cycloalkyl, optionally substituted by -CO2H, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form a bridged C-C cycloalkyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atom to which they are attached, form a spiro C-C cycloalkyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form an unsubstituted, fused, bridged, or spiro C-C cycloalkyl, provided that at least one other R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C3-C5 cycloalkyl substituted by -CO2H.

[0089] In some embodiments, two R 4The groups, together with the carbon atoms to which they are attached, form a fused cyclopropyl or spirocyclobutyl, each of which is optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atom to which they are attached, form a fused cyclopropyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety. In some embodiments, two R 4 The groups, together with the carbon atoms to which they are attached, form a spirocyclobutyl, optionally substituted by -COH, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety.

[0090] In some embodiments, z is 1 to 5. In some embodiments, z is 1 to 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5.

[0091] In some embodiments, the formula: [ka] is the expression: [ka] It is.

[0092] In some embodiments, the compound has formula Ia: [ka] Ia is [In the formula, R 1 , R 2 , R 3a , R3b , x, y, and n are as described for formula I; Each R4 is independently -CO2H, halo, C1-C6 haloalkyl, or C1-C6 alkyl.

[0093] In some embodiments, the compound has formula Ib: [ka] Ib is [In the formula, R 1 , R 2 , R 3a , R 3b , x, y, z, and n are as described for formula I; The Two R's 4 The groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C-C cycloalkyl, optionally substituted by -COH, where (R 4 ) z A 4- to 6-membered heterocyclyl ring substituted by up to three R 4 may be further optionally substituted by R 4 groups are each independently -COH, halo, C1-C6 haloalkyl, or C1-C6 alkyl, provided that at least one R 4 The group is -CO2H or contains a -CO2H moiety.

[0094] In some embodiments, the compound of formula I has formula IA, IB, or IC: [ka] is a compound of [In the formula, R 1 , R 2 , R 3a , R 3b , R 4 , x, y, and z are as described for formula I.

[0095] In some embodiments, the compound of formula I has formula Ia, Ib, or Ic: [ka] is a compound of [In the formula, R 1 , R 2 , R 3a , R 3b , R 4 , x, and y are as described for formula I].

[0096] In some embodiments, the compound of formula I has formula I-1, I-2, or I-3: [ka] is a compound of [In the formula, R 1 , R 2 , R 3a , R 3b , x, and y are as described for formula I; R 4 are each -CO2H, halo, C1-C6 haloalkyl, or C1-C6 alkyl. When -CO2H is depicted across two ring systems (i.e., said spiro bicyclic ring), it is understood that one of the two rings of said spiro bicyclic ring system can be replaced by -CO2H. In some embodiments, the heterocyclic ring of the spirobicyclic system is substituted by -CO2H. In some embodiments, the cycloalkyl ring of the spirobicyclic system is substituted by -CO2H.

[0097] In some embodiments, the compound of formula I has formula IA, IB, or IC: [ka] is a compound of [In the formula, R 1 , R 2 , R 3a , R 3b, x, and y are as described for formula I; R 4 are each -CO2H, halo, C1-C6 haloalkyl, or C1-C6 alkyl. When -CO2H is depicted across two ring systems (i.e., a fused bicyclic ring), it is understood that one of the two rings of the fused bicyclic ring system can be replaced by -CO2H. In some embodiments, the heterocyclic ring of the fused bicyclic ring system is replaced by -CO2H. In some embodiments, the cycloalkyl ring of the fused bicyclic ring system is replaced by -CO2H.

[0098] It is understood herein that any description, variation, embodiment, or aspect of a moiety may be combined with any description, variation, embodiment, or aspect of any other moiety, just as if each and every combination of descriptions were specifically and individually set forth. For example, R 1 Any description, variation, embodiment, or aspect of 2 , R 3a , R 3b , R 4 , x, y, z, and n may be combined with any description, variation, embodiment, or aspect thereof as if each and every combination were specifically and individually described. It is also understood that every description, variation, embodiment, or aspect in formula I applies equally to and is described equally to other formulas described herein, where applicable, as if each and every description, variation, embodiment, or aspect were described separately and individually for every formula. For example, every description, variation, embodiment, or aspect in formula I applies equally to and is described equally to any formula described herein, such as formulas Ia, Ib, IA, IB, IC, Ia, Ib, Ic, I-1, I-2, I-3, IA, IB, and IC, where applicable, as if each and every description, variation, embodiment, or aspect were described separately and individually for every formula.

[0099] In some embodiments, provided is a compound selected from the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof. Although some compounds described in this disclosure, including those in Table 1, are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any compound in this disclosure, including those in Table 1, are described herein. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] "or1" indicates that the absolute stereochemistry was not determined. or a pharma- ceutically acceptable salt thereof.

[0100] It is understood that combinations of substituents and / or variables of the depicted formulae herein are permissible only if such contributions result in stable compounds.

[0101] Furthermore, all compounds of formula I that exist in free base or free acid form can be converted into their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid in a manner known to those skilled in the art. Salts of compounds of formula I can be converted into the free base or free acid form by standard techniques. (Synthesis method)

[0102] The compounds described herein can be synthesized by conventional organic synthesis methods and commercially available starting materials, or by methods provided herein. By way of example, but not limitation, compounds of formula I can be prepared as shown in scheme 1, as well as the examples provided herein. It should be noted that those skilled in the art will understand how to modify the procedures provided in the illustrated schemes and examples to obtain the desired product. [ka] Scheme 1 [In the scheme, R 1 , R 2 , R 3a , R 3b , x, and y are as described in Formula I, [ka] is 1 to 4 R 4 represents a 4- to 6-membered heterocyclyl ring optionally substituted by a group, 4 is as described in formula I, and the 4- to 6-membered heterocyclyl ring or two R 4 The groups taken together form a fused, bridged, or spiro C3-C5 cycloalkyl, which is substituted with -CO2H.

[0103] As shown in Scheme 1, compounds of formula I can be synthesized as follows: aryl alcohol a undergoes Mitsunobu coupling with benzyl alcohol b to generate intermediate c, which subsequently undergoes reductive amination with amino acid ester d to generate intermediate e, which is then hydrolyzed to give compounds of formula I.

[0104] It is understood that compounds of formula I may be synthesized by other procedures known to those skilled in the art. The starting materials and intermediates shown in Scheme 1 may be derivatized using procedures known to those skilled in the art. (How to use)

[0105] An embodiment of the present disclosure provides a method for modulating sphingosine 1-phosphate receptor 5 (S1P5) in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of formula I. Modulation (e.g., inhibition or activation) of S1P5 can be assessed and demonstrated by a variety of means known in the art. Kits and commercially available assays can be used to determine whether and to what extent S1P5 is modulated (e.g., inhibited or activated).

[0106] In one aspect, provided herein is a method of modulating S1P5, comprising contacting S1P5 with an effective amount of a compound of formula I or any embodiment or variant thereof. In some embodiments, the compound of formula I inhibits S1P5. In other embodiments, the compound of formula I activates S1P5. In some embodiments, the compound of formula I is an agonist of S1P5. In some embodiments, the compound of formula I is an antagonist of S1P5.

[0107] In some embodiments, compounds of Formula I modulate the activity of S1P5 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compounds of formula I reduce or inhibit S1P5 activity by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 40 ... Adjust to 100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0108] In another aspect, provided herein is a method for treating a neurological disorder in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of Formula I. In some embodiments, provided herein is a method for preventing a neurological disorder in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of Formula I. Non-limiting examples of neurological disorders include Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Bell's palsy, ataxia, cerebral aneurysm, epilepsy, seizures, acute spinal cord injury, Guillain-Barre syndrome, meningitis, Niemann-Pick disease, and Parkinson's disease. In some embodiments, the neurological disorder is Alzheimer's disease or multiple sclerosis. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments, the neurological disorder is multiple sclerosis.

[0109] In some embodiments, administering a compound of Formula I to a subject susceptible to a neurological disorder prevents the subject from developing any symptoms of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject not yet exhibiting symptoms of a neurological disorder prevents the subject from developing any symptoms of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication reduces the extent of the neurological disorder in the subject. In some embodiments, administering a compound of Formula I to a subject in need of medication stabilizes (prevents or slows the worsening of) the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication delays the onset or recurrence of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication slows the progression of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication provides a partial remission of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication provides complete remission of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication reduces the dose of one or more other therapeutic agents required to treat the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication improves the effectiveness of other therapeutic agents used to treat the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication slows the progression of the neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication increases the quality of life of a subject suffering from a neurological disorder. In some embodiments, administering a compound of Formula I to a subject in need of medication prolongs the survival of a subject suffering from a neurological disorder.

[0110] In one aspect, provided herein is a method of preventing a subject susceptible to a neurological disease from developing any symptom of a neurological disease, comprising administering to said subject a compound of formula I. In some embodiments, provided herein is a method of preventing a subject who does not yet exhibit symptoms of a neurological disease from developing any symptom of a neurological disease, comprising administering to said subject a compound of formula I.

[0111] In some aspects, provided herein is a method of reducing the extent of a neurological disorder in a subject, comprising administering to the subject a compound of formula I. In some embodiments, provided is a method of stabilizing a neurological disorder in a subject, comprising administering to the subject a compound of formula I. In some embodiments, the method prevents the deterioration of the neurological disorder. In some embodiments, the method slows the deterioration of the neurological disorder.

[0112] In another aspect, provided herein is a method of delaying the onset or recurrence of a neurological disorder in a subject, comprising administering to said subject a compound of formula I.

[0113] In some embodiments, provided herein is a method of slowing the progression of a neurological disorder in a subject, comprising administering to the subject a compound of formula I. In some embodiments, the method provides a partial remission of the neurological disorder. In some embodiments, the method provides a complete remission of the neurological disorder.

[0114] In a further aspect, provided herein is a method of reducing the dosage of one or more other therapeutic agents required to treat a neurological disorder in a subject, comprising administering to the subject a compound of formula I. In some embodiments, provided herein is a method of increasing the effectiveness of other therapeutic agents used to treat a neurological disorder in a subject, comprising administering to the subject a compound of formula I.

[0115] Also provided herein is a method of slowing the progression of a neurological disease in a subject, comprising administering to the subject a compound of formula I. In some embodiments, the method improves the quality of life of the subject suffering from a neurological disease. In some embodiments, the method extends the survival of the subject suffering from a neurological disease.

[0116] In another aspect, provided herein is a method for treating a neurological symptom caused by a disease in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of formula I. In some embodiments, provided herein is a method for preventing a neurological symptom caused by a disease in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of formula I. In some embodiments, administering a compound of formula I to a subject susceptible to a disease causing a neurological symptom prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of formula I to a subject who has not yet shown a neurological symptom of a disease causing a neurological symptom prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of formula I to a subject in need of treatment reduces the degree of a neurological symptom caused by the disease in the subject. In some embodiments, administering a compound of formula I to a subject in need of treatment stabilizes (prevents or slows the worsening of) the neurological symptoms of the disease. In some embodiments, administering a compound of Formula I to a subject in need of a medication delays the onset or recurrence of a neurological symptom caused by the disease. In some embodiments, administering a compound of Formula I to a subject in need of a medication delays the progression of a neurological symptom caused by the disease. In some embodiments, administering a compound of Formula I to a subject in need of a medication provides a partial remission of the disease causing a neurological symptom. In some embodiments, administering a compound of Formula I to a subject in need of a medication provides a complete remission of the disease causing a neurological symptom. In some embodiments, administering a compound of Formula I to a subject in need of a medication reduces the dose of one or more other therapeutic agents required to treat the disease causing a neurological symptom. In some embodiments, administering a compound of Formula I to a subject in need of a medication improves the effectiveness of other therapeutic agents used to treat the neurological symptoms of the disease. In some embodiments, administering a compound of Formula I to a subject in need of a medication delays the progression of the disease causing a neurological symptom.In some embodiments, administering a compound of Formula I to a subject in need of the medication increases the quality of life of the subject suffering from a disease that causes neurological symptoms. In some embodiments, administering a compound of Formula I to a subject in need of the medication extends the survival of the subject suffering from a disease that causes neurological symptoms. In some embodiments, the disease is Niemann-Pick disease.

[0117] In some embodiments, the compounds of Formula I are useful for treating a disorder selected from the following: Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis, scleroderma, graft versus host disease, organ graft rejection (including, but not limited to, bone marrow and solid organ rejection), acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schönlein purpura, microscopic vasculitits of the renalkidneys), chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, septic syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's disease, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, sporadic diseases, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, associated with ulcerative colitis Arthropathy, enteropathy synovitis, arthropathy associated with chlamydia, Yersinia infection and Salmonella infection, atherosclerosis / arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs test positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Royal Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, idiopathic autoimmune hepatitis, acquired immune deficiency syndrome, acquired autoimmune deficiency-related diseases, hepatitis B, hepatitis C, Common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, infertility, female infertility, ovarian failure, premature ovarian failure, pulmonary fibrosis, chronic wound healing, idiopathic pulmonary fibrosis, postinflammatory interstitial lung disease, fibrosis, interstitial pneumonia, interstitial lung disease associated with collagen disease, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, lung disease associated with Sjogren's disease, lung disease associated with ankylosing spondylitis, vasculitic diffuse lung disease, hemo Pulmonary disease associated with siderosis, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrate lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, autoimmune hepatitis type 1 (classic autoimmune hepatitis or lupus hepatitis), autoimmune hepatitis type 2 (anti-LKM antibody hepatitis), autoimmune hypoglycemia, type II insulin resistance associated with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type II2), idiopathic leukopenia, autoimmune neutropenia, chronic kidney disease NOS, glomerulonephritis, microscopic vasulitits of the kidneys), Lyme disease, discoid lupus erythematosus, idiopathic or NOS male infertility, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatic spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goiter, autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lens-induced uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver disease , alcoholic cirrhosis, alcohol-induced liver damage, cholestasis, specific liver diseases, drug-induced hepatitis, non-alcoholic steatohepatitis, allergies and asthma, group B streptococcus (GBS) infections, psychiatric disorders (e.g. depression and schizophrenia), Th2- and Th1-mediated diseases, acute and chronic pain (different pain forms), and cancer, e.g. lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate, and rectal cancer, as well as hematopoietic malignancies (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes. and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinoma, aerial ectopic contractionsbeats, AIDS dementia complications, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, antireceptor hypersensitivity reaction, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (persistent or paroxysmal), atrial flutter, atrioventricular block, B-cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome), cardiac tumors, cardiomyopathy, inflammatory response to cardiopulmonary bypass, cartilage graft rejection, cerebellar cortical degeneration, cerebellar disease, chaotic or multifocal atrial tachycardia, chemotherapy-associated disorders, chronic myeloid leukemia (CML), chronic alcoholism, chronic inflammatory pathology, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal cancer, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture-negative septic cystic fibrosis, cytokine therapy-associated disorders, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes,mellitus), diabetic arteriosclerosis, diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders in the basal ganglia, Down's syndrome in middle age, drug-induced movement disorders induced by drugs that block central nervous system dopamine receptors, drug hypersensitivity, eczema, encephalomyelitis, endocarditis, endocrine disorders, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymus graft rejection, Friedreich's ataxia, functional peripheral arterial disease, fungal sepsis, gas gangrene , gastric ulcer, glomerulonephritis, transplant rejection of any organ or tissue, gram-negative sepsis, gram-positive sepsis, granulomas due to endobiotics, Hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, cardiac transplant rejection, hemochromatosis, dialysis, hemolytic uraemic syndrome / thrombolytic thrombocytopenic purpura, bleeding, hepatitis A, His bundle arrhythmia, HIV infection / HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorder, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorder disorders), evaluation of the hypothalamic-pituitary-adrenal axis, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, asthenia, childhood spinal muscular atrophy, aortitis, influenza A, exposure to ionizing radiation, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionellosis, leishmaniasis, leprosy, corticospinal system lesions, lipedema, liver transplants Rejection, Lymphoedema, Malaria, Malignant Lymphoma, Malignant Histiocytosis, Malignant Melanoma, Meningitis, Meningococcemia, Metabolic / Idiopathic, Migraine, Multisystem Mitochondrial Disease, Mixed Connective Tissue Disease, Monoclonal Gammopathy, Multiple Myeloma, Multiple System Atrophy (Mencel's Disease, Dejerine-Thomas Syndrome, Shy-Dregger Syndrome, and Machado-Joseph Disease), Myasthenia Gravis, Mycobacterium avium Intracellulareintracellulare, Mycobacterium tuberculosis, Myelodysplastic syndrome, Myocardial infarction, Myocardial ischemic disorder, Nasopharyngeal carcinoma, Chronic lung disease of the newborn, Nephritis, Nephrosis, Neurodegenerative disease, Neurogenic muscular atrophy type I, Neutropenic fever, Non-Hodgkin's lymphoma, Occlusion of abdominal aorta and its branches, Arterial occlusive disease, Muromonab-CD3 treatment, Orchitis / epididymitis, Orchitis / vasectomy reconstruction, Organomegaly, Osteoporosis, Pancreatic graft rejection, Pancreatic cancer, Paraneoplastic syndrome / tumor hypercalcemia, Parathyroid graft rejection, Pelvic inflammatory disease, Perennial rhinitis, Pericardial disease, Peripheral arteriosclerosis, Peripheral vascular disease, Peritonitis, Pernicious anemia, Pneumocystis pneumonia, POEMS syndrome (Polyneuropathy, Organomegaly, Endocrine Disorders, Monoclonal Gammopathy, and Skin Anomalies Syndrome), Post perfusion syndrome syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and Raynaud's disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renal vascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, senile chorea, senile dementia with Lewy bodies, seronegative arthropathy, shock, sickle cell anemia, skin allograft rejection, skin anomaly syndrome, small bowel graft rejection, solid tumors, specific arrhythmiasarrythmias, spinal ataxia, spinocerebellar degeneration, streptococcal myositis, structural lesions in the cerebellum, subacute sclerosing panencephalitis, collapse, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory response syndrome, systemic-onset juvenile rheumatoid arthritis, T-cell or FAB acute lymphoblastic leukemia, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxicity, transplantation, trauma / bleeding, type III hypersensitivity reactions, type IV hypersensitivity reactions, unstable angina, uremia, urinary Sepsis, urticaria, valvular heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis / aseptic meningitis, viral-associated hemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection in any organ or tissue, acute pain, age-associated memory impairment (AAMI), anxiety, attention deficit disorder, generalized attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, Central neuropathic pain syndromes, central post-stroke pain, chemotherapy-induced neuropathy, cognitive and functional impairment in psychiatric disorders, cognitive impairment associated with ageing and neurodegeneration, cognitive impairment associated with diabetes, cognitive impairment associated with schizophrenia, complex regional pain syndrome, cognitive decline in Alzheimer's disease and associated dementia, attention deficit, dementia, dementia associated with Down's syndrome, dementia associated with Lewy body disease, depression associated with Cushing's syndrome, reduced central nervous system function associated with traumatic brain injury, disorders associated with memory impairment, dizziness, substance abuse, epilepsy, HIV sensory neuropathy, Huntington's disease, hyperalgesia including neuropathic pain, inflammation and inflammatory disorders, inflammatory hyperalgesia, inflammatory pain, insulin resistance syndrome, jet lag, circulatory insufficiency, learning disabilities, major depressive disorder, medullary thyroid cancer, Meniere's disease, metabolic syndrome, mild cognitive impairment, dysthymia, motion sickness, multiple sclerosis pain, narcolepsy, angiogenesis and circulatory insufficiency associated with skin grafts Neovascularization requirement (need for new blood vessel growth associated with vascularization of skin grafts and lack of circulation), Neovascularization requirement associated with wound healing, Neuropathic pain, Neuropathy, Neuropathy secondary to tumour infiltration, Non-inflammatory pain, Obesity, Obsessive-compulsive disorder, Painful diabetic neuropathy, Panic disorder, Parkinson's disease pain, Pathological sleepiness, Phantom limb pain, Pick's disease, Polycystic ovary syndrome, Post traumatic stress disorder, Post herpetic neuralgia, Post mastectomy pain, Post operative pain, Hypochondriacal depression, Schizoaffective disorder, Seizures, Senile dementia, Sepsis syndrome, Sleep disorder, Smoking cessation, Spinal cord injury pain, Steroid-induced acute psychosis, Subcategories of neuropathic pain including peripheral neuropathic pain syndromes, Substance abuse including alcohol abuse, Syndrome X, Tourette's syndrome, Treatment resistant depression, Trigeminal neuralgia, Type II diabetes mellitus, Vertigo, and Vestibular disorders. Pharmaceutical Compositions and Routes of Administration

[0118] The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0119] The compounds disclosed herein may be administered to a subject orally, topically, or parenterally in conventional formulations, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared by commonly used methods using conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and / or other suitable agents. starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavors (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinyl pyrroliclone, or aluminum stearate), dispersing agents (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and wax bases (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula I in the pharmaceutical composition may be that which produces the desired effect; for example, about 0.005 mg to about 10 mg per kg of subject body weight for unit doses in oral and parenteral administration.

[0120] The dose of the compound of formula I to be administered to a subject may vary over a rather wide range and be left to the discretion of the physician. In general, the compounds disclosed herein may be administered at a dose of about 0.001 mg to about 10 mg per kg of subject's body weight, 1 to 4 times per day, although the dose may vary appropriately depending on the age, body weight, and health condition of the subject, as well as the mode of administration. In one embodiment, the dose is about 0.001 mg to about 5 mg per kg of subject's body weight, about 0.01 mg to about 5 mg per kg of subject's body weight, about 0.05 mg to about 1 mg per kg of subject's body weight, about 0.1 mg to about 0.75 mg per kg of subject's body weight, or about 0.25 mg to about 0.5 mg per kg of subject's body weight. In one embodiment, one dose is given per day. The dosage of the compound of formula I in any given case will depend on factors such as the solubility of the active ingredient, the dosage form used, and the route of administration.

[0121] In some embodiments, the compound of formula I is administered to a subject at a dose of about 0.001 mg to about 750 mg, about 0.1 mg to about 375 mg, about 0.1 mg to about 150 mg, about 0.1 mg to about 75 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, or about 0.1 mg to about 10 mg per day.

[0122] In other embodiments, provided herein are unit dose formulations comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of formula I.

[0123] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg or 100 mg of a compound of formula I.

[0124] In other embodiments, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound of formula I.

[0125] Compounds of formula I may be administered once, twice, three times, four or more times per day, In certain embodiments, doses of 100 mg or less are administered as a single dose per day, and doses of more than 100 mg are administered twice per day in an amount equal to half the total daily dose.

[0126] The compound of formula I can be administered orally for convenience. In one embodiment, when administered orally, the compound of formula I is administered with food and water. In another embodiment, the compound of formula I is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0127] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, intrarectally, to a mucous membrane, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the physician and may depend in part on the site of the condition.

[0128] In one embodiment, provided herein is a capsule comprising a compound of formula I, the capsule containing no additional carriers, excipients, or vehicles.

[0129] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula I and a pharma- ceutically acceptable carrier or vehicle, where the pharma- ceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0130] The compositions may be in the form of tablets, chewable tablets, capsules, liquids, injections, lozenges, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosage unit, such as a single tablet, a single capsule, or a suitable amount of liquid. In one embodiment, the liquid is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to methods well known in pharmaceutical chemistry. Capsules may be prepared by mixing a compound of formula I with a suitable carrier or diluent and filling a capsule with a suitable amount of the mixture. Examples of typical carriers and diluents include, but are not limited to, inert powdered substances such as starch, which come in various types, powdered cellulose, especially crystalline cellulose and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours and similar edible powders, and the like.

[0131] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually contain not only the compound, but also diluents, binders, lubricants, and disintegrants. Typical diluents include various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include materials such as starch, gelatin, and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, etc. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0132] Lubricants may be necessary in tablet formulations to prevent colorants from sticking to the tablet and punch. The lubricants may be selected from slippery solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon absorption of water to break the tablet and release the compound. Disintegrants include starch, clay, cellulose, algins, and gums. More specifically, by way of example, corn starch, potato starch, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, citrus syrup, and carboxymethylcellulose may be used as well as sodium lauryl sulfate. Tablets may be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the dissolution properties of the tablet. The composition may also be formulated as a chewable tablet, for example, using substances such as mannitol in the formulation process.

[0133] When it is desired to administer the compound of formula I as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, and the melting point can be raised slightly by adding waxes. Water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0134] The effect of the compound of formula I can be delayed or sustained by suitable formulation. For example, pellets of the compound of formula I that dissolve slowly can be prepared and included in tablets or capsules, or incorporated as a slow-release implantable device. The technique also includes preparing pellets with different dissolution rates and filling capsules with a mixture of the pellets. The tablet or capsule can be coated with a film that prevents dissolution for a foreseeable period of time. Even for injections, the duration of effect can be extended by dissolving or suspending the compound of formula I in an oily or emulsion vehicle that has the effect of delaying dispersion in the serum. EXAMPLES

[0135] The following examples are presented by way of non-limiting illustration. Compounds are named using an automatic naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names based on chemical structures, with stereochemistry following the Cahn-Ingold-Prelog precedence rules. Those skilled in the art may modify the procedures described in the examples shown to obtain the desired products.

[0136] Salts of the compounds described herein may be prepared by standard methods such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification or by stirring the product after chromatographic purification with an acidic solution (e.g., hydrochloric acid).

[0137] As used in the specific chemical structures provided in the Examples below, the designation "orl" at an atom indicates that the absolute stereochemistry of the indicated atom has not been determined.

[0138] The following abbreviations may be relevant to this application: List of abbreviations TIFF2024546678000042.tif212160 Synthesis Examples (Example S1. Synthesis of 1-(5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (1)) [ka]

[0139] Synthesis of 5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (1.2 g, 8.11 mmol, 1.00 equiv.) in THF (15.0 mL) was added (3-chloro-4-methyl-phenyl)methanol (1.5 g, 9.62 mmol, 1.20 equiv.) and PPh3 (3 mg, 12.2 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 10 min, followed by the addition of DIAD (0.8 mL, 12.2 mmol, 1.50 equiv.). The resulting mixture was purged with nitrogen for 5 min and stirred overnight. The reaction was confirmed to be complete by LCMS. The mixture was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (2.0 g, 86%) as a yellow solid. LCMS (ESI, m / z): 287 [M+H] + .

[0140] Synthesis of methyl 1-(5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (3.1 g, 54.3 mmol, 4.10 equiv.) in methanol (15.0 mL) was added 2M ZnCl2 / THF (14.0 mL, 27.1 mmol, 2.00 equiv.) and the mixture was stirred at room temperature for 10 min. 5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (3.9 g, 19.9 mmol, 1.50 equiv.) and methyl azetidine-3-carboxylate hydrochloride (2.8 g, 13.3 mmol, 1.00 equiv.) were added. The resulting mixture was stirred at 70° C. overnight. The reaction was complete by LCMS. The mixture was purified by silica gel flash chromatography (EA) to give methyl 1-(5-((3-chloro-4-methylbenzyl)-oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (3.4 g, 8.83 mmol, 66%) as a pale yellow oil. LCMS (ESI, m / z): 386 [M+H] + .

[0141] Synthesis of 1-(5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (600 mg, 1.55 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·HO (132 mg, 3.14 mmol, 2.00 equiv.). The resulting mixture was stirred overnight. The reaction was confirmed to be complete by LCMS. The crude product was purified by Prep-HPLC (column: Sunfire prep C18 column, 30 * Purification by 150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 39% B (7 min); 254 / 210 nm; RT: 7.32 min) afforded 11-(5-((3-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (106 mg, 18%) as an off-white solid.

[0142] LCMS(ESI,m / z):372[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 nm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2.00 min), hold at 95% (0.70 min), 95% B to 5% B (0.05 min); 220 nm; RT: 1.584 min.

[0143] 1H NMR (400 MHz, methanol-d4) δ 7.45 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.34-7.23 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.5, 2.4 Hz, 1H), 5.10 (s, 2H), 4.50-4.41 (m, 2H), 4.37-4.28 (m, 2H), 3.71-3.62 (m, 1H), 3.16 (dt, J = 16.5, 8.2 Hz, 1H), 2.97 (ddd, J = 16.8, 9.3, 2.8Hz, 1H), 2.52 (dq, J = 16.6, 8.4 Hz, 1H), 2.37 (s, 3H), 2.20 (dt, J = 14.1, 5.4 Hz, 1H). (Example S2. Synthesis of 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (2)) [ka]

[0144] Synthesis of 5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (350 mg, 2.36 mmol, 1.00 equiv.) and 4-(bromomethyl)-1-methyl-2-(trifluoromethyl)benzene (657 mg, 2.60 mmol, 1.1 equiv.) in MeCN (10.0 mL) was added K2CO3 (978 mg, 7.09 mmol, 3.00 equiv.). The flask was evacuated and purged with nitrogen. The mixture was stirred overnight at 50° C. under nitrogen atmosphere. The reaction was complete by LCMS. The resulting solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate / petroleum ether (1:6) to give 5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one (420 mg, 55%) as a yellow solid. LCMS(ESI,m / z):321[M+H] + .

[0145] Synthesis of methyl 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (330 mg, 5.24 mmol, 4.00 equiv.) in methanol (10.0 mL) was added 2M ZnCl2 / THF (1.4 mL, 2.62 mmol, 2.00 equiv.) and stirred for 10 minutes. To the resulting mixture was added methyl azetidine-3-carboxylate hydrochloride (298 mg, 1.97 mmol, 1.50 equiv.) and 5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one (420 mg, 1.31 mmol, 1.00 equiv.). The flask was evacuated and purged with nitrogen. The mixture was stirred overnight at 70° C. under a nitrogen atmosphere. The reaction was complete by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography in dichloromethane / methanol (25:1) to give methyl 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (439 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 420 [M+H] + .

[0146] Synthesis of 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (350 mg, 0.830 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·H2O (70 mg, 1.67 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was completed by LCMS. The reaction was diluted with 10 mL of water and adjusted to pH 2-3 with 4 M HCl, then extracted with EA. The mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30 * Purification by 150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 39% B (7 min); 254 / 210 nm; RT: 7.00 min) afforded 1-(5-((4-methyl-3-(trifluoromethyl)benzyl)-oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (165 mg, 99%) as an off-white solid.

[0147] LCMS(ESI,m / z):406[M+H] + Analytical conditions: Column: Poroshell HPH-C18, 3.0 * 50 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.00 min), hold 100% B (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.629 min.

[0148] 1H NMR (400 MHz, methanol-d4) δ 7.68 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H), 5.15 (s, 2H), 4.84 (s, 1H), 4.70-4.15 (m, 4H), 3.64 (s, 1H), 3.13 (dt, J = 16.6, 8.2 Hz, 1H), 2.95 (ddd, J = 16.9, 9.4, 2.9 Hz, 1H), 2.57-2.43 (m, 4H), 2.15 (m, 1H). (Example S3. Synthesis of 1-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (3)) [ka]

[0149] Synthesis of 5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of (2-chloro-4-methyl-phenyl)methanol (500 mg, 3.19 mmol, 1.00 equiv.) in THF (30 mL), 5-hydroxyindan-1-one (520 mg, 3.51 mmol, 1.10 equiv.) and PPh3 (1256 mg, 4.79 mmol, 1.50 equiv.) were added. Then, DIAD (0.9 mL, 4.79 mmol, 1.50 equiv.) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The mixture was concentrated and purified by flash chromatography (PE:EA=5:1) to give 5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (800 mg, 87%). LCMS (ESI, m / z): 287 [M+H] + .

[0150] Synthesis of methyl 1-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (439 mg, 6.97 mmol, 4.00 equiv) in methanol (20 mL) was added ZnCl2 (1.7 mL, 3.49 mmol, 2.00 equiv). Then 5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (500 mg, 1.74 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (528 mg, 3.49 mmol, 2.00 equiv) were added. The mixture was stirred at 70° C. overnight. LCMS confirmed the desired product. The mixture was diluted with water (5 mL) and extracted with EA (2×5 mL). The organic layers were combined and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 1-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (300 mg, 44%). LCMS (ESI, m / z): 386 [M+H] + .

[0151] Synthesis of 1-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (300 mg, 0.780 mmol, 1.00 equiv.) in THF (5 mL) and water (0.5 mL) was added LiOH·HO (65 mg, 1.56 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. LCMS confirmed the formation of the desired product. The reaction was diluted with 10 mL of water and the pH was adjusted to 6 with 4 M hydrochloric acid. The solution was concentrated under reduced pressure and the residue was analyzed by Prep-HPLC (column: YMC-Actus Triart C18 ExRS, 30 * 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% to 50% mobile phase B (7 min); 254 / 210 nm; RT: 5.65 min) to give 11-(5-((2-chloro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (111 mg, 38%) as an off-white solid.

[0152] LCMS(ESI,m / z):372[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2.00 min), maintain 95% B (0.70 min), 95% B to 5% B (0.05 min); 220 nm; RT: 1.603 min.

[0153] 1H NMR (400 MHz, methanol-d4) δ 7.47 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.13 (d, J = 7.9 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H), 4.87 (s, 1H), 4.70-4.20 (m, 4H), 4.32 (s, 2H), 3.65 (s, 1H), 3.14 (dt, J = 16.6, 8.1 Hz, 1H), 3.01-2.90 (m, 1H), 2.51 (dq, J = 16.3, 8.5 Hz, 1H), 2.33 (s, 3H), 2.23-2.13 (m, 1H). (Example S4. Synthesis of 1-(5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (4)) [ka]

[0154] Synthesis of 5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (270 mg, 1.82 mmol, 1.00 equiv) and 1-(bromomethyl)-2-fluoro-4-methyl-benzene (407 mg, 2.00 mmol, 1.10 equiv) in MeCN (10.0 mL) was added K2CO3 (754 mg, 5.47 mmol, 3.00 equiv). The flask was evacuated and purged with nitrogen. The mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. LCMS confirmed the reaction was complete. The resulting solution was diluted with EA and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography in ethyl acetate / petroleum ether (1:1) to give 5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (393 mg, 80%). LCMS (ESI, m / z): 271 [M+H] + .

[0155] Synthesis of methyl 1-(5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (279 mg, 4.44 mmol, 4.00 equiv.) in methanol (10.0 mL), 2M ZnCl2 / THF (1.2 mL, 2.22 mmol, 2.00 equiv.) was added and stirred at room temperature for 10 minutes. To the resulting mixture, methyl azetidine-3-carboxylate hydrochloride (252 mg, 1.66 mmol, 1.50 equiv.) and 5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (300 mg, 1.11 mmol, 1.00 equiv.) were added. The mixture was stirred overnight at 70° C. under a nitrogen atmosphere. The reaction was complete by LCMS. The resulting mixture was concentrated and purified by silica gel flash chromatography in dichloromethane / methanol (25:1) to give methyl 1-(5-((2-fluoro-4-methyl-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (328 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 370 [M+H] + .

[0156] Synthesis of 1-(5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (300 mg, 0.810 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·HO (68 mg, 1.62 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was confirmed to be complete by LCMS. The reaction was diluted with 10 mL of water and the pH was adjusted to 2 with 4 M hydrochloric acid. The resulting solution was concentrated under reduced pressure and purified by Prep-HPLC (column: Sunfire prep C18 column, 30 *Purification by 150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 10% to 39% (7 min); 254 / 210 nm; RT: 7.42 min) gave 1-(5-((2-fluoro-4-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (138 mg, 95%) as an off-white solid.

[0157] LCMS(ESI,m / z):356[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (water / 0.05% TFA), Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 15% to 100% B (2.00 min), maintain 100% B (0.70 min), 100% to 5% B (0.05 min); 210 nm; RT: 1.524 min.

[0158] 1 H NMR (400 MHz, methanol-d4) δ 7.46 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.02-6.89 (m, 4H), 5.11 (s, 2H), 4.83 (s, 1H), 4.50-4.00 (br, 4H), 3.63 (s, 1H), 3.12 (dt, J = 16.5, 8.2 Hz, 1H), 2.94 (ddd, J = 16.8, 9.3, 2.8 Hz, 1H), 2.50 (dq, J = 16.8, 8.5 Hz, 1H), 2.34 (s, 3H), 2.20 (m, 1H). (Example S5. Synthesis of 1-(5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (5)) [ka]

[0159] Synthesis of methyl 4-isopropoxy-3-(trifluoromethyl)benzoate [ka] A 200 mL round bottom flask was charged with a solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (600 mg, 2.42 mmol, 1.00 equiv) in DCM (8.0 mL) and methanol (2.0 mL). Diazomethyl(trimethyl)silane (1.8 mL, 3.63 mmol, 1.50 equiv) was then added dropwise over 3 min at 0° C. under nitrogen atmosphere. The pale yellow solution was allowed to warm to room temperature over 15 min. The reaction was stirred at room temperature for 1.5 h. Excess diazomethyl(trimethyl)silane was quenched by slow addition of acetic acid (0.5 ml) at room temperature until the yellow color disappeared. The reaction was concentrated under vacuum and diluted with 20.0 mL of EA. The organic layer was washed with 10 mL of saturated NaHCO3 solution and 10 mL of saturated brine, dried over sodium sulfate, and concentrated to give methyl 4-isopropoxy-3-(trifluoromethyl)benzoate (620 mg, 97%) (crude product) as a yellow oil. LCMS (ESI, m / z): 263 [M+H] + .

[0160] Synthesis of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol [ka] To a solution of methyl 4-isopropoxy-3-(trifluoromethyl)benzoate (693 mg, 2.64 mmol, 1.00 equiv) in THF (5.0 mL) and ethanol (0.5 mL) was added LiBH4 (0.2 mL, 7.93 mmol, 3.00 equiv). The reaction was stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. The mixture was diluted with 10 mL of water and extracted with EA (1×10 mL). The organic layer was washed with 3 mL of HCl (0.5 mol / L). The organic layer was dried over anhydrous NaSO4. The solid was filtered off and the filtrate was concentrated under reduced pressure to give (4-iso-propoxy-3-(trifluoromethyl)phenyl)methanol (553 mg, 89%) as a yellow oil. LCMS (ESI, m / z): 235 [M+H] + .

[0161] Synthesis of 5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] A 50 mL three-neck round bottom flask was charged with a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (610 mg, 2.60 mmol, 1.00 equiv) and 5-hydroxy-indan-1-one (501 mg, 3.39 mmol, 1.30 equiv) in THF (10.0 mL). Under nitrogen atmosphere, PPh3 (1024 mg, 3.91 mmol, 1.50 equiv) in THF was added. The reaction was stirred for 20 min. Then, DIAD (789 mg, 3.91 mmol, 1.50 equiv) in THF was added dropwise over 15 min at 0° C. with stirring. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was complete by LCMS. The reaction was quenched with 50 mL water and extracted with 1×50 mL EA. The organic layer was dried over anhydrous Na2SO4. The solid was filtered off, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one (690 mg, 72%) as a yellow oil. LCMS (ESI, m / z): 365 [M+H] + .

[0162] Synthesis of methyl 1-(5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (476 mg, 7.57 mmol, 3.00 equiv) in MeOH (10.0 mL) was added ZnCl2 (2.0 mL, 3.79 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 15 min. Then, 5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one (690 mg, 1.89 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate (327 mg, 2.84 mmol, 1.50 equiv) were added. The reaction mixture was stirred at 60° C. for 12 h. The reaction was complete by LCMS. The resulting solution was quenched with 30 mL of water and extracted with 1×30 mL of EA. The organic layer was dried over anhydrous Na2SO4 and the solid was filtered off. The filtrate was concentrated under reduced pressure to give methyl 1-(5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (1.0 g, 118%) (crude product) as a yellow oil. LCMS (ESI, m / z): 464 [M+H] + .

[0163] Synthesis of 1-(5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((4-isopropoxy-3-(trifluoromethyl)-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (300 mg, 0.650 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·H2O (81 mg, 1.94 mmol, 3.00 equiv.). The reaction was stirred at room temperature for 2 h. Completion of the reaction was confirmed by LCMS. The mixture was concentrated under vacuum and diluted with water. The pH value of the solution was adjusted to 5-6 with 4 M hydrochloric acid. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 52% B (7 min); 254 / 210 nm; RT: 7.77 min) to give 1-(5-((4-isopropoxy-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (110 mg, 37%) as a white solid.

[0164] LCMS(ESI,m / z):450[M+H] + Analytical conditions: Column: Titank C18, 3.0 * 50mm, 3.0μm; Mobile phase A: water (5mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B (1.80 min), 60% B to 95% B (0.45 min), hold at 95% (0.80 min), 95% B to 10% B (0.15 min); 224nm; RT: 1.443 min.

[0165] 1 H NMR (400 MHz, methanol-d4) δ 7.61 (d, J = 9.5 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 2.45 (m, 1H), 2.15 (m, 1H), 1.35 (s, 6H). (Example S6. Synthesis of 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (6)) [ka]

[0166] Synthesis of methyl 3-cyano-4-isopropoxy-benzoate [ka] To a solution of 3-cyano-4-isopropoxy-benzoic acid (600 mg, 2.92 mmol, 1.00 equiv) in MeOH (2.0 mL) and DCM (8.0 mL) was added diazomethyl(trimethyl)silane (1.9 mL, 3.80 mmol, 1.30 equiv) dropwise at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was completed by LCMS. AcOH (1.5 mL) was added slowly to the reaction until no more bubbles were generated. The resulting solution was concentrated in vacuo and extracted with EA (3×50 mL). The organic layer was washed with NaHCO3 solution and saturated brine. The combined organic layers were dried over anhydrous Na2SO4. The solid was filtered off and the filtrate was concentrated in vacuo to give methyl 3-cyano-4-isopropoxy-benzoate (610 mg, 95%) as a yellow oil. LCMS(ESI,m / z):220[M+H] + .

[0167] Synthesis of 5-(hydroxymethyl)-2-isopropoxy-benzonitrile [ka] To a solution of methyl 3-cyano-4-isopropoxy-benzonate (570 mg, 2.60 mmol, 1.00 equiv) in THF (20.0 mL) and EtOH (2.0 mL) was added LiBH4 (170 mg, 7.80 mmol, 3.00 equiv). The reaction was stirred at room temperature for 16 h. The reaction was complete by TLC. The reaction mixture was quenched with ice water (40 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure to give 5-(hydroxymethyl)-2-isopropoxy-benzonitrile (480 mg, 97%) as a yellow oil. LCMS (ESI, m / z): 192 [M+H] + .

[0168] Synthesis of 2-isopropoxy-5-(((1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)methyl-benzonitrile [ka] To a solution of 5-(hydroxymethyl)-2-isopropoxy-benzonitrile (430 mg, 2.25 mmol, 1.00 equiv) in THF (30.0 mL) was added 5-hydroxyindan-1-one (400 mg, 2.70 mmol, 1.20 equiv). To the above mixture was added PPh3 (885 mg, 3.37 mmol, 1.50 equiv) at 0° C. and the reaction was stirred at room temperature for 0.5 h. Then DIAD (0.66 mL, 3.37 mmol, 1.50 equiv) was added dropwise at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was completed by TLC. The mixture was quenched with water (50 mL) and extracted with EA (3×50 mL). The organic layer was washed with saturated brine, concentrated, and purified by silica gel flash chromatography (PE / EA=3 / 1) to give 2-isopropoxy-5-(((1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (440 mg, 61%) as a yellow solid. LCMS (ESI, m / z): 322 [M+H] + .

[0169] Synthesis of methyl 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (297 mg, 4.73 mmol, 4.00 equiv) in MeOH (10.0 mL) was added ZnCl2 (2M / THF) (1.2 mL, 2.36 mmol, 2.00 equiv). The reaction was stirred at room temperature for 15 min. 2-Isopropoxy-5-(((1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (380 mg, 1.18 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (233 mg, 1.54 mmol, 2.00 equiv) were added. The reaction was stirred at 60° C. for 16 h. The reaction was complete by TLC. The mixture was quenched with water (40.0 mL) and extracted with EA (3×50 mL). The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give methyl 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (450 mg, 91%) as a yellow oil. LCMS (ESI, m / z): 421 [M+H] + .

[0170] Synthesis of 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of the compound methyl 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (200 mg, 0.480 mmol, 1.00 equiv.) in THF (5.0 mL) and water (1.0 mL) was added LiOH·HO (80 mg, 1.90 mmol, 4.00 equiv.). The reaction was stirred at room temperature for 1 h. The reaction was confirmed to be complete by LCMS. The reaction was diluted with 10 mL of water. The pH value of the solution was adjusted to 6 with AcOH, and then the solution was concentrated in vacuum. The residue was analyzed by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 17% to 47% (7 min); 254 / 210 nm; RT: 6.48 min) to give 1-(5-((3-cyano-4-isopropoxybenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (101 mg, 52%) as a white solid.

[0171] LCMS(ESI,m / z):407[M+H] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.0 min), maintain 95% B (0.70 min), 100% B to 5% B (0.05 min); 220 nm; RT: 1.520 min.

[0172] 1H NMR (400 MHz, methanol-d4) δ 7.66 (dq, J = 4.5, 2.3 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.5, 2.5 Hz, 1H), 5.10 (s, 2H), 4.83-4.73 (m, 2H), 4.34-4.24 (m, 2H), 4.16 (t, J = 8.7 Hz, 2H), 3.41-3.28 (m, 1H), 3.12 (dt, J = 16.4, 8.2 Hz, 1H), 2.96 (ddd, J = 16.8, 9.2, 3.0 Hz, 1H), 2.47 (dq, J = 15.0, 8.3 Hz, 1H), 2.16 (ddt, J = 14.2, 8.1, 2.8 Hz, 1H), 1.39 (d, J = 6.1 Hz, 6H). (Example S7. Synthesis of 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (7)) [ka]

[0173] Synthesis of 5-((4-bromo-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (600 mg, 4.05 mmol, 1.00 equiv) in MeCN (20.0 mL) was added 4-bromo-1-(bromomethyl)-2-fluoro-benzene (1301 mg, 4.86 mmol, 1.20 equiv) and K2CO3 (1676 mg, 12.1 mmol, 3.00 equiv). The resulting mixture was purged with nitrogen and stirred at 80° C. for 2 h. LCMS confirmed the reaction was complete. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give 5-((4-bromo-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.3 g, 96%) as a brown solid. LCMS (ESI, m / z): 335 [M+H] + .

[0174] Synthesis of 5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-((4-bromo-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (350 mg, 1.04 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was added cyclopropylboronic acid (179 mg, 2.09 mmol, 2.00 equiv), Pd(dppf)Cl2 (170 mg, 0.210 mmol, 0.20 equiv) and K2CO3 (432 mg, 3.13 mmol, 3.00 equiv). The resulting mixture was purged with nitrogen and stirred at 80 °C for 2 h. The reaction was complete by LCMS. The mixture was purified by Prep-TLC (PE:EA=1:1) to give 5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (178 mg, 59%) as an off-white solid. LCMS (ESI, m / z): 297 [M+H] + .

[0175] Synthesis of methyl 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (127 mg, 2.02 mmol, 4.00 equiv) in methanol (5.0 mL) was added 2M ZnCl2 / THF (0.1 mL, 1.01 mmol, 2.00 equiv). The resulting mixture was stirred for 10 min, after which 5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (150 mg, 0.510 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (115 mg, 0.760 mmol, 1.50 equiv) were added. The resulting mixture was purged with nitrogen and stirred at 60 °C overnight. The reaction was complete by LCMS. The mixture was purified by Prep-TLC (MeOH:DCM=1:17) to give methyl 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (144 mg, 71%) as a pale yellow oil. LCMS (ESI, m / z): 396 [M+H] + .

[0176] Synthesis of 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (140 mg, 0.350 mmol, 1.00 equiv.) in THF (5.0 mL) and water (1.0 mL) was added LiOH·H2O (59 mg, 1.42 mmol, 4.00 equiv.). The resulting mixture was stirred overnight. The reaction was complete by LCMS. The reaction was diluted with 10 mL of water. THF was removed under reduced pressure and the aqueous layer was adjusted to pH 2 with 4 M hydrochloric acid. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC ((Column: Sunfire prep C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 39% B (7 min); 254 / 210 nm; RT: 7.12 min) to give 1-(5-((4-cyclopropyl-2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (100 mg, 74%) as an off-white solid.

[0177] LCMS(ESI,m / z):382[M+H] + . Analytical conditions: Column: Shim-pack XR-ODS, 50 mm, 3.0 mm, 2.2 μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: Acetonitrile (0.05% TFA), Flow rate: 1.20 mL / min; Gradient: B 20% to B 60% (2.50 min), B 60% to B 95% (0.50 min), B 95% (0.60 min), B 95% to B 20% (0.10 min); 210 nm; RT: 2.142 min.

[0178] 1H NMR (400 MHz, methanol-d4) δ 7.48-7.46 (d, J = 8.5 Hz, 1H), 7.36-7.32 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.96-6.90 (ddd, J = 12.1, 8.2, 2.1 Hz, 2H), 6.85-6.81 (dd, J = 11.5, 1.8 Hz, 1H), 5.09 (s, 2H), 4.84-4.20 (m, 4H), 3.65 (s, 1H), 3.18-3.10 (dt, J = 16.5, 8.2Hz, 1H), 3.00-2.93 (ddd, J = 16.8, 9.3, 2.8 Hz, 1H), 2.56-2.46 (dq, J = 16.7, 8.4 Hz, 1H), 2.21-2.15 (m, 1H), 1.96-1.90 (m, 1H), 1.01-0.98 (m, 2H), 0.72-0.68 (dt, J = 6.6, 4.6 Hz, 2H). (Example S8. Synthesis of 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (8)) [ka]

[0179] Synthesis of 5-((4-bromo-2-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (500 mg, 3.37 mmol, 1.00 equiv) in MeCN (10.0 mL) was added 4-bromo-1-(bromomethyl)-2-chloro-benzene (1151 mg, 4.05 mmol, 1.20 equiv) and K2CO3 (1398 mg, 10.1 mmol, 3.00 equiv). The resulting mixture was stirred at 80° C. overnight. The solid was filtered off and the filtrate was concentrated and purified by silica gel flash chromatography (PE:EA=1:1) to give the product 5-((4-bromo-2-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 84%) as a yellow solid. LCMS (ESI, m / z): 353 [M+H] + .

[0180] Synthesis of 5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-((4-bromo-2-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (600 mg, 1.71 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) and water (2.0 mL) was added Pd(dppf)Cl2 (278 mg, 0.340 mmol, 2.00 equiv), cyclopropylboronic acid (293 mg, 3.41 mmol, 2.00 equiv) and K2CO3 (707 mg, 5.12 mmol, 3.00 equiv). The mixture was stirred at 80° C. overnight. The reaction was complete by LCMS. The resulting solution was diluted with 20 mL of EA and dried over anhydrous Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to give the product 5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (380 mg, 71%). LCMS (ESI, m / z): 313 [M+H] + .

[0181] Synthesis of methyl 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (306 mg, 4.86 mmol, 4.00 equiv) in methanol (20.0 mL) was added ZnCl2 (1.2 mL, 2.43 mmol, 2.00 equiv). Then, 5-((2-chloro-4-cyclo-propylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (380 mg, 1.21 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate; hydrochloride (368 mg, 2.43 mmol, 2.00 equiv) were added. The mixture was stirred at 60° C. overnight. The mixture was diluted with 20 mL of water and extracted with EA (3×20 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH:DCM=1:20) to give methyl 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (400 mg, 80%). LCMS (ESI, m / z): 412 [M+H] + .

[0182] Synthesis of 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (400 mg, 0.97 mmol, 1.00 equiv.) in THF (5.0 mL) and water (0.5 mL) was added LiOH·HO (81.57 mg, 1.94 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was diluted with 10 mL of water, THF was removed under vacuum, and the pH was adjusted to 6 with 2 M hydrochloric acid. The solution was concentrated under reduced pressure and the residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 ExRS.30 * 250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 25% to 50% (7 min); 254 / 210 nm; RT: 5.70 min) to give 1-(5-((2-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (115 mg, 30%) as an off-white solid.

[0183] LCMS(ESI,m / z): 398[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2 min), hold at 95% (0.70 min), 95% B to 5% B (0.05 min); 220 nm; RT: 1.678 min.

[0184] 1H NMR (400 MHz, methanol-d4) δ 7.47 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.01 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8.5 Hz, 1H), 5.13 (s, 2H), 4.87 (s, 1H), 4.70-4.20 (m, 4H), 3.65 (s, 1H), 3.18-3.08 (m, 1H), 2.95 (dd, J = 16.9, 9.3 Hz, 1H), 2.49 (d, J = 15.2 Hz, 1H), 2.18 (s, 1H), 1.94-1.87 (m, 1H), 1.00 (dd, J = 8.5, 2.6 Hz, 2H), 0.69 (d, J = 5.3 Hz, 2H). (Example S9. Synthesis of 1-(5-((4-cyclopropyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (9)) [ka]

[0185] A solution of methyl 1-(5-((4-cyclopropyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (480 mg, 1.08 mmol, 1.00 equiv.) and LiOH·HO (91 mg, 2.16 mmol, 2.00 equiv.) in water (1.0 mL) and THF (10.0 mL) was stirred at room temperature overnight. The completion of the reaction was confirmed by LCMS. The pH value of the solution was adjusted to 3-5 with 2 M hydrochloric acid. The mixture was purified by Prep-HPLC (Column: XSelect CSH Prep C18 OBD Column, 19 *250 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50% B to 80% B (7 min), 80% B; wavelength: 254 / 210 nm; RT: 6.78) to give 1-(5-((4-cyclo-propyl-3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (136.8 mg, 29%) as an off-white solid.

[0186] LCMS(ESI,m / z):432[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.00 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.704 min.

[0187] 1 H NMR (400 MHz, methanol-d4) δ 7.65 (d, J = 1.9 Hz, 1H), 7.56-7.49 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.92 (dd, J = 8.4, 2.6 Hz, 1H), 5.11 (s, 2H), 4.89-4.83 (s, 1H), 4.57 (t, J = 10.3 Hz, 1H), 4.40-4.20 (m, 3H), 3.72-3.52 (m, 1H), 3.11 (dt, J = 17.1, 8.5 Hz, 1H), 2.98-2.87 (m, 1H), 2.46 (dq, J = 17.4, 8.7 Hz, 1H), 2.21-2.11 (m, 2H), 1.06-0.95 (m, 2H), 0.80-0.72 (m, 2H). (Example S10. Synthesis of 1-(5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (10)) [ka]

[0188] Synthesis of 5-((4-bromo-3-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-hydroxyindan-1-one (1.0 g, 6.75 mmol, 1.00 equiv), (4-bromo-3-chloro-phenyl)methanol (1.5 g, 6.75 mmol, 1.00 equiv), PPh3 (2.7 g, 10.12 mmol, 1.50 equiv) in THF (50.0 mL) was added DIAD (2.0 mL, 10.1 mmol, 1.50 equiv) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was confirmed to be complete by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography (PE / EA=4:1) to give 5-((4-bromo-3-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.2 g, 51%) as a pale yellow solid. LCMS(ESI,m / z):351[M+H] + .

[0189] Synthesis of 5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-((4-bromo-3-chlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 2.84 mmol, 1.00 equiv), cyclopropylboronic acid (0.49 g, 5.69 mmol, 2.00 equiv), K2CO3 (1.2 g, 8.53 mmol, 3.00 equiv) in 1,4-dioxane (50.0 mL) and water (5.0 mL) under nitrogen atmosphere was added Pd(dppf)Cl2 (0.5 g, 0.570 mmol, 0.20 equiv). The reaction mixture was stirred at 80° C. overnight. LCMS confirmed the reaction was complete. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=5:1) to give 5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (475 mg, 50%) as a pale yellow solid. LCMS (ESI, m / z): 313 [M+H] + .

[0190] Synthesis of methyl 1-(5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A solution of NaBH3CN (337 mg, 5.37 mmol, 4.00 equiv) and ZnCl2 / THF (1.5 mL, 2.69 mmol, 2.00 equiv) in methanol (30.0 mL) was added to a 100 mL round bottom flask. To the above solution, 5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-one (420 mg, 1.34 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (305 mg, 2.01 mmol, 1.50 equiv) were added. The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The reaction was quenched with NH4Cl (sat. aq, 80 mL) and extracted with EA (3 x 80 mL). The combined organic layers were dried over Na2SO4. The solid was filtered and the filtrate was concentrated under reduced pressure and then purified by TLC chromatography (DCM:CH2Cl2=30:1) to give methyl 1-(5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (340 mg, 58%) as a pale yellow oil. LCMS (ESI, m / z): 412 [M+H] + .

[0191] Synthesis of 1-(5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((3-chloro-4-cyclopropylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (310 mg, 0.750 mmol, 1.00 equiv.) in THF (20 mL) and water (2 mL) was added LiOH·H2O (63 mg, 1.51 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with 20 mL of water and the THF was removed under vacuum. The aqueous layer was adjusted to pH 2 with 4 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30* 150,5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 15% to B 38% (7 min); 254 / 210 nm; RT: 10.8 min) to give 1-(5-((3-chloro-4-cyclopropyl-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (174.3 mg, 58.092%) as an off-white solid.

[0192] LCMS(ESI,m / z): 398[M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.0 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.686 min.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 7.5-7.46 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.1, 1.8 Hz, 1H), 7.04 (m, 2H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 5.08 (s, 2H), 4.82-4.76 (m, 1H), 4.29 (s, 2H), 4.10 (t, J = 9.2 Hz, 2H), 3.56 (p, J = 8.7 Hz, 2H), 3.25-3.12 (m, 2H), 2.80 (ddd, J = 16.5, 9.1, 2.8Hz, 1H), 2.33 (dq, J = 16.5, 8.5 Hz, 1H), 2.12 (tdd, J = 11.1, 8.4, 5.3 Hz, 2H), 1.07-0.94 (m, 2H), 0.74-0.66 (m, 2H). (Example S11. Synthesis of 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (11)) [ka]

[0194] Synthesis of 5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] A 100 mL round bottom flask was charged with a solution of 5-hydroxyindan-1-one (1.0 g, 6.75 mmol), 1-(bromomethyl)-2-fluoro-benzene (1.53 g, 8.1 mmol) and K2CO3 (2.79 g, 20.25 mmol) in MeCN (40.0 mL). The reaction mixture was stirred overnight at 50° C. under nitrogen atmosphere. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.6 g, 85%) as a yellow solid. LCMS (ESI, m / z): 257 [M+H] + .

[0195] Synthesis of methyl 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A 100 mL round bottom flask was charged with a solution of NaBH3CN (981 mg, 15.6 mmol, 4.00 equiv.), ZnCl2 / THF (4.0 mL, 7.80 mmol, 2.00 equiv.) in methanol (30.0 mL). The mixture was stirred at room temperature for 10 minutes. Then, 5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 3.90 mmol, 1.00 equiv.) and methyl azetidine-3-carboxylate hydrochloride (0.9 g, 5.85 mmol, 1.50 equiv.) were added. The resulting solution was stirred overnight at 70° C. under a nitrogen atmosphere. The mixture was concentrated and purified by silica gel flash chromatography (dichloromethane / methanol=25:1) to give methyl 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (1.0 g, 72%) as a yellow oil. LCMS (ESI, m / z): 356 [M+H] + .

[0196] Synthesis of 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (300 mg, 0.840 mmol, 1.00 equiv) in THF (20.0 mL) and water (2.0 mL) was added LiOH·HO (71 mg, 1.69 mmol, 2.00 equiv). The resulting mixture was stirred overnight. The reaction mixture was diluted with 20 mL of water. THF was removed under reduced pressure and the pH was adjusted to 6 with 2 M hydrochloric acid. The solid was collected by filtration and recrystallized from water (3 mL) to give 1-(5-((2-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (105 mg, 36%) as an off-white solid.

[0197] LCMS(ESI,m / z): 342[M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.00 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min) at 210 nm; Rt: 1.433 min.

[0198] 1 H NMR (400 MHz, methanol-d4) δ 7.56-7.44 (m, 2H), 7.38 (tdd, J = 7.5, 5.3, 1.8 Hz, 1H), 7.20-7.15 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.5, 2.4 Hz, 1H), 5.18 (s, 2H), 4.80 (dd, J = 7.7, 2.2 Hz, 1H), 4.38-4.27 (m, 2H), 4.19 (dd, J = 10.1, 8.0 Hz, 2H), 3.43-3.34 (m, 1H), 3.14 (dt, J = 16.6, 8.3 Hz, 1H), 2.96 (ddd, J = 16.7, 9.2, 2.9 Hz, 1H), 2.45 (ddt, J = 16.0, 9.3, 8.0 Hz, 1H), 2.18 (ddt, J = 14.7, 8.0, 2.7 Hz, 1H). (Example S12. Synthesis of 1-(5-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (12)) [ka]

[0199] To a stirred solution of methyl 1-(5-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (750 mg, 2.11 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·HO (133 mg, 3.17 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 2 h. The reaction was diluted with 10 mL of water and the pH was adjusted to 2 with 4 M hydrochloric acid. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 ExRS.30 * 250, 5 μm; mobile phase A: water (0.05 HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 25% to 50% (7 min); 254 / 210 nm; RT: 5.90 min) to give 1-(5-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (175 mg, 24%) as an off-white solid.

[0200] LCMS(ESI,m / z):342[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA), Flow rate: 1.20 mL / min; Gradient: 5% B to 55% B (2.80 min), 55% B to 95% B (0.40 min), hold at 95% B (0.50 min), 95% B to 10% B (0.10 min); 210 nm; RT: 2.440 min.

[0201] 1H NMR (400 MHz, methanol-d4) δ 7.47 (d, J = 8.4 Hz, 1H), 7.37 (td, J = 8.0, 5.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.19 (dd, J = 9.5, 2.6 Hz, 1H), 7.10-7.01 (m, 2H), 6.97 (dd, J = 8.5, 2.5 Hz, 1H), 5.13 (s, 2H), 4.70-(br, 4H), 3.67 (s, 1H), 3.15 (dt, J = 16.6, 8.2 Hz, 1H), 2.95 (m, 1H), 2.52 (dq, J = 16.3, 8.4 Hz, 1H), 2.15 (m, 1H). (Example S13. Synthesis of 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (13)) [ka]

[0202] Synthesis of 5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (1.0 g, 6.75 mmol, 1.00 equiv.) and 1-(bromomethyl)-4-fluoro-benzene (1.4 g, 7.42 mmol, 1.10 equiv.) in MeCN (20.0 mL) was added K2CO3 (2.8 g, 20.3 mmol, 3.00 equiv.). The flask was evacuated and flushed with nitrogen five times. The mixture was stirred overnight at 50° C. under nitrogen atmosphere. LCMS confirmed the reaction was complete. The resulting solution was diluted with 20 mL of EA. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA:PE=1:3) to give 5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.5 g, 86.72%) as a yellow solid. LCMS(ESI,m / z):256[M+H] + .

[0203] Synthesis of methyl 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (492 mg, 7.80 mmol, 4.00 equiv) in methanol (10.0 mL) was added 2M ZnCl2 / THF (2.0 mL, 3.90 mmol, 2.00 equiv) and the mixture was stirred for 10 minutes followed by the addition of methyl azetidine-3-carboxylate hydrochloride (443.64 mg, 2.93 mmol, 1.50 equiv) and 5-((4-fluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (500 mg, 1.95 mmol, 1.00 equiv). The reaction was stirred overnight at 70° C. The reaction was complete by LCMS. The resulting mixture was concentrated and purified by silica gel flash chromatography with dichloromethane / methanol (25:1) to give methyl 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate (600 mg, 87%) as a yellow solid. LCMS (ESI, m / z): 356 [M+H]+ .

[0204] Synthesis of 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (600 mg, 1.69 mmol, 1.00 equiv) in THF (10.0 mL) and water (1.0 mL) was added LiOH·HO (141.81 mg, 3.38 mmol, 2.00 equiv). The mixture was stirred at room temperature overnight. The reaction was diluted with 10 mL of water and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The solid was collected by filtration to give 1-(5-((4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (164.3 mg, 28%) as an off-white solid.

[0205] LCMS(ESI,m / z):342[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2 min), maintain 100% B (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.458 min.

[0206] 1H NMR (400 MHz, methanol-d4) δ 7.50-7.41 (m, 3H), 7.16-7.06 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 5.07 (s, 2H), 4.75 (dd, J = 7.7, 2.2 Hz, 1H), 4.37-4.26 (m, 2H), 4.18-4.13 (dd, J = 10.2, 7.7 Hz, 2H), 3.35 (m, 1H), 3.15-3.07 (dt, J = 16.5, 8.2 Hz, 1H), 2.95-2.88 (ddd, J = 16.7, 9.3, 2.9 Hz, 1H), 2.49-2.43 (m, 1H), 2.18-2.13 (ddt, J = 14.3, 8.1, 2.7 Hz, 1H). (Example S14. Synthesis of 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (14)) [ka]

[0207] Synthesis of 5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (1000 mg, 6.75 mmol, 1.00 equiv.) in THF (30.0 mL) was added (2,4-difluorophenyl)methanol (1167 mg, 8.10 mmol, 1.20 equiv.), PPh3 (2665 mg, 10.2 mmol, 1.50 equiv.) and DIAD (2047 mg, 10.1 mmol, 1.50 equiv.). The resulting mixture was purged with nitrogen and stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((2,4-difluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.47 g, 80%) as a yellow solid. LCMS (ESI, m / z): 275 [M+H] + .

[0208] Synthesis of methyl 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate [ka] To a solution of NaBH3CN (559 mg, 8.87 mmol, 4.00 equiv) in MeOH (20.0 mL) was added 2M ZnCl2 / THF (2.1 mL, 4.43 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 10 min, followed by the addition of 5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (600 mg, 2.19 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (497 mg, 3.28 mmol, 1.50 equiv). The reaction was flushed with nitrogen and stirred at 70 °C overnight. The reaction was quenched with 20 mL of saturated NH4Cl solution and extracted with EA (3 x 30 mL). The organic layers were combined and dried over Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel TLC chromatography (100% EA) to give methyl 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (192 mg, 23%) as a yellow solid. LCMS (ESI, m / z): 374 [M+H] + .

[0209] Synthesis of 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (192 mg, 0.510 mmol, 1.00 equiv.) in THF (10.0 mL) and water (1.0 mL) was added LiOH·HO (43 mg, 1.03 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was diluted with 10 mL of water. THF was removed under reduced pressure, and the pH of the aqueous layer was adjusted to 3 with 4 M hydrochloric acid. The solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Sunfire prep C18 column, 30 *150,5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 15% to 38% (7 min); 254 / 210 nm; RT: 9.8 min) to give 1-(5-((2,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (78 mg, 41%) as an off-white solid.

[0210] LCMS(ESI,m / z):360[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 60% B (3 min), 60% B to 95% B (0.30 min), hold at 95% (0.40 min), 95% B to 5% B (0.10 min); 220 nm; RT: 2.355 min.

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 10.61 (s, 1H), 7.61 (td, J = 8.5, 6.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (td, J = 9.9, 2.6 Hz, 1H), 7.18- 7.09 (m, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.3, 2.4 Hz, 1H), 5.13 (s, 2H), 4.82 (s, 1H), 4.70-4.10 (m, 4H), 3.55 (d, J = 9.6 Hz, 1H), 3.14-3.03 (m, 1H), 2.84 (dd, J = 16.7, 9.1 Hz, 1H), 2.41-2.33 (m, 1H), 2.13-2.02 (m, 1H). (Example S15. Synthesis of 1-(5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (15)) [ka]

[0212] Synthesis of 5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] A 100 mL round bottom flask was charged with a solution of 5-hydroxyindan-1-one (700.0 mg, 4.72 mmol), 2-(bromomethyl)-1,4-difluoro-benzene (1.2 g, 5.67 mmol), K2CO3 (2.0 g, 14.2 mmol) and MeCN (30.0 mL). The reaction mixture was stirred at 80° C. under nitrogen for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from water (5 mL) and acetone (5 mL) to give 5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.26 g, 95.878%) as a yellow solid. LCMS (ESI, m / z): 275 [M+H] + .

[0213] Synthesis of methyl 1-(5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A 100 mL round bottom flask was charged with a solution of NaBH3CN (1.1 g, 17.5 mmol) and ZnCl2 / THF (1.19 g, 8.75 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 10 min, followed by the addition of 5-((2,5-difluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.2 g, 4.38 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.99 g, 6.56 mmol). The resulting mixture was stirred overnight at 70° C. under nitrogen. The reaction was quenched with NH4Cl (sat. aq., 80 mL) and extracted with EA (3×80 mL). The organic layers were combined and dried over Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel TLC (DCM:CH2Cl2=30:1) to give methyl 1-(5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (1.4 g, 84%) as a yellow oil. LCMS (ESI, m / z): 374 [M+H] + .

[0214] Synthesis of 1-(5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,5-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (500.0 mg, 1.34 mmol) in THF (40 mL) and water (4 mL) was added LiOH·HO (56.19 mg, 1.34 mmol) slowly at 25° C. The resulting mixture was stirred overnight. The reaction was complete by LCMS. The reaction was diluted with 10 mL of water and the pH was adjusted to 3 with 1 M hydrochloric acid. The solid was collected by filtration and recrystallized from water (5 mL) to give 1-(5-((2,5-difluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (114 mg, 23%) as an off-white solid.

[0215] LCMS(ESI,m / z):360[M+H] + Analytical conditions: Column: EVO C18, 3.0 * 50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile, Flow rate: 1.20 mL / min; Gradient: 10% B to 45% B (1.74 min), 45% B to 95% B (0.55 min), hold at 95% B (0.40 min), 95% B to 10% B (0.10 min); 254 nm; RT: 1.497 min.

[0216] 1H NMR (400 MHz, methanol-d4) δ 7.49 (d, J = 8.4 Hz, 1H), 7.28 (m, 1H), 7.19-7.05 (m, 3H), 6.99 (dd, J = 8.4, 2.5 Hz, 1H), 5.18 (s, 2H), 4.87 (dd, J = 7.7, 2.2 Hz, 1H), 4.50-4.40 (m, 2H), 4.36-4.26 (m, 2H), 3.67-3.54 (m, 1H), 3.17 (dt, J = 16.6, 8.2 Hz, 1H), 2.98 (ddd, J = 16.9, 9.3, 2.9Hz, 1H), 2.52 (dq, J = 16.7, 8.5, 7.7 Hz, 1H), 2.20 (ddt, J = 14.9, 8.2, 2.7 Hz, 1H). (Example S16. Synthesis of 1-(5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (16)) [ka]

[0217] Synthesis of 5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (600 mg, 4.05 mmol, 1.00 equiv) and 4-(bromomethyl)-2-chloro-1-fluoro-benzene (995 mg, 4.45 mmol, 1.10 equiv) in MeCN (12.0 mL) was added K2CO3 (1679 mg, 12.2 mmol, 3.00 equiv). The mixture was stirred at 50° C. overnight. LCMS confirmed the reaction was complete. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using petroleum ether / ethyl acetate (6:1) to give 5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.06 g, 90%) as a yellow solid. LCMS (ESI, m / z): 291[M+H] + .

[0218] Synthesis of methyl 1-(5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (433 mg, 6.88 mmol, 4.00 equiv) in methanol (10.0 mL) was added 2M ZnCl2 / THF (1.8 mL, 3.44 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 5 min, followed by the addition of 5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (500 mg, 1.72 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate; hydrochloride (391 mg, 2.58 mmol, 1.50 equiv). The resulting mixture was stirred overnight at 70° C. under nitrogen. LCMS confirmed the reaction was complete. The reaction was quenched with 20 mL of saturated NH4Cl solution and extracted with 3×30 mL of EA. The organic layers were combined, dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and purified by TLC using dichloromethane / methanol (20:1) to give methyl 1-(5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (250 mg, 37%) as a colorless oil. LCMS (ESI, m / z): 390 [M+H] + .

[0219] Synthesis of 1-(5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((3-chloro-4-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (250 mg, 0.640 mmol, 1.00 equiv.) in THF (5 mL) and water (0.5 mL) was added LiOH·H2O (54 mg, 1.28 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was diluted with 10 mL of water and the pH was adjusted to 3-4 with 2 M hydrochloric acid. The solvent was removed under reduced pressure and the residue was purified by Prep-HPLC (column: XSelect CSH Prep C18 OBD Column, 19 *250 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 50% B to 80% B (7 min), 80% B; wavelength: 254 / 210 nm; RT: 6.78) to give 1-(5-((3-chloro-4-fluorobenzyl)-oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (134 mg, 99%) as an off-white solid.

[0220] LCMS(ESI,m / z):376[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 60% B (3.00 min), 60% B to 95% B (0.30 min), hold at 95% B (0.40 min), 95% B to 5% B (0.10 min); 220 nm; RT: 2.547 min.

[0221] 1 H NMR (400 MHz, methanol-d4) δ 7.55 (dd, J = 7.1, 2.2 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.40 (ddd, J = 7.0, 4.6, 2.1 Hz, 1H), 7.24 (t, J = 8.9 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.5 Hz, 1H), 5.10 (s, 2H), 4.70-4.21 (m, 4H), 3.65 (s, 1H), 3.14 (dt, J = 16.5, 8.2 Hz, 1H), 2.96 (ddd, J = 16.8, 9.2, 2.8 Hz, 1H), 2.57-2.49 (m, 1H), 2.18 (s, 1H). (Example S17. Synthesis of 1-(5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (17)) [ka]

[0222] Synthesis of 5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (1000 mg, 6.75 mmol, 1.00 equiv) in MeCN (30.0 mL) was added 1-(bromomethyl)-2,4,5-trifluoro-benzene (1800 mg, 8.00 mmol, 1.20 equiv) and K2CO3 (2778 mg, 13.1 mmol, 3.00 equiv). The resulting mixture was stirred at 90° C. under nitrogen for 3 h. LCMS confirmed the completion of the reaction. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (2.0 g, 93%) as a brown solid. LCMS (ESI, m / z): 293 [M+H] + .

[0223] Synthesis of methyl 1-(5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (689 mg, 11.0 mmol, 4.00 equiv) in methanol (15.0 mL) was added 2M ZnCl2 / THF (2.7 mL, 1.82 mmol, 2.00 equiv) and the mixture was stirred for 10 min, followed by the addition of 5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (800 mg, 2.74 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (622 mg, 4.11 mmol, 1.50 equiv). The resulting mixture was purged with nitrogen and stirred at 70° C. overnight. The reaction was complete by LCMS. The mixture was purified by Prep-TLC (PE:EA=1:1) to give methyl 1-(5-((2,4,5-trifluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (782 mg, 73%) as a yellow solid. LCMS (ESI, m / z): 392 [M+H] + .

[0224] Synthesis of 1-(5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (782 mg, 2.00 mmol, 1.00 equiv.) in THF (15.0 mL) and water (1.5 mL) was added LiOH·HO (167 mg, 4.00 mmol, 4.00 equiv.) and the mixture was stirred at room temperature overnight. The reaction was diluted with 15 mL of water and the pH was adjusted to 3 with 4 M hydrochloric acid. The solvent was removed under reduced pressure. The crude product was purified by Prep-HPLC (column: YMC-Actus Triart C18 ExRS.30 *250, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 25% to B 50% (7 min); 254 / 210 nm; RT: 6.00 min) to give 1-(5-((2,4,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (139 mg, 18%) as an off-white solid.

[0225] LCMS(ESI,m / z):378[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 30% B to 65% B (3.00 min), 65% B to 90% B (0.20 min), maintain 95% B (0.10 min), 95% B to 5% B (0.20 min); 210 nm; RT: 1.195 min.

[0226] 1 H NMR (400 MHz, CD3OD-d4) δ 7.51-7.41 (m, 2H), 7.27-7.18 (m, 1H), 7.06-7.01 (d, 1H), 6.95 (d, 2H), 5.12 (s, 1H), 4.86 (s, 1H), 4.70-4.27 (m, 4H), 3.65 (s, 1H), 3.17 (m, 1H), 2.97 (m, 1H), 2.51 (m, 1H), 2.18 (m, 1H). (Example S18. Synthesis of 1-(5-((2,3,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (18)) [ka]

[0227] To a stirred solution of 1-(5-((2,3,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (150 mg, 0.380 mmol, 1.00 equiv) in THF (5.0 mL) was added LiOH·HO (33 mg, 0.770 mmol, 2.00 equiv) in THF (5.0 mL) and water (0.5 mL). The reaction was stirred at room temperature overnight. Completion of the reaction was confirmed by LCMS. The pH value was adjusted to 4-5 with 2 M hydrochloric acid. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 40% B (7 min), 40% B; 254 / 210 nm; RT: 6.97) to give 1-(5-((2,3,5-trifluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (57 mg, 38%) as an off-white solid.

[0228] LCMS(ESI,m / z):378[M+H] + .Analysis conditions: Column: EVO C18, 50 mm, 3.0 mm, 2.6 μm; Mobile phase A: Water (5 mM NH4HCO3), Mobile phase B: Acetonitrile, Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2 min), maintain 95% B (0.60 min), 95% B to 10% B (0.15 min); 210 nm; RT: 1.040 min.

[0229] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (dddd, J = 11.2, 9.0, 6.2, 3.2 Hz, 1H), 7.5 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.2, 2.5 Hz, 1H), 5.10 (s, 2H), 3.65 (dd, J = 6.8, 2.8 Hz, 1H), 3.25 (d, J = 7.4 Hz, 3H), 3.20-3.00 (m, 2H), 2.80 (m, 1H), 2.65 (ddd, J = 16.3, 8.8, 3.7 Hz, 1H), 1.95 (dq, J = 15.2, 8.1 Hz, 1H), 1.75 (ddt, J = 12.2, 7.6, 3.5 Hz, 1H). (Example S19. Synthesis of 1-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (19)) [ka]

[0230] Synthesis of 5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 4-(bromomethyl)-1,2-difluoro-benzene (500 mg, 2.42 mmol, 1.00 equiv.) and K2CO3 (1.0 g, 7.26 mmol, 3.00 equiv.) in MeCN (10.0 mL) was added 5-hydroxyindan-1-one (429 mg, 2.90 mmol, 2.00 equiv.). The mixture was stirred at 80° C. overnight. LCMS confirmed the formation of the desired product. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA:PE=1:3) to give 5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (610 mg, 92%). LCMS (ESI, m / z): 275 [M+H] + .

[0231] Synthesis of methyl 1-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of NaBH3CN (560 mg, 8.90 mmol, 4.00 equiv) in methanol (20.0 mL) was added 2M ZnCl2 (2.2 mL, 4.45 mmol, 2.00 equiv). Then 5-((3,4-difluoro-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (610 mg, 2.22 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate hydrochloride (674 mg, 4.45 mmol, 2.00 equiv) were added. The mixture was stirred at 70° C. overnight. LCMS confirmed the formation of the desired product. The mixture was diluted with 10 mL of water and extracted with EA (3×20 mL). The organic layers were combined, washed with saturated brine (3×10 mL), concentrated, and purified by silica gel flash chromatography (MeOH:DCM=1:3) to give methyl 1-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (420 mg, 50%) as a yellow oil. LCMS (ESI, m / z): 374 [M+H] + .

[0232] Synthesis of 1-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of methyl 1-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (420 mg, 1.12 mmol, 1.00 equiv.) in THF (5.0 mL) and water (0.5 mL) was added LiOH·HO (94 mg, 2.25 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 4-5 with 2 M hydrochloric acid. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC (column: XSelect CSH Prep C18 OBD Column, 19 * 250 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 49% B (7 min); 210 / 254 nm; RT: 6.45 min) to give 11-(5-((3,4-difluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylic acid (176 mg, 43%) as an off-white solid.

[0233] LCMS(ESI,m / z): 360[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA, Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2.00 min), maintain 95% B (0.70 min), 95% B to 5% B (0.25 min); 210 nm; RT: 1.494 min.

[0234] 1H NMR (400 MHz, methanol-d4) δ 7.46 (d, J = 8.5 Hz, 1H), 7.40-7.27 (m, 1H), 7.30-7.21 (m, 1H), 7.24 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.5, 2.5 Hz, 1H), 5.1-5.01(s, 2H), 4.87 (s, 1H), 4.70-4.20 (m, 4H), 3.65 (s, 1H), 3.13 (dt, J = 16.5, 8.2 Hz, 1H), 3.01-2.90 (m, 1H), 2.50 (m, J = 16.7, 8.6 Hz, 1H), 2.18 (s, 1H). (Example S20. Synthesis of 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (20)) [ka]

[0235] Synthesis of 5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of the 5-hydroxyindan-1-one (1.3 g, 9.25 mmol, 1.00 equiv) in MeCN (10.0 mL) was added 1-(bromomethyl)-3-iodo-benzene (3.0 g, 10.1 mmol, 1.00 equiv) and K2CO3 (3.8 g, 27.7 mmol, 3.00 equiv). The reaction was stirred at 80° C. for 1 h. LCMS confirmed the reaction was complete. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA:PE=1:6) to give the desired product 5-((3-iodo-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (3.1 g, 92%) as a yellow solid. LCMS (ESI, m / z): 365 [M+H] + .

[0236] Synthesis of tert-butyl 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate [ka] To a solution of NaBH3CN (0.7 g, 12.4 mmol, 3.00 equiv) in methanol (5.0 mL) was added ZnCl2 (4.1 mL, 8.24 mmol, 2.00 equiv) (2M / THF). The reaction was stirred at room temperature for 15 min. Then, 5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.5 g, 4.12 mmol, 1.00 equiv) and tert-butyl azetidin-1-ium-3-carboxylate hydrochloride (1.2 g, 6.180 mmol, 1.50 equiv) were added separately. The reaction mixture was stirred at 60° C. for 12 h. The reaction was complete by LCMS. The reaction mixture was quenched with water (20 mL) and extracted with EA (3×30 mL). The organic layers were combined, washed with saturated brine (30.0 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH:DCM=25:1) to give tert-butyl 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (1.0 g, 48%) as a yellow oil. LCMS (ESI, m / z): 506 [M+H] + .

[0237] Synthesis of 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of the compound tert-butyl 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (200 mg, 0.400 mmol, 1.00 equiv.) in THF (3.0 mL) and water (0.6 mL) was added LiOH·H2O (24 mg, 0.590 mmol, 2.00 equiv.). The reaction was stirred at room temperature for 12 hours. The reaction was diluted with 10 mL of water. THF was removed under reduced pressure. 4 M hydrochloric acid was added to the reaction mixture to adjust the pH to 6. The solvent was removed under reduced pressure. The residue was purified by Perp-HPLC (column: XBridge Shield RP18 OBD Column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 44% B (7 min); wavelength: 254 / 210 nm; RT: 6.60 min) to give 1-(5-((3-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (46 mg, 25%) as a white solid.

[0238] LCMS(ESI,m / z):450[M+H] + Analytical conditions: Column: EVO C18, 3.0 * 50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile, Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.00 min), hold at 95% (0.60 min), 95% B to 10% B (0.15 min); 254 nm; RT: 1.141 min.

[0239] 1H NMR (400 MHz, methanol-d4) δ 7.79 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.3, 4.5 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.99-6.93 (m, 1H), 5.08 (s, 2H), 4.74 (d, J = 7.5 Hz, 1H), 4.26 (d, J = 7.4 Hz, 2H), 4.13 (t, J = 8.7 Hz, 2H), 3.34 (d, J = 8.6 Hz, 1H), 3.10 (dt, J = 16.5, 8.0 Hz, 1H), 2.93 (ddd, J = 16.8, 9.3, 3.0 Hz, 1H), 2.46 (dq, J = 16.5, 8.4 Hz, 1H), 2.13 (dd, J = 14.5, 7.9 Hz, 1H). (Example S21. Synthesis of 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (21)) [ka]

[0240] Synthesis of 5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (2.5 g, 16.8 mmol, 1.00 equiv) in DMF (20.0 mL) was added 1-(bromomethyl)-4-iodo-benzene (5.5 g, 18.560 mmol, 1.10 equiv) and K2CO3 (7.0 g, 50.6 mmol, 3.00 equiv). The reaction was stirred at 60° C. for 12 h. LCMS confirmed the reaction was complete. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA:PE=1:6) to give 5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (5.6 g, 91%). LCMS (ESI, m / z): 365 [M+H] + .

[0241] Synthesis of tert-butyl 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate [ka] To a solution of NaBH3CN (776 mg, 12.360 mmol, 3.00 equiv) in methanol (8.0 mL) was added ZnCl2 (4.0 mL, 8.24 mmol, 2.00 equiv) (2M / THF). The reaction was stirred at room temperature for 15 min. Then, 5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.5 g, 4.120 mmol, 1.00 equiv) and tert-butyl azetidine-3-carboxylate hydrochloride (1.2 g, 6.18 mmol, 1.50 equiv) were added separately. The reaction mixture was heated at 60° C. for 12 h. The reaction was complete by LCMS. The reaction was poured into 50 mL of H2O and extracted with EA (3×50 mL). The combined organic layers were washed with saturated brine (1×50 mL) and dried over anhydrous Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH:DCM=25:1) to give tert-butyl 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (1.5 g, 72%). LCMS (ESI, m / z): 506 [M+H] + .

[0242] Synthesis of 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of tert-butyl 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate (100 mg, 0.200 mmol, 1.00 equiv) in THF (3.0 mL) and water (0.5 mL) was added LiOH·HO (17 mg, 0.400 mmol, 2.00 equiv) at 25° C. The mixture was stirred at 25° C. for 24 h. The reaction was diluted with 10 mL of water. THF was removed under reduced pressure. The pH was adjusted to 6 with 4 M hydrochloric acid. The mixture was concentrated and purified by Prep-HPLC (column: X Bridge Prep C18 OBD Column, 19×150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: B concentration 26% to B concentration 40% (7 min); 210 / 254 nm; RT: 6.83 min) to give 1-(5-((4-iodobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (26.9 mg) as an off-white solid.

[0243] LCMS(ESI,m / z):450[M+H] + Analytical conditions: Column: Shim-pack XR-ODS 3.0 * 50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (1.99 min), maintain 95% B (0.70 min), 95% B to 5% B (0.05 min); 220 nm; RT: 1.640 min.

[0244] 1H NMR (400 MHz, methanol-d4) δ 7.72-7.69 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.99 (s, 1H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 5.07 (s, 2H), 4.70 (d, J = 7.4 Hz, 1H), 4.27 (t, J = 9.3 Hz, 2H), 4.13 (m, J = 7.5 Hz, 2H), 3.34 (s, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.44 (dq, J = 16.3, 8.3 Hz, 1H), 2.15 (dd, J = 14.6, 8.1 Hz, 1H). (Example S22. Synthesis of (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (22)) [ka]

[0245] Synthesis of ethyl (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate [ka] A 25 mL round bottom flask was charged with a solution of NaBH3CN (98 mg, 1.56 mmol, 4.00 equiv.) and ZnCl2 / 2-Me-THF (2.0 M) (0.39 mL, 0.780 mmol, 2.00 equiv.) in methanol (2.0 mL). The resulting solution was stirred at room temperature for 10 minutes, followed by the addition of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (120 mg, 0.390 mmol, 1.00 equiv.) and ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate (91 mg, 0.590 mmol, 1.50 equiv.). The reaction solution was stirred at 60° C. under nitrogen for 16 hours. The reaction was complete by LCMS. The reaction was quenched with 10 mL of saturated NH4Cl solution and extracted with EA (3 x 10 mL). The organic layers were combined and dried over Na2SO4. The solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:5) to give ethyl (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (75 mg, 43%) as a colorless semi-solid. LCMS (ESI, m / z): 446 [M+H] + .

[0246] Synthesis of (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid [ka] A 25 mL round bottom flask was charged with a solution of ethyl (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (50 mg, 0.110 mmol, 1.00 equiv), LiOH·HO (47 mg, 1.120 mmol, 10.00 equiv) in THF (1.0 mL) and water (1.0 mL) (solvent mixture). The resulting mixture was stirred at 80 °C for 5 days. The reaction was completed by LCMS. The resulting mixture was filtered and purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 45% B (7 min); 254 / 210 nm; Rt: 6.63 min) to give (1R,5S,6r)-3-(5-((2,6-dichlorobenzyl)-oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (4.2 mg, 9%) as a white solid.

[0247] LCMS(ESI,m / z):418[M+H] + Analytical conditions: Column: Poroshell HPH-C18 Column 3.0 * 50 mm, 2.7 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2 min); Maintain 95% B (0.60 min), 95% B to 10% B (0.20 min); 220 nm; Rt: 1.363 min.

[0248] 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 9.0, 7.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.23 (s, 2H), 4.45 (s, 1H), 3.07 (t, J = 7.5 Hz, 5H), 2.85 (s, 1H), 2.21 (d, J = 7.1 Hz, 2H), 1.95 (d, J = 8.1 Hz, 2H), 1.59 (t, J = 8.1 Hz, 1H). (Example S23. Synthesis of (1R,5S,6s)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (23)) [ka]

[0249] Synthesis of ethyl (1R,5S,6s)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate [ka] A round bottom flask purged and maintained with a nitrogen inert atmosphere was charged with a solution of NaBH3CN (98 mg, 1.560 mmol, 4.00 equiv) in methanol (2.0 mL). ZnCl2 / 2-Me-THF (2.0 M) (0.39 mL, 0.7800 mmol, 2.00 equiv) was added. The resulting solution was stirred at room temperature for 5-10 minutes. 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (120 mg, 0.390 mmol, 1.00 equiv) and ethyl (1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-carboxylate (91 mg, 0.590 mmol, 1.50 equiv) were added. The mixture was stirred under nitrogen at 60° C. for 16 hours. The reaction was complete by LCMS. The reaction mixture was purified by silica gel flash chromatography with ethyl acetate / petroleum ether (1:5) to give ethyl (1R,5S,6s)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo-[3.1.0]hexane-6-carboxylate. LCMS (ESI, m / z): 446 [M+H] + .

[0250] Synthesis of (1R,5S,6s)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid [ka] A 25 mL round bottom flask was charged with a solution of ethyl (1R,5S,6s)-3-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (100 mg, 0.220 mmol, 1.00 equiv), LiOH·HO (56 mg, 1.340 mmol, 6.00 equiv), THF (1.0 mL) and water (1.0 mL). The resulting mixture was stirred at 80 °C for 14 h. The reaction was complete by LCMS. The resulting mixture was filtered and directly purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 19×150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: B concentration 28% to B concentration 42% (7 min); 254 / 210 nm; Rt: 6.22 min) to give (1R,5S,6s)-3-(5-((2,6-dichloro-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (55.4 mg, 58%) as a white solid.

[0251] LCMS(ESI,m / z):418[M+H] + Analytical conditions: Column: Poroshell HPH-C18 Column 3.0 * 50 mm, 2.7 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2 min), maintain 95% B (0.60 min), 95% B to 10% B (0.20 min); 220 nm; RT: 1.296 min.

[0252] 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.55 (m, 2H), 7.48 (dd, J = 8.9, 7.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.3, 2.6 Hz, 1H), 5.20 (s, 2H), 4.20-4.13 (m, 1H), 2.89 (dd, J = 17.7, 8.3 Hz, 2H), 2.76 (dd, J = 18.3, 8.4 Hz, 2H), 2.61-2.52 (m, 2H), 2.08-1.93 (m, 2H), 1.87-1.78 (m, 3H). (Example S24. Synthesis of (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (24a & 24b)) [ka]

[0253] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (2.0 g, 13.5 mmol, 1.00 equiv) in MeCN (10 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (0.5 mL, 13.5 mmol, 1.10 equiv) and K2CO3 (5.6 g, 40.5 mmol, 3.00 equiv). The reaction was stirred at 60° C. for 12 h. LCMS confirmed the reaction was complete. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by C18 silica flash chromatography (eluting with water / MeCN, 20 / 80) to give 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (3.6 g, 87%) as a yellow solid. LCMS (ESI, m / z): 307 [M+H] + .

[0254] Synthesis of methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate [ka] To a solution of NaBH3CN (184 mg, 2.93 mmol, 3.00 equiv) in methanol (10 mL) was added ZnCl2 (2M / THF, 1.0 mL, 1.95 mmol, 2.00 equiv). The mixture was stirred at room temperature for 15 minutes. Then, 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (300 mg, 0.98 mmol, 1.00 equiv) and methyl (3S)-pyrrolidine-3-carboxylate (378 mg, 2.93 mmol, 3.00 equiv) were added. The resulting mixture was stirred at 60° C. overnight. The reaction was complete by LCMS. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by C18 silica flash chromatography (eluted with water / MeCN, 35 / 65) to give methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (200 mg, 49%) as a yellow oil. LCMS (ESI, m / z): 420 [M+H] + .

[0255] Chiral Resolution of Methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] The racemic form of methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (200 mg) was purified by Prep-Chiral-HPLC (column: CHIRALPAK IG, 2 *25cm, 5μm; Mobile phase A: Hexane (8mM NH3·MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20mL / min; Gradient: B concentration 10% to B concentration 10% (16min); 220 / 254nm; RT1: 9.4min; RT2: 12.8min) to separate the two enantiomers (60mg). LCMS (ESI,m / z): 420[M+H] + .

[0256] Synthesis of (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (24a) [ka] To a solution of methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (chiral resolution product 1,60 mg, 0.14 mmol, 1.00 equiv.) in THF (3 mL) and water (1 mL) was added LiOH·H2O (18 mg, 0.43 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 6 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep C18 OBD Column, 19 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 43% B (7 min); wavelength: 210 / 254 nm; RT: 6.32 min) to give (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (39.8 mg, 67%) as an off-white solid.

[0257] LCMS(ESI,m / z):406[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 *50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 60% B (2.80 min), 60% B to 95% B (0.40 min), hold at 95% (0.50 min), 95% B to 5% B (0.10 min); 210 nm; RT: 2.616 min.

[0258] 1 H NMR (300 MHz, CD3OD-d4) δ 7.53 (d, J = 8.7 Hz, 1H), 7.47-7.44 (m, 2H), 7.39-7.34 (m, 1H), 7.07-7.05 (m, 1H), 7.00-6.96 (m, 1H), 5.31 (s, 2H), 4.81-4.85 (m, 1H), 3.61-3.55 (m, 1H), 3.42-3.33 (m, 3H), 3.24-3.16 (m, 1H), 3.10-2.93 (m, 2H), 2.61-2.39 (m, 2H), 2.34-2.15 (m, 2H).

[0259] Synthesis of (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (24b) [ka] To a solution of methyl (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (chiral resolution product 2,60 mg, 0.14 mmol, 1.00 equiv.) in THF (3 mL) and water (1 mL) was added LiOH·H2O (18 mg, 0.43 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 6 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was purified by Prep-HPLC (column: XBridge Prep C18 OBD Column, 19 *150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 42% B (7 min); wavelength: 210 / 254 nm; RT: 6.32 min) to give (3S)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (24.7 mg, 42%) as an off-white solid.

[0260] LCMS(ESI,m / z):406[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 60% B (2.80 min), 60% B to 95% B (0.40 min), hold at 95% (0.50 min), 95% B to 5% B (0.10 min); 210 nm; RT: 2.621 min.

[0261] 1 H NMR (300 MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.51-7.46 (m, 1H), 7.27-7.24 (m, 1H), 6.98-6.95 (m, 1H), 6.89-6.84 (m, 1H), 5.22 (s, 2H), 4.14-4.07 (m, 1H), 2.96-2.85 (m, 3H), 2.76-2.73 (m, 2H), 2.66-2.63 (m, 2H), 2.13-2.07 (m, 2H), 1.97-1.90 (m, 2H). (Example S25. Synthesis of (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (25a & 25b)) [ka]

[0262] Synthesis of methyl (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate [ka] To a solution of NaBH3CN (184 mg, 2.93 mmol, 3.00 equiv) in methanol (10 mL) was added ZnCl2 (2M / THF, 1.0 mL, 1.95 mmol, 2.00 equiv). The mixture was stirred at room temperature for 15 min. Then, 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (300 mg, 0.98 mmol, 1.00 equiv) and methyl (3R)-pyrrolidine-3-carboxylate (378 mg, 2.93 mmol, 3.00 equiv) were added. The resulting mixture was stirred at 60° C. overnight. The reaction was complete by LCMS. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by C18 silica flash chromatography (eluted with water / MeCN, 35 / 65) to give methyl (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (200 mg, 49%) as a yellow oil. LCMS (ESI, m / z): 420 [M+H] + .

[0263] Chiral Resolution of Methyl (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] The racemic mixture (200 mg) was purified by Prep-Chiral-HPLC (column: CHIRALPAK IG, 2 *25 cm, 5 μm; Mobile phase A: Hexane (8 mM NH3·MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Concentration gradient: B concentration 10% to B concentration 10% (10 min); 220 / 254 nm; RT1: 7.17 min; RT2: 8.523 min) to obtain 70 mg of both enantiomers. LCMS (ESI, m / z): 420 [M+H] + .

[0264] Synthesis of (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (25a) [ka] To a stirred solution of methyl (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (chiral resolution product 1,70 mg, 0.17 mmol, 1.00 equiv.) in THF (2.0 mL) and water (0.2 mL) was added LiOH·H2O (21 mg, 0.50 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was analyzed by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 22% to B concentration 40% (7 min); wavelength: 254 nm; RT: 6.85 min) to give (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (14.7 mg, 21%) as a white solid.

[0265] LCMS(ESI,m / z):406[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 *50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2.00 min), hold at 95% (0.70 min), 95% B to 5% B (0.05 min); 210 nm; RT: 1.586 min.

[0266] 1 H NMR (300 MHz, DMSO-d6) δ 7.58-7.55 (m, 2H), 7.49-7.44 (m, 1H), 7.21-7.19 (m, 1H), 6.96-6.92 (m, 1H), 6.85-6.82 (m, 1H), 5.19 (s, 2H), 4.07-4.03 (m, 1H), 2.98-2.82 (m, 2H), 2.78-2.63 (m, 3H), 2.58-2.53 (m, 2H), 2.08-2.01 (m, 2H), 1.93-1.88 (m, 2H).

[0267] Synthesis of (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (25b) [ka] To a stirred solution of methyl (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (chiral resolution product 2,70 mg, 0.17 mmol, 1.00 equiv.) in THF (2.0 mL) and water (0.2 mL) was added LiOH·H2O (21 mg, 0.50 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was analyzed by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 30 *150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 20% to B concentration 43% (7 min); wavelength: 254 nm; RT: 6.67 min) to give (3R)-1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (26.8 mg, 39%) as a white solid.

[0268] LCMS(ESI,m / z):406[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B (2 min), hold at 95% (0.70 min), 95% B to 5% B (0.05 min); 210 nm; RT: 1.580 min.

[0269] 1 H NMR (300 MHz, DMSO-d6) δ 7.58-7.55 (m, 2H), 7.49-7.44 (m, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.1, 2.4 Hz, 1H), 5.19 (s, 2H), 4.05 (t, J = 2.4 Hz, 1H), 2.99-2.83 (m, 2H), 2.80-2.66 (m, 3H), 2.62-2.55 (m, 2H), 2.10-2.03 (m, 2H), 1.95-1.88 (m, 2H). Example S26. Synthesis of 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26a & 26b) [ka]

[0270] Synthesis of 5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxyindan-1-one (2.0 g, 13.5 mmol, 1.00 equiv.) in MeCN (10.0 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene (3.2 g, 13.5 mmol, 1.10 equiv.) and K2CO3 (5.5 g, 40.5 mmol, 3.00 equiv.). The resulting mixture was stirred at 60° C. overnight. LCMS confirmed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluted with water / MeCN, 20 / 80) to give 5-((3-(trifluoromethyl)-benzyl)oxy)-2,3-dihydro-1H-inden-1-one (3.2 g, 77%) as a yellow solid. LCMS (ESI, m / z): 307 [M+H] + .

[0271] Synthesis of methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A solution of ZnCl2 (2M / THF, 1.3 mL, 2.61 mmol, 2.00 equiv.) and NaBH3CN (328 mg, 5.22 mmol, 4.00 equiv.) in methanol (5.0 mL) was stirred at room temperature for 0.5 h. Then, 5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-one (400 mg, 1.31 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (280 mg, 1.96 mmol, 1.50 equiv.) were added. The resulting mixture was stirred at 60° C. overnight. The reaction was complete as determined by LCMS. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by C18 silica flash chromatography (eluted with water / MeCN, 35 / 65) to give methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 434 [M+H] + .

[0272] Chiral Resolution of Methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] The racemic mixture of methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg) was purified by prep-chiral-HPLC (CHIRALPAK IE, 2 * 25 cm, 5 μm; Mobile phase A: Hexane (8 mM NH3·MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Concentration gradient: B concentration 5% to B concentration 5% (15 min); 220 / 254 nm; RT1: 10.785 min; RT2: 11.612 min) to separate both enantiomers (63 mg). LCMS (ESI, m / z): 434 [M+H] + .

[0273] Synthesis of 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26a) [ka] To a solution of methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral resolution product 1, 63 mg, 0.15 mmol, 1.00 equiv.) in THF (3.0 mL) and water (0.6 mL) was added LiOH·H2O (18 mg, 0.44 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 6 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was purified by Prep-HPLC (column: Xselect CSH C18 OBD Column 30 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 22% to B concentration 52% (7 min); wavelength: 254 / 210 nm; RT: 6.42 min) to give 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (35.8 mg, 58.3%) as a white solid.

[0274] LCMS(ESI,m / z):420[M+H] + Analytical conditions: Column: Titank C18, 3.0 * 50 mm, 3.0 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B (1.40 min), hold at 95% (0.80 min), 95% to 10% B (0.03 min); 220 nm; RT: 1.164 min.

[0275] 1H NMR (300 MHz, DMSO-d6) δ 11.73 (br, 1H), 7.80-7.75 (m, 2H), 7.72-7.62 (m, 2H), 7.17 (d, J = 8.1 Hz, 1H), 6.90-6.83 (m, 2H), 5.18 (s, 2H), 4.24-4.18 (m, 1H), 2.86-2.66 (m, 3H), 2.46-2.43 (m, 1H), 2.26-2.08 (m, 3H), 2.00-1.96 (m, 2H), 1.82-1.72 (m, 2H), 1.62-1.42 (m, 2H).

[0276] Synthesis of 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26b) [ka] To a solution of methyl 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral resolution product 2,63 mg, 0.15 mmol, 1.00 equiv.) in THF (3.0 mL) and water (0.6 mL) was added LiOH·H2O (18 mg, 0.44 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 6 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was purified by Prep-HPLC (column: Xselect CSH C18 OBD Column 30 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B concentration 22% to B concentration 52% (7 min); wavelength: 254 / 210 nm; RT: 6.77 min) to give 1-(5-((3-(trifluoromethyl)benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (36.3 mg, 59.0%) as a white solid.

[0277] LCMS(ESI,m / z):420[M+H] + Analytical conditions: Column: Titank C18, 3.0 * 50 mm, 3.0 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B (1.40 min), hold at 95% (0.80 min), 95% B to 10% B (0.03 min); 220 nm; RT: 1.167 min.

[0278] 1 H NMR (300 MHz, DMSO-d6) δ 7.80-7.75 (m, 2H), 7.72-7.62 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.90-6.84 (m, 2H), 5.18 (s, 2H), 4.24-4.18 (m, 1H), 2.83-2.65 (m, 3H), 2.45-2.41 (m, 1H), 2.27-2.12 (m, 3H), 2.01-1.96 (m, 2H), 1.82-1.72 (m, 2H), 1.58-1.42 (m, 2H). (Example S27. Synthesis of 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]-heptane-6-carboxylic acid (27)) [ka]

[0279] Synthesis of methyl 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro-[3.3]heptane-6-carboxylate [ka] A mixture of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (300 mg, 0.980 mmol, 1.00 equiv), methyl 2-azaspiro[3.3]heptane-6-carboxylate (152 mg, 0.980 mmol, 1.00 equiv), zinc chloride (1.9 M / 2-Me-THF, 1.5 mL, 2.00 equiv) and NaBH3CN (250 mg, 3.920 mmol, 4.00 equiv) in methanol (8.0 mL) was stirred at 60° C. for 12 h. LCMS confirmed the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH=50:1) to give the desired product, methyl 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (100 mg, 23%) as a pale yellow oil. LCMS (ESI, m / z): 446 [M+H] + .

[0280] Synthesis of 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]-heptane-6-carboxylic acid [ka] A mixture of methyl 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro-[3.3]heptane-6-carboxylate (100 mg, 0.220 mmol, 1.00 equiv.) and LiOH·H2O (47 mg, 1.110 mmol, 5.00 equiv.) in THF (4.0 mL) and water (4.0 mL) was stirred at room temperature for 1 h. The reaction was complete by LCMS. The reaction mixture was acidified to pH 4-5 with 1 M hydrochloric acid and then concentrated. The residue was purified by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 5 μm, 19 *150 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 35% B (10 min), hold at 35% (3 min); 210 / 254 nm; RT: 11.6 min) to give 2-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (38.7 mg, 38%) as a white solid.

[0281] LCMS(ESI,m / z):432[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.594 min.

[0282] 1 H NMR (400 MHz, CD3OD-d4) δ 7.49-7.43 (m, 3H), 7.38 (dd, J = 8.8, 7.2 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 5.32 (s, 2H), 4.62-4.58 (m, 1H), 4.16-4.09 (m, 2H), 4.03-3.97 (m, 2H), 3.19-3.11 (m, 1H), 2.99-2.94 (m, 1H), 2.89-2.82 (m, 1H), 2.45-2.30 (m, 5H), 2.14-2.07 (m, 1H). (Example S28. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-piperidine-4-carboxylic acid (28)) [ka]

[0283] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethylpiperidine-4-carboxylate [ka] To a stirred solution of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene (300 mg, 0.920 mmol, 1.00 equiv) and methyl 2,2-dimethylpiperidine-4-carboxylate (156 mg, 0.920 mmol, 1.00 equiv) in MeCN (10.0 mL) was added Cs2CO3 (895 mg, 2.750 mmol, 3.00 equiv). The mixture was stirred at 90° C. for 16 h. The reaction was complete by LCMS. The reaction mixture was poured into water (10 mL) and EtOAc (2 * The mixture was extracted with 10 mL of ethyl acetate (1,2-dichloro-1,3-dimethylpiperidine-4-carboxylate). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE / EtOAc, 3 / 1) to give methyl 1-(5-((2,6-dichloro-benzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethylpiperidine-4-carboxylate (70 mg, 16% yield) as an off-white solid. LCMS (ESI, m / z): 462 [M+H] + .

[0284] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethylpiperidine-4-carboxylate (55 mg, 0.120 mmol, 1.00 equiv.) in THF (1.0 mL) and water (0.1 mL) was added LiOH·H2O (15 mg, 0.360 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 16 h. The reaction was confirmed to be complete by LCMS. The reaction was acidified to pH 4-5 by adding 1N hydrochloric acid. The mixture was then concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18, 30 * 250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 21% B to 51% B (7 min); 254 / 210 nm; RT: 6.42 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-piperidine-4-carboxylic acid (15.2 mg, 27% yield) as an off-white solid.

[0285] LCMS(ESI,m / z):448[M+H] + .Analysis conditions: EVO C18,3.0 * 50 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.0 min), maintain 95% B (0.60 min), 95% B to 10% B (0.15 min); 210 nm; RT: 1.261 min.

[0286] 1H NMR (300 MHz, CD3OD-d4) δ 7.47-7.42 (m, 3H), 7.39-7.33 (m, 1H), 7.07-6.97 (m, 2H), 5.31 (d, J = 2.7 Hz, 2H), 5.19-5.15 (m, 1H), 3.21-2.85 (m, 3H), 2.67-2.36 (m, 4H), 2.06-1.89 (m, 3H), 1.62-1.44 (m, 7H). (Example S29. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1-inden-1-yl)-4-methylpiperidine-4-carboxylic acid (29)) [ka]

[0287] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one [ka] A mixture of 5-hydroxyindan-1-one (2.00 g, 13.5 mmol, 1.00 equiv), 2-(bromomethyl)-1,3-dichloro-benzene (6.48 g, 27.0 mmol, 2.00 equiv) and Ag2CO3 (7.45 g, 27.0 mmol, 2.00 equiv) in toluene (40 mL) was stirred at 80° C. overnight. The reaction was complete as confirmed by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (100 mL) and diluted with DCM (3 * The combined organic layer was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE:EA=1:1) to give 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (2.80 g, 67.5%) as a pale yellow solid. LCMS (ESI, m / z): 307 [M+H] + .

[0288] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-ol [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (1.00 g, 3.26 mmol, 1.00 equiv) in methanol (4 mL) was slowly added sodium borohydride (246 mg, 6.51 mmol, 2.00 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The reaction was confirmed to be complete by TLC. The reaction was quenched by adding aqueous NH4Cl at 0° C. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH, 91 / 9) to give 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-ol (700 mg, 69.5%) as a pale yellow solid. LCMS (ESI, m / z): 291 [M+H] + .

[0289] Synthesis of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-ol (200 mg, 0.650 mmol, 1.00 equiv) in DCM (3 mL) was added SOCl2 (0.24 mL, 3.23 mmol, 5.00 equiv) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 20 min. The reaction was complete by TLC. The reaction mixture was concentrated to dryness under vacuum for 20 min. The resulting crude product, 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene (160 mg, 75.5%), was used directly in the next step as a purple oil.

[0290] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidine-4-carboxylate [ka] A mixture of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene (140 mg, 0.430 mmol, 1.00 equiv), methyl 4-methylpiperidine-4-carboxylate (67.2 mg, 0.430 mmol, 1.00 equiv) and K2CO3 (118 mg, 0.860 mmol, 2.00 equiv) in MeCN (4 mL) was stirred at 60° C. overnight. The reaction was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with PE / EtOAc, 1 / 1) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidine-4-carboxylate (80.0 mg, 41.7%) as a grey solid. LCMS(ESI,m / z):448[M+H] + .

[0291] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidine-4-carboxylate (80.0 mg, 0.180 mmol, 1.00 equiv.) and sodium hydroxide (14.3 mg, 0.360 mmol, 2.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at 60° C. overnight. The reaction mixture was acidified to pH 4-5 using 1N aqueous hydrochloric acid solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge Shield RP18 OBD Column, 30 *150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B (7 min); 210 / 254 nm; RT: 6.05 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidine-4-carboxylic acid (25.9 mg, 33.1%) as a white solid.

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (br, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.56 (s, 1H), 7.50-7.46 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.0, 2.4 Hz, 1H), 5.19 (s, 2H), 4.24-4.20 (m, 1H), 2.90-2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.64-2.58 (m, 1H), 2.46-2.39 (m, 1H), 2.28-2.22 (m, 2H), 2.02-1.92 (m, 4H), 1.43-1.30 (m, 2H), 1.11 (s, 3H).

[0293] LCMS(ESI,m / z):434[M+H] + .Analysis conditions: EVO C18,3.0 * 50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2 min), maintain 95% B (0.6 min), 95% B to 10% B (0.15 min); 210 nm; RT: 1.125 min. (Example S30. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methylpiperidine-4-carboxylic acid (30)) [ka]

[0294] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methyl-piperidine-4-carboxylate [ka] To a stirred solution of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene (160 mg, 0.490 mmol, 1.00 equiv) and methyl 2-methylpiperidine-4-carboxylate (76.8 mg, 0.490 mmol, 1.00 equiv) in MeCN (4 mL) was added K2CO3 (135 mg, 0.980 mmol, 2.00 equiv). The resulting mixture was stirred at 60° C. overnight. The reaction was complete as confirmed by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and diluted with DCM (2 * The mixture was extracted with 10 mL of ethyl acetate (1,2-dichlorobenzyl)oxy (1H-inden-1-yl)-2-methyl-piperidine-4-carboxylate. The combined organic layers were washed with saturated brine. The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with DCM / MeOH, 97 / 3) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methyl-piperidine-4-carboxylate (160 mg, 73.1% yield) as a grey solid. LCMS (ESI, m / z): 448 [M+H] + .

[0295] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methylpiperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methyl-piperidine-4-carboxylate (120 mg, 0.270 mmol, 1.00 equiv.) and sodium hydroxide (16.1 mg, 0.400 mmol, 1.50 equiv.) in THF (1 mL) and water (1 mL) was stirred at 60° C. overnight. The reaction was acidified to pH 4-5 using 1 M hydrochloric acid solution. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30 * 250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 30% to B 48% (7 min); 254 / 210 nm; RT: 6.63 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2-methyl-piperidine-4-carboxylic acid (74.1 mg, 62.8% yield) as a white solid.

[0296] 1 H NMR (400 MHz, DMSO-d6) δ 7.58-7.55 (m, 2H), 7.49-7.45 (m, 1H), 7.14 (dd, J = 13.6, 8.0 Hz, 1H), 6.93 (dd, J = 2.4, 2.0 Hz, 1H), 6.88-6.81 (m, 1H), 5.18 (s, 2H), 4.69-4.65 (m, 1H), 3.00-2.92 (m, 1H), 2.81-2.65 (m, 2H), 2.42-2.39 (m, 1H), 2.34-2.29 (m, 1H), 2.24-2.07 (m,1H), 2.03-1.95 (m, 1H), 1.93-1.67 (m, 3H), 1.45-1.25 (m, 2H), 1.20 (dd, J = 8.8, 6.0 Hz, 3H).

[0297] LCMS(ESI,m / z):434[M+H] + .Analysis conditions: EVO C18,3.0* 50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 50% B (2.0 min), 50% B to 95% B (0.25 min), maintain 95% B (0.45 min), 95% B to 10% B (0.10 min); 210 nm; RT: 1.789 / 1.815 min (isomers). (Example S31. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethyl-piperidine-4-carboxylic acid (31)) [ka]

[0298] Synthesis of ethyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethylpiperidine-4-carboxylate [ka] A mixture of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-indene (200 mg, 0.650 mmol, 1.00 equiv.), ethyl 2,6-dimethylpiperidine-4-carboxylate (144 mg, 0.780 mmol, 1.2 equiv.) and K2CO3 (179 mg, 1.29 mmol, 2.00 equiv.) in MeCN (4 mL) was stirred at 90° C. for 4 days. The reaction mixture was poured into water (10 mL) and EtOAc (2 * The mixture was extracted with 10 mL of ethyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethylpiperidine-4-carboxylate (30 mg, 9.7%) as a pale yellow oil. LCMS (ESI, m / z): 476 [M+H] + .

[0299] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethyl-piperidine-4-carboxylic acid [ka] A mixture of ethyl 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethyl-piperidine-4-carboxylate (30 mg, 0.060 mmol, 1.00 equiv.) and lithium hydroxide (3.0 mg, 0.120 mmol, 2.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature overnight. The reaction was confirmed to be complete by LCMS. The reaction mixture was acidified to pH 4-5 with 1N hydrochloric acid. The mixture was then concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Triart Diol Hilic, 20 * 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 75% B to 95% B (7 min); 254 / 210 nm; RT: 6.32 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-2,6-dimethylpiperidine-4-carboxylic acid (1.1 mg, 3.6%) as a white solid.

[0300] 1H NMR (400 MHz, DMSO-d6) δ 7.58-7.55 (m, 2H), 7.48-7.44 (m, 1H), 7.17 (dd, J = 8.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 5.17 (s, 2H), 4.75 (t, J = 8.8 Hz, 1H), 2.94-2.88 (m, 1H), 2.80-2.73 (m, 1H), 2.70-2.64 (m, 1H), 2.60-2.55 (m, 1H), 2.34-2.25 (m, 1H), 2.09-2.03 (m,2H), 1.84-1.81 (m, 1H), 1.75-1.71 (m, 1H), 1.38-1.24 (m, 2H), 1.13 (d, J = 6.0 Hz, 3H), 0.65 (d, J = 6.0 Hz, 3H).

[0301] LCMS(ESI,m / z):Fragment 291[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.00 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min); 220 nm; RT: 1.617 min. (Example S32. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (32)) [ka]

[0302] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-one [ka] A mixture of 7-fluoro-5-hydroxy-indan-1-one (300 mg, 1.810 mmol, 1.00 equiv), 2-(bromomethyl)-1,3-dichloro-benzene (520 mg, 2.170 mmol, 1.50 equiv) and K2CO3 (748 mg, 5.420 mmol, 3.00 equiv) in DMF (10 mL) was stirred at 80° C. for 15 h under nitrogen atmosphere. TLC confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EA / PE=30%) to give 5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-one (320 mg, 55%) as a white solid. LCMS (ESI, m / z): 325 [M+H] + .

[0303] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of 5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-one (300 mg, 0.920 mmol, 1.00 equiv), methyl piperidine-4-carboxylate (198 mg, 1.380 mmol, 1.50 equiv), NaBH3CN (236 mg, 3.690 mmol, 4.00 equiv) and ZnCl2 (1.9 M / THF, 1.0 mL, 1.850 mmol, 2.00 equiv) in methanol (20 mL) was stirred at 60° C. for 15 hours. The reaction was complete by LCMS. The reaction was quenched with 50 mL of water and filtered. The filtrate was extracted with ethyl acetate (20 mL). *3) The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (EA / PE=25%) to give methyl 1-(5-((2,6-dichloro-benzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 48%) as a yellow oil. LCMS (ESI, m / z): 452 [M+H] + .

[0304] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.220 mmol, 1.00 equiv.) and LiOH (16 mg, 0.660 mmol, 3.00 equiv.) in THF (2 mL) and water (1 mL) was stirred at room temperature for 1 h. The reaction was complete by LCMS. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30 * 250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 35% B (10 min); 254 / 210 nm; RT: 9.67 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperazine-4-carboxylic acid (27.8 mg, 28%) as a white solid.

[0305] LCMS(ESI,m / z):438[M+H] + Analytical conditions: Column: HALO C18, 3.0 *30 mm, 2.0 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (1.20 min), hold at 100% (0.60 min), 100% B to 5% B (0.03 min); 210 nm; RT: 0.918 min.

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 7.59-7.57 (m, 2H), 7.50-7.46 (m, 1H), 6.81-6.79 (m, 1H), 6.75-6.72 (m, 1H), 5.21 (s, 2H), 4.33-4.30 (m, 1H), 2.97-2.89 (m, 1H), 2.80-2.70 (m, 2H), 2.60-2.57 (m, 1H), 2.20-1.98 (m, 5H), 1.76-1.73 (m, 2H), 1.55-1.35 (m, 2H). (Example S33. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (33)) [ka]

[0307] Synthesis of 6-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-bromo-6-fluoro-indan-1-one (300 mg, 1.310 mmol, 1.00 equiv) and t-BuBrettphos (126 mg, 0.260 mmol, 0.20 equiv) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added Pd2(dba)3CHCl3 (135 mg, 0.130 mmol, 0.10 equiv) and KOH (220 mg, 3.930 mmol, 3.00 equiv). The mixture was stirred at 90° C. for 16 h. LCMS confirmed the reaction was complete. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluted with water (5 mM NH4HCO3 / ACN, 80 / 20) to give 6-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (180 mg, 82% yield) as an off-white solid. LCMS (ESI, m / z): 167 [M+H] + .

[0308] Synthesis of P5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 6-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (160 mg, 0.960 mmol, 1.00 equiv.) and 2-(bromomethyl)-1,3-dichloro-benzene (254 mg, 1.060 mmol, 1.10 equiv.) in MeCN (5.0 mL) was added K2CO3 (398 mg, 2.890 mmol, 3.00 equiv.). The mixture was stirred at 80° C. for 16 h. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE=55 / 45) to give 5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-one (260 mg, 83% yield) as an off-white solid. LCMS (ESI, m / z): 325 [M+H] + .

[0309] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-one (240 mg, 0.740 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (211 mg, 1.480 mmol, 2.00 equiv.) in methanol (10.0 mL) was added NaBH3CN (141 mg, 2.210 mmol, 3.00 equiv.) and ZnCl2 (2M / THF, 0.7 mL, 1.480 mmol, 2.00 equiv.). The mixture was stirred at 60° C. for 16 hours. The reaction was complete by LCMS. The reaction was quenched by the addition of 50 mL of water and filtered. The filtrate was purified by ethyl acetate (20 mL). * 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (EA / PE=25 / 75) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 44% yield) as an off-white solid. LCMS (ESI, m / z): 452 [M+H] + .

[0310] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.220 mmol, 1.00 equiv.) in THF (1 mL) and water (0.1 mL), LiOH was added.* H2O (27 mg, 0.660 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction was confirmed to be complete by LCMS. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge C18 OBD Prep Column, 5 μm, 19 * 250 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20% B to 43% B (7 min); 254 / 210 nm; RT: 6.16 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-6-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (33 mg, 33%) as an off-white solid.

[0311] LCMS(ESI,m / z):438[M+H] + Analytical conditions: Column: Poroshell HPH-C18, 3.0 * 50 mm, 2.7 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.00 min), hold at 95% (0.60 min), 95% B to 10% B (0.15 min); 254 nm; RT: 1.145 min.

[0312] 1 H NMR (300 MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.52-7.47 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 11.1 Hz, 1H), 5.27 (s, 2H), 4.25 (t, J = 6.9 Hz, 1H), 2.92-2.70 (m, 3H), 2.49-2.44 (m, 1H), 2.28-2.11 (m, 3H), 2.05-1.98 (m, 2H), 1.83-1.74 (m, 2H), 1.65-1.40 (m, 2H). (Example S34. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (34)) [ka]

[0313] Synthesis of 4-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-bromo-4-fluoro-indan-1-one (450 mg, 1.96 mmol, 1.00 equiv) and K2CO3 (814 mg, 5.88 mmol, 3.00 equiv) in DMF (5 mL) was added PhCHNOH (442 mg, 2.95 mmol, 1.50 equiv) and RockPhos Pd G3 (163 mg, 0.196 mmol, 0.100 equiv). The resulting mixture was stirred at 90° C. overnight. The reaction was complete by LCMS. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (5 mM NH4HCO3 / ACN, 70 / 30) to give 4-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (300 mg, 1.81 mmol, 91.9%) as a yellow oil. LCMS (ESI, m / z): 167 [M+H] + .

[0314] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 4-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (300 mg, 1.81 mmol, 1.00 equiv.) and 2-(bromomethyl)-1,3-dichloro-benzene (650 mg, 2.71 mmol, 1.50 equiv.) in MeCN (6 mL) was added K2CO3 (748 mg, 5.42 mmol, 3.00 equiv.). The resulting mixture was stirred at 80° C. overnight. The reaction was complete by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE / EA, 2 / 1) to give 5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-one (300 mg, 0.923 mmol, 51.1%) as a yellow oil. LCMS(ESI,m / z):325[M+H] + .

[0315] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of ZnCl2 (1.0 mL, 1.9 M in methyl THF) and NaBH3CN (236 mg, 3.69 mmol, 4.00 equiv.) in methanol (5 mL) was added 5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-one (300 mg, 0.920 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (264 mg, 1.85 mmol, 2.00 equiv.). The resulting mixture was stirred at 80° C. overnight. The reaction was complete by LCMS. The reaction was quenched with 50 mL of water and filtered. The filtrate was dissolved in ethyl acetate (20 mL). *3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (eluted with PE / EA, 1 / 1) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.221 mmol, 24.0%) as a yellow oil. LCMS (ESI, m / z): 452 [M+H] + .

[0316] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (70 mg, 0.150 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH (11 mg, 0.450 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 h. The reaction was complete by LCMS. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge Prep OBD C18 Column, 30 * Purification by 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B 80% to B 95% (7 min); 254 nm; RT: 7.5 min) afforded 1-(5-((2,6-dichlorobenzyl)oxy)-4-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (53.5 mg, 77.6%) as a white solid.

[0317] LCMS(ESI,m / z):438[M+H] + .Analysis conditions: EVO C18,3.0 *50 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.0 min), maintain 95% B (0.60 min), 95% B to 10% B (0.15 min); 210 nm; RT: 1.125 min.

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (br, 1H), 7.59-7.57 (m, 2H), 7.51-7.47 (m, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 4.28 (t, J = 7.2 Hz, 1H), 2.92-2.72 (m, 3H), 2.49-2.47 (m, 1H), 2.25-2.15 (m, 3H), 2.07-2.01 (m, 2H), 1.82-1.75 (m, 2H), 1.63-1.57 (m, 1H), 1.54-1.42 (m, 1H). (Example S35. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (35)) [ka]

[0319] Synthesis of 5-hydroxy-7-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-bromo-7-methyl-indan-1-one (300 mg, 1.330 mmol, 1.00 equiv) and t-BuBrettPhos (129 mg, 0.270 mmol, 0.20 equiv) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added Pd2(dba)3CHCl3 (122 mg, 0.130 mmol, 0.10 equiv) and KOH (224 mg, 4.000 mmol, 3.00 equiv). The resulting mixture was stirred at 90° C. for 16 h. The reaction was complete by LCMS. The resulting solution was extracted with ethyl acetate (3×300 mL). The reaction was acidified to pH 4-5 using 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (5 mM NH4HCO3 / ACN, 33 / 67) to give 5-hydroxy-7-methyl-2,3-dihydro-1H-inden-1-one (180 mg, 83% yield) as an off-white solid. LCMS (ESI, m / z): 163 [M+H] + .

[0320] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-hydroxy-7-methyl-2,3-dihydro-1H-inden-1-one (160 mg, 0.990 mmol, 1.00 equiv.) and 2-(bromomethyl)-1,3-dichloro-benzene (260 mg, 1.090 mmol, 1.10 equiv.) in MeCN (10.0 mL) was added K2CO3 (408 mg, 2.960 mmol, 3.00 equiv.). The mixture was stirred at 80° C. for 16 h. LCMS confirmed the completion of the reaction. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE, 3 / 2) to give 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-one (260 mg, 82% yield) as an off-white solid. LCMS (ESI, m / z): 321 [M+H] + .

[0321] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-ol [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-one (260 mg, 0.810 mmol, 1.00 equiv) in methanol (10.0 mL) was added NaBH4 (91 mg, 2.430 mmol, 3.00 equiv). The resulting mixture was stirred at 0° C. for 2 h. LCMS confirmed the reaction was complete. The resulting solution was quenched with water (20 mL) and ethyl acetate (10 mL). * 3). The organic layers were combined, dried and concentrated under vacuum. The residue was purified by silica gel flash chromatography (EA / PE, 5 / 1) to give 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-ol (240 mg, 91%) as an off-white solid. LCMS (ESI, m / z): 323 [M+H] + .

[0322] Synthesis of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-indene [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-ol (240 mg, 0.740 mmol, 1.00 equiv.) in 1,4-dioxane (10.0 mL) was added SOCl2 (0.2 mL, 2.230 mmol, 3.00 equiv.). The mixture was stirred at 0° C. for 1 h. LCMS confirmed the reaction was complete. The reaction was concentrated under reduced pressure and the crude product, 1-chloro-5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-indene, was used directly in the next step without further purification. LCMS (ESI, m / z): 342 [M+H]+ .

[0323] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 1-chloro-5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-indene (240 mg, 0.700 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (201 mg, 1.400 mmol, 2.00 equiv.) in MeCN (10.0 mL) was added K2CO3 (290 mg, 2.110 mmol, 3.00 equiv.). The resulting mixture was stirred at 90° C. for 16 h. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE, 3 / 2) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (50 mg, 15%) as an off-white solid. LCMS(ESI,m / z):448[M+H] + .

[0324] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (50 mg, 0.110 mmol, 1.00 equiv.) in THF (1.0 mL) and water (0.5 mL) was added LiOH·H2O (14 mg, 0.330 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 16 h. The reaction was complete by LCMS. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge Prep C18 OBD Column, 19 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min; 254 / 210 nm, RT: 5.78 min) to give 1-(5-((2,6-dichloro-benzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (10.5 mg, 20%) as an off-white solid.

[0325] LCMS(ESI,m / z):434[M+H] + Analytical conditions: Column: Poroshell HPH-C18, 3.0 * 50 mm, 2.7 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.00 min), hold at 95% (0.60 min), 95% B to 10% B (0.15 min); 254 nm; RT: 1.215 min.

[0326] 1H NMR (300 MHz, methanol l-d4) δ 7.49-7.46 (m, 2H), 7.40-7.35 (m, 1H), 6.87-6.79 (m, 2H), 5.30 (s, 2H), 4.70-4.67 (m, 1H), 3.25-3.12 (m, 3H), 2.94-2.80 (m, 3H), 2.54-2.49 (m, 1H), 2.45 (s, 3H), 2.37-2.24 (m, 2H), 2.05-1.87 (m, 4H). (Example S36. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (36)) [ka]

[0327] Synthesis of 5-hydroxy-4-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-bromo-4-methyl-indan-1-one (400 mg, 1.780 mmol, 1.00 equiv) in 1,4-dioxane (10.0 mL) and water (2.0 mL) was added t-BuBrettPhos (172 mg, 0.360 mmol, 0.20 equiv), Pd2(dba)3 (162 mg, 0.180 mmol, 0.10 equiv) and KOH (298 mg, 5.330 mmol, 3.00 equiv). The reaction was stirred at 90° C. for 3 h. The reaction was complete by LCMS. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (5 mM NH4HCO3 / ACN, 80 / 20) to give 5-hydroxy-4-methyl-2,3-dihydro-1H-inden-1-one (200 mg, 69%) as an off-white solid. LCMS (ESI, m / z): 163 [M+H] + .

[0328] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-hydroxy-4-methyl-2,3-dihydro-1H-inden-1-one (100 mg, 0.620 mmol, 1.00 equiv) in MeCN (5.0 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (222 mg, 0.920 mmol, 1.50 equiv) and K2CO3 (255 mg, 1.850 mmol, 3.00 equiv). The reaction was stirred at 60° C. for 12 h. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE, 3 / 2) to give 5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-one (150 mg, 75% yield) as an off-white solid. LCMS (ESI, m / z): 321 [M+H] + .

[0329] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-one (300 mg, 0.93 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (267 mg, 1.86 mmol, 2.00 equiv.) in methanol (10.0 mL) was added NaBH3CN (120 mg, 2.79 mmol, 3.00 equiv.) and ZnCl2 (2M / THF, 0.9 mL, 1.86 mmol, 2.00 equiv.). The mixture was stirred at 60° C. for 16 hours. The reaction was complete by LCMS. The reaction was quenched with 50 mL of water and filtered. The filtrate was diluted with ethyl acetate (20 mL). *3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (EA / PE, 3 / 1) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 72%) as an off-white solid. LCMS (ESI, m / z): 448 [M+H] + .

[0330] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 0.67 mmol, 1.00 equiv.) in THF (3.0 mL) and water (1.0 mL) was added LiOH·H2O (84 mg, 2.01 mmol, 3.00 equiv.). The reaction was stirred at room temperature for 3 h. Completion of the reaction was confirmed by LCMS. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was analyzed by prep-HPLC (column: XBridge Prep C18 OBD Column, 19 * 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 26% B to 47% B (7 min); 254 / 210 nm; RT: 5.93 min) to give 1-(5-((2,6-dichloro-benzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (18.5 mg, 6%) as a white solid.

[0331] LCMS(ESI,m / z):434[M+H] + Analysis conditions: Column: Xbridge Shield RP18, 4.6* 50 mm, 3.5 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B (1.75 min), hold at 95% (0.05 min), 95% B to 10% B (0.01 min); 210 nm; RT: 1.416 min.

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.59-7.57 (m, 2H), 7.49-7.45 (m, 1H), 7.09-7.02 (m, 2H), 5.20 (s, 2H), 4.26-4.22 (m, 1H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, 2H), 2.28-2.10 (m, 3H), 2.03-1.95 (m, 5H), 1.83-1.74 (m, 2H), 1.62-1.42 (m, 2H). (Example S37. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (37)) [ka]

[0333] Synthesis of 5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-bromo-6-methyl-indan-1-one (400 mg, 1.780 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was added KOH (299 mg, 5.330 mmol, 3.00 equiv), Pd2(dba)3 (162 mg, 0.180 mmol, 0.10 equiv) and t-BuBrettPhos (172 mg, 0.360 mmol, 0.20 equiv) under nitrogen atmosphere. The reaction was stirred at 80° C. for 12 hours. The reaction was complete by LCMS. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (5 mM NH4HCO3 / ACN, 40 / 60) to give 5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one (250 mg, 86%) as a yellow solid. LCMS (ESI, m / z): 163 [M+H] + .

[0334] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-one [ka] To a solution of 5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one (250 mg, 1.54 mmol, 1.00 equiv) in MeCN (5.0 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (554 mg, 2.31 mmol, 1.50 equiv) and K2CO3 (638 mg, 4.620 mmol, 3.00 equiv). The reaction was stirred at 60° C. for 12 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE, 2 / 3) to give 5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-one (250 mg, 50%) as a yellow solid. LCMS (ESI, m / z): 321 [M+H] + .

[0335] Synthesis of isopropyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a solution of 5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-one (250 mg, 0.780 mmol, 1.00 equiv) in THF (3.0 mL) was added methyl piperidine-4-carboxylate (334 mg, 2.330 mmol, 3.00 equiv) and Ti(OiPr)4 (663 mg, 2.330 mmol, 3.00 equiv). The resulting mixture was stirred at 60° C. for 12 h. LCMS confirmed the formation of the imine intermediate. The reaction was cooled to room temperature and NaBH4 (88 mg, 2.330 mmol, 3.00 equiv) was added. The resulting mixture was stirred for 0.5 h. LCMS confirmed the reaction was complete. The reaction was quenched with 10 mL of water and filtered. The filtrate was diluted with ethyl acetate (20 mL) and diluted with ethyl acetate (20 mL). * 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by C18 silica flash chromatography (5 mM NH4HCO3) / ACN, 30 / 70) to give isopropyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 26%) as a yellow solid. LCMS (ESI, m / z): 476 [M+H] + .

[0336] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a solution of isopropyl 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.210 mmol, 1.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was added KOH (35 mg, 0.630 mmol, 3.00 equiv.). The reaction was stirred at 70° C. overnight. LCMS confirmed completion of the reaction. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30 * 250, 5 μm, mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 38% B (10 min), maintain 38% B (3 min); 254 / 210 nm; RT: 10.25 min) to give 1-(5-((2,6-dichloro-benzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (21.4 mg, 22%) as an off-white solid.

[0337] LCMS(ESI,m / z):434[M+H] + .Analysis conditions: EVO C18,3.0 * 50 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.0 min), maintain 95% B (0.60 min), 95% B to 10% B (0.15 min); 210 nm; RT: 1.154 min.

[0338] 1H NMR (400 MHz, DMSO-d6) δ 7.51-7.49 (m, 2H), 7.42-7.38 (m, 1H), 6.95 (s, 2H), 5.12 (s, 2H), 4.12 (t, J = 6.8 Hz, 1H), 2.81-2.62 (m, 4H), 2.19-2.13 (m, 1H), 2.10-2.02 (m, 2H), 1.99 (s, 3H), 1.95-1.87 (m, 2H), 1.74-1.65 (m, 2H), 1.55-1.45 (m, 1H), 1.42-1.33 (m, 1H). (Example S38. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (38)) [ka]

[0339] Synthesis of 5-hydroxy-3-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-bromo-3-methyl-indan-1-one (500 mg, 2.22 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was added KOH (373 mg, 6.66 mmol, 3.00 equiv), Pd2(dba)3 (203 mg, 0.22 mmol, 0.10 equiv) and t-BuBrettPhos (215 mg, 0.440 mmol, 0.20 equiv). The reaction was stirred at 80° C. under nitrogen atmosphere for 12 hours. LCMS confirmed the reaction was complete. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (5 mM NH4HCO3 / ACN, 80 / 20) to give 5-hydroxy-3-methyl-2,3-dihydro-1H-inden-1-one (350 mg, 97%) as a yellow solid. LCMS (ESI, m / z): 163 [M+H]+ .

[0340] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-one [ka] To a stirred solution of 5-hydroxy-3-methyl-2,3-dihydro-1H-inden-1-one (250 mg, 1.54 mmol, 1.00 equiv) in MeCN (5.0 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (554 mg, 2.31 mmol, 1.50 equiv) and K2CO3 (638 mg, 4.62 mmol, 3.00 equiv). The reaction was stirred at 60° C. for 4 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA / PE=1 / 1) to give 5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-one (200 mg, 40%) as a yellow solid. LCMS (ESI, m / z): 321 [M+H] + .

[0341] Synthesis of isopropyl 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-one (200 mg, 0.62 mmol, 1.00 equiv) in THF (5.0 mL) was added Ti(OiPr)4 (0.5 mL, 1.87 mmol, 3.00 equiv) and methyl piperidine-4-carboxylate (89 mg, 0.62 mmol, 1.00 equiv). The reaction was stirred at 60° C. for 12 hours. LCMS confirmed the formation of the imine intermediate. The reaction was cooled to room temperature and NaBH4 (70 mg, 1.87 mmol, 3.00 equiv) was added. The resulting mixture was stirred for 0.5 hours. LCMS confirmed the reaction was complete. The reaction was quenched with 10 mL of water and filtered. The filtrate was diluted with ethyl acetate (20 mL). * 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on C18 silica eluting with water (5 mM NH4CO3 / ACN, 30 / 70) to give isopropyl 1-(5-((2,6-dichloro-benzyl)-oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 67%) as a yellow solid. LCMS (ESI, m / z): 476 [M+H] + .

[0342] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylic acid [ka] To a solution of isopropyl 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.42 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was added KOH (70 mg, 1.26 mmol, 3.00 equiv.). The reaction was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge C18 OBD Prep Column, 5 μm, 19 * 250 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 50% B (7 min); 254 / 210 nm; RT: 6.42 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (28.8 mg, 15%) as an off-white solid.

[0343] LCMS(ESI,m / z):434[M+H] + Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B (2.00 min), hold at 100% (0.70 min), 100% B to 5% B (0.05 min); 210 nm; RT: 1.590 min.

[0344] 1H NMR (300 MHz, DMSO-d6) δ 12.12 (br, 1H), 7.58-7.55 (m, 2H), 7.49-7.44 (m, 1H), 7.18-7.10 (m, 1H), 6.92-6.87 (m, 2H), 5.20 (s, 2H), 4.24-4.18 (m, 1H), 3.23-3.10 (m, 1H), 2.99-2.91 (m, 1H), 2.85-2.73 (m, 1H), 2.37-2.25 (m, 1H), 2.23-2.04 (m, 3H), 1.84-1.75 (m, 2H), 1.63-1.44 (m, 3H), 1.28-1.19 (m, 3H). (Example S39. Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-3-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (39)) [ka]

[0345] Step 1: Synthesis of 5-hydroxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one [ka] A mixture of 5-bromo-3,3-dimethyl-indan-1-one (500 mg, 2.09 mmol, 1.00 equiv), PhCHNOH (1518.13 mg, 3.14 mmol, 1.50 equiv), RockPhos G3 Pd (191.49 mg, 0.21 mmol, 0.10 equiv) and K2CO3 (865.71 mg, 6.270 mmol, 3.00 equiv) in DMF (5.0 mL) was stirred at 90 °C for 12 h. The reaction was complete by LCMS. The reaction was acidified to pH 4-5 with 1 M hydrochloric acid. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE / EA, 1 / 1) to give 5-hydroxy-3,3-dimethyl-indan-1-one (300 mg, 81%) as a pale yellow oil. LCMS(ESI,m / z):177[M+H] +.

[0346] Synthesis of 5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-one [ka] A mixture of 5-hydroxy-3,3-dimethyl-indan-1-one (300 mg, 1.70 mmol, 1.00 equiv), 2-(bromomethyl)-1,3-dichloro-benzene (408 mg, 1.70 mmol, 1.00 equiv) and K2CO3 (704 mg, 5.10 mmol, 3.00 equiv) in MeCN (6.0 mL) was stirred at 80° C. for 12 h. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE / EA, 2 / 1) to give 5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (200 mg, 35%) as a pale yellow oil. LCMS (ESI, m / z): 335 [M+H] + .

[0347] Synthesis of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of 5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (200 mg, 0.60 mmol, 1.00 equiv.), methyl piperidine-4-carboxylate (170.85 mg, 1.20 mmol, 2.00 equiv.), zinc chloride (1.9 M / 2-Me-THF, 0.64 mL, 1.20 mmol, 2.00 equiv.) and NaBH3CN (152.74 mg, 2.400 mmol, 4.00 equiv.) in methanol (5.0 mL) was stirred at 60° C. for 12 hours. The reaction was complete by LCMS. The reaction was quenched by the addition of 50 mL of water and filtered. The filtrate was dissolved in ethyl acetate (20 mL).* 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (PE / EA, 3 / 1) to give methyl 1-(5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 36%) as a pale yellow oil. LCMS (ESI, m / z): 462 [M+H] + .

[0348] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.22 mmol, 1.00 equiv.) and LiOH·HO (45.41 mg, 1.08 mmol, 5.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. The mixture was acidified to pH 4-5 with 1 M hydrochloric acid and filtered. The solid was collected to give 1-(5-((2,6-dichlorobenzyl)oxy)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (54.4 mg, 56%) as a white solid.

[0349] LCMS(ESI,m / z):448[M+H] + .Analysis conditions: EVO C18,3.0 * 50 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B (2.0 min), maintain 95% B (0.60 min), 95% B to 10% B (0.15 min); 220 nm; RT: 1.255 min.

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 11.08 (s, 1H), 7.90-7.85 (m, 1H), 7.59-7.57 (m, 2H), 7.51-7.47 (m, 1H), 7.06-7.00 (m, 2H), 5.26 (s, 2H), 5.12-5.07 (m, 1H), 3.49-3.46 (m, 1H), 3.07-2.95 (m, 3H), 2.63-2.56 (m, 1H), 2.26-2.14 (m, 3H), 2.08-2.00 (m, 2H), 1.92-1.89 (m, 1H), 1.41 (m, 3H), 1.19 (s, 3H). Biological Examples Example B1. Cell Membrane Preparation

[0351] CHO cells expressing recombinant S1P5 receptor were cultured at 500 cm 2 Cells were grown in culture trays, once confluent, rinsed, and detached using cell-lifting buffer (10 mM HEPES, 154 mM NaCl, 6.85 mM EDTA, pH 7.4). Cells were then pelleted by centrifugation, resuspended, and homogenized in membrane preparation buffer (10 mM HEPES and 10 mM EDTA, pH 7.4) using a Polytron PT 1200E homogenizer (Kinematica, Luzern, Switzerland). Cellular proteins were pelleted by centrifugation at 48,000×g for 30 min at 4° C. The resulting supernatant was discarded, and the pellet was resuspended in membrane preparation buffer, homogenized a second time, and then centrifuged again as above. The final cell protein pellet was suspended in ice-cold resuspension buffer (10 mM HEPES and 0.1 mM EDTA, pH 7.4), aliquoted and stored at -80°C until use. Example B2. GTPγS Binding Assay

[0352] [35 Functional binding assays for [S]-GTPγS were performed in 96-well plates with a non-binding surface in a final volume of 200 μL. Test compounds were serially diluted in DMSO and added to the assay plate in a total volume of 0.4 μL using a Tecan D300E digital printer. Sphingosine-1-phosphate (S1P) controls were prepared separately by preparing a 400 μM stock solution from S1P pellet (100 nmol) / Na2CO3 (10 mM) (containing 2% β-cyclodextrin). Serial dilutions of S1P were made in complete assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.1% fatty acid-free bovine serum albumin (BSA), and 30 μg / mL saponin, pH 7.4) and transferred to wells already containing 0.4 μL of DMSO. All wells were then loaded with a total of 40 μL complete assay buffer, except for the non-specific binding (NSB) wells. For the NSB wells, 50 μM GTPγS (Sigma Aldrich, cat#G8634, St. Louis, MO) was added at 40 μL / well to wells containing 0.4 μL DMSO. The assay was started by adding 120 μL / well of CHO-S1P receptor membrane solution containing 40 μg / mL membrane protein, 16.67 μM guanosine diphosphate (GDP; Sigma Aldrich, cat#G7127, St. Louis, MO), and 2.5 mg / mL WGA PVT SPA beads / complete buffer. The assay plate was then sealed and gently shaken for 30 minutes at room temperature. 1 nM [ 35S]-GTPγS (PerkinElmer, cat#NEG030X250UC, Waltham, MA) / basic assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, and 1 mM EDTA, pH 7.4) was added to the assay plate at 40 μL / well to a final concentration of 200 pM, and the plate was incubated for an additional 40 min at room temperature with gentle shaking. The assay was terminated by centrifugation of the plate at 1000 rpm for 3 min using an Eppendorf 5810R centrifuge (Eppendorf, Hamburg, Germany), and G protein-bound radioactivity was quantified using a MicroBeta2 microplate scintillation counter (PerkinElmer, Waltham, MA). This assay is a measure of S1P5 agonism, as G protein-bound radioactivity directly correlates with receptor activation and coupling to G proteins. Results are shown in Table 2. Table 2. S1P5 GTPγS binding in example compounds [Table 10] [Table 11] ND = Not Detected +++++ indicates binding < 1 nM. ++++ indicates binding >1 nM and <= 10 nM. +++ indicates binding greater than 10 nM and <= 100 nM. ++ indicates binding >100nM and <=1000nM. + indicates binding is greater than 1000 nM and ≦10000 nM.

[0353] Although the present invention has been specifically described by way of illustration and example for purposes of clarity of understanding, the above description and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Formula I: 【Chemistry 1】 I or a pharmaceutically acceptable salt thereof [In the formula, R １ are each independently halo, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ６ is cycloalkyl; R ２ are each independently halo, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; R ３ａ and R ３ｂ are independently H, C １ ~C ６ Alkyl, halo, or C １ ~C ６ haloalkyl; x is 1 to 5; y is 0 to 3; z is 1 to 5; n is 1, 2, or 3; R ４ are each independently -CO ２ H, halo, C １ ~C ６ haloalkyl, or C １ ~C ６ alkyl, or two R ４ The groups, together with the carbon atoms to which they are attached, form -CO ２ fused, bridged, or spiro C optionally substituted with H ３ ~C ５ Forms a cycloalkyl, provided that at least one R ４ The group is -CO ２ H or -CO ２ H moiety].

2. R １ each independently represents halo, -CN, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, or C ３ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R １ are each independently F, Cl, I, —CN, or —CH ３ , -CF ３ , -OCH(CH ３ ) ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2; or R is 2 or 3; or R is 4 or 5;

4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein x is 1, 2, or 3.

5. formula: 【Chemistry 2】 But the formula: 【Transformation 3】 2. The compound of claim 1, wherein:

6. R ２ are independently halo, C １ ~C ３ Alkyl, or C １ ~C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

7. R ２ are each independently F or —CH ３ 7. The compound of claim 6, wherein:

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein y is 1.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein y is 0.

10. formula: 【Chemistry 4】 But the formula: 【Transformation 5】 2. The compound of claim 1, wherein:

11. R ３ａ and R ３ｂ are independent and H, C １ ~C ３ Alkyl, halo, or C １ ~C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

12. R ３ａ and R ３ｂ are independently H or —CH ３ 12. The compound of claim 11, wherein:

13. formula: 【Transformation 6】 But the formula: 【Transformation 7】 2. The compound of claim 1, wherein:

14. formula: 【Transformation 8】 But the formula: 【Chemistry 9】 14. The compound of claim 13, wherein:

15. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

16. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

17. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 3.

18. R ４ are each independently -CO ２ H, halo, C １ ~C ３ haloalkyl, or C １ ~C ３ alkyl, provided that at least one R ４ The group is -CO ２ 2. The compound of claim 1, wherein R is H, or a pharmaceutically acceptable salt thereof.

19. Two R's ４ The groups, together with the carbon atoms to which they are attached, form -CO ２ fused or spiro C optionally substituted by H; ３ ~C ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl.

20. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein z is 1 to 3.

21. formula: 【Chemistry 10】 But the formula: 【Chemistry 11】 2. The compound of claim 1, wherein:

22. formula: 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A modulator of sphingosine-1-phosphate receptor 5 (S1P5), comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

25. 23. A pharmaceutical composition for use in treating a neurological disorder in a subject in need thereof, comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

26. 26. The pharmaceutical composition of claim 25, wherein the neurological disease is Alzheimer's disease or multiple sclerosis.

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