Azetidinyl compounds containing a carboxylic acid group for the treatment of neurodegenerative diseases - Patent Application 20070229633

Abstract

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. [Formula 1] TIFF2024522718000499.tif4353

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 211,313, filed June 16, 2021, which is incorporated by reference herein in its entirety for all purposes.

[0002] Field The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of the compounds and compositions to treat neurodegenerative diseases. [Background technology]

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate) is a bioactive sphingolipid synthesized by sphingolipid turnover in cells 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 receptor family are S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P mediates various cellular responses, such as proliferation, cytoskeletal organization and migration, adhesion and tight junction assembly, and morphogenesis.

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

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

[0006] In certain embodiments, compounds and compositions thereof for modulating S1P5 are described herein. In various embodiments, the compounds and compositions thereof may be used to treat neurodegenerative diseases.

[0007] The present embodiments may be more fully understood by reference to the detailed description and examples, which are intended to be exemplary of non-limiting embodiments.

[0008] Embodiment 1 is a compound of formula (I): [ka] [In the formula, Ring A is [ka] and; Z1 and Z2 are independently CR0 or N; L is azetidinyl optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl; R0 are each independently H, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C6 haloalkyl, or C1-C6 alkoxy; or two R groups together with the carbon atoms to which they are attached form a fused phenylene; R1 is C6-C 10 aryl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 R' groups, and the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen; R' are each independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; or two R' groups together with the carbon atoms to which they are attached form a fused phenylene; R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H; Alternatively, the dashed line between R2 and R3 represents a ring structure in which R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H; x is 1 to 5; Each R4 is independently -CO2H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; R5 and R6 are independently H or C1-C6 alkyl; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0009] In embodiment 2, Ring A [ka] That is, The compound of embodiment 1, or a pharmaceutically acceptable salt thereof.

[0010] Embodiment 3 is Ring A [ka] That is, The compound of embodiment 1, or a pharmaceutically acceptable salt thereof.

[0011] Embodiment 4 is Z1 and Z2 are each independently CR0; The compound of embodiment 3, or a pharmaceutically acceptable salt thereof.

[0012] Embodiment 5 is Z1 is N; Z2 is CR0, The compound of embodiment 3, or a pharmaceutically acceptable salt thereof.

[0013] Embodiment 6 is Z1 is CR0; Z2 is N, The compound of embodiment 3, or a pharmaceutically acceptable salt thereof.

[0014] Embodiment 7 is each R0 is independently H, —CN, C1-C3 alkyl, C3-C5 cycloalkyl, halo, C1-C3 haloalkyl, or C1-C3 alkoxy; or two R groups together with the carbon atoms to which they are attached form a fused phenylene; The compound according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof.

[0015] Embodiment 8 is R0 are each independently H, -CN, methyl, ethyl, isopropyl, cyclopropyl, Cl, F, -CF3, or -OCH3; or two R groups together with the carbon atoms to which they are attached form a fused phenylene; The compound of embodiment 7, or a pharmaceutically acceptable salt thereof.

[0016] Embodiment 9 is Ring A is [ka] That is, The compound according to any one of embodiments 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 10 is Ring A is [ka] That is, The compound according to any one of embodiments 1 and 3-8, or a pharmaceutically acceptable salt thereof.

[0018] Embodiment 11 is L, [ka] each of which is optionally substituted with 1 to 2 substituents independently selected from halo and C1-C3 alkyl; A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment 12 is L, [ka] each of which may be optionally substituted with one F, Cl, or methyl; The compound of embodiment 11, or a pharmaceutically acceptable salt thereof.

[0020] Embodiment 13 is L, [ka] That is, The compound of embodiment 12, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment 14 is R1 is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R' groups, and the heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen; A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment 15 is R1 is phenyl optionally substituted with 1 to 3 R' groups; The compound of embodiment 14, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 16 is R' are each independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl; or two R' groups together with the carbon atoms to which they are attached form a fused phenylene; A compound according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt thereof.

[0024] Embodiment 17 is R' are each independently halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; or two R' groups together with the carbon atoms to which they are attached form a fused phenylene; The compound of embodiment 16, or a pharmaceutically acceptable salt thereof.

[0025] Embodiment 18 is R' is independently F, Cl, methyl, ethyl, isopropyl, -CHF2, or cyclopropyl; or two R' groups together with the carbon atoms to which they are attached form a fused phenylene; The compound of embodiment 17, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 19 is R1, [ka] That is, A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 20 is R2 is H or C1-C3 alkyl; R3 is -(CH2) x -CO2H; x is 1 to 3; A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 21 is [ka] but, [ka] That is, The compound of embodiment 20, or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 22 is R2 and R3 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl substituted with 1 to 3 R4 groups, wherein at least one R4 group is -CO2H; A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof.

[0030] Embodiment 23 is each R4 is independently -CO2H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; The compound of embodiment 22, or a pharmaceutically acceptable salt thereof.

[0031] Embodiment 24 is R4 is, independently at each occurrence, -CO2H, methyl, F, Cl, -CF3, or -OCH3; The compound of embodiment 23, or a pharmaceutically acceptable salt thereof.

[0032] Embodiment 25 is [ka] but, [ka] That is, A compound according to any one of embodiments 1 to 19 and 22 to 24, or a pharmaceutically acceptable salt thereof.

[0033] Embodiment 26 is n is 0, A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof.

[0034] Embodiment 27 is n is 1, A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof.

[0035] Embodiment 28 is R5 and R6 are independently H or C1-C3 alkyl; The compound of embodiment 27, or a pharmaceutically acceptable salt thereof.

[0036] Embodiment 29 is R5 and R6 are independently H or methyl; The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof.

[0037] Embodiment 30 is -CR5R6- is -CH2-, -CH(CH3)-, or -C(CH3)2-; 30. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof.

[0038] Embodiment 31 is Formula (II): [ka] is expressed as A compound according to any one of embodiments 1, 2, and 7-9, and 11-26, or a pharmaceutically acceptable salt thereof.

[0039] Embodiment 32 is Formula (III): [ka] [In the formula, [ka] is a 4- to 6-membered heterocyclyl and at least one R group is —COH] is expressed as The compound according to any one of embodiments 1, 3-8, 10-19, 22-25, and 27-30, or a pharmaceutically acceptable salt thereof.

[0040] Embodiment 33 is a compound selected from the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0041] Embodiment 34 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0042] Embodiment 35 is a method of modulating sphingosine 1-phosphate receptor 5 (S1P5), comprising contacting S1P5 with an effective amount of a compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

[0043] Embodiment 36 is a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

[0044] Embodiment 37 is the method of embodiment 36, wherein the neurological disease is Alzheimer's disease or multiple sclerosis. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the stated features or components as referred to, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Consequently, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0046] The term "consisting of" means that the subject matter of the patented invention has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In another embodiment, the term "consisting of" excludes from the scope of any succeeding recitation any other features or components, excluding those that are not essential to the technical effect to be achieved.

[0047] The term "or" as used herein should be interpreted as an inclusive "or" meaning either 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 inherently mutually exclusive in some way.

[0048] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include every integer value within the stated range, and fractions thereof (such as tenths and hundredths of integers), where appropriate, unless otherwise specified. Also, any numerical range described herein with respect to any physical characteristic (e.g., polymer subunits, size, or thickness, etc.) should be understood to include every integer within the stated range, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise specified.

[0049] An "alkyl" group is an alkyl group containing 1 to 10 carbon atoms (C1-C 10An alkyl group is a saturated, partially saturated, or unsaturated, straight-chain or branched, acyclic hydrocarbon, 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) carbon atoms. 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 alkyls 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 containing 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(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH, -C(CH)=CH, -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When an alkyl group described herein is referred to as "substituted," it means any and all substituents found in the representative compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkoy; and optionally substituted with alkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when an alkyl group described herein is referred to as "substituted," it can be substituted with any of the substituents found in the representative compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; 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.

[0050] A "cycloalkyl" group is an alkyl group having 3 to 10 carbon atoms (C3-C6) having a single ring or multiple fused or bridged rings, which may be optionally substituted. 10In some embodiments, a cycloalkyl group is a saturated or partially saturated cyclic alkyl group (e.g., C-C cycloalkyl). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (C-C cycloalkyl), while in other embodiments, the number of ring carbon atoms is 3 to 5 (C-C cycloalkyl), 3 to 6 (C-C cycloalkyl), or 3 to 7 (C-C cycloalkyl). In some embodiments, a cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, by way of example, 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 group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0051] An "aryl" group is an alkyl group having 6 to 14 carbon atoms (C-C) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). 14 In some embodiments, an aryl group is an aromatic carbocyclic group of 6 to 14 carbons (C-C 14 aryl), in other embodiments, 6 to 12 (C-C 12 aryl) or 6 to 10 carbon atoms (C6-C 10The term "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Particular aryls include 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 fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0052] "Halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0053] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo radicals (C-C haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo radicals (C-C haloalkyl). The halo radicals can be identical, or the halo radicals can be different. Unless explicitly stated otherwise, haloalkyl groups can be optionally substituted.

[0054] A "heteroaryl" group is an aromatic ring system having 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 3 to 6 ring atoms, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (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), imidazopyridyl (e.g., azaindolyl, benzo[d]imidazolyl), benzo[d]isoxazolyl, ... Heteroaryl groups include, but are not limited to, groups such as benzoimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0055] A "heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are replaced with heteroatoms independently selected from O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include saturated and partially saturated ring systems. Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, and the ring may be fused to an aryl or heteroaryl ring, regardless 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]phenoxathiinyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono- or multiply substituted (e.g., pyridyl or morpholinyl groups that are di-, tri-, tetra-, penta-, or hexa-substituted or di-substituted with various substituents, including, but not limited to, those described below).

[0056] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0057] A "carboxy" group is a radical of the formula: --C(O)OH.

[0058] When a group described herein (excluding alkyl groups) is referred to as "substituted," it can be substituted with any suitable substituent. Illustrative substituents include those found in the representative compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; 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; monocyclic or fused or fused rings. is cycloalkyl, which may be non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0059] Certain alternative chemical names of common use may be used, e.g., divalent groups such as a divalent "alkyl" group, a divalent "phenyl" group, a divalent "heteroaryl" group, or a divalent "heterocyclyl" group may also be referred to as an "alkylene" group, a "phenylene" group, a "heteroarylene" group, or a "heterocyclylene" group, respectively.

[0060] Embodiments of the present disclosure are intended to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein (e.g., compounds of Formula (I)).

[0061] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, such as inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of 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, but are not limited to, inorganic and organic acids such as 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. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride, formate, and mesylate. Other examples are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0062] Unless otherwise specified, the terms "stereoisomer" or "stereoisomerically pure," as used herein, 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 will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, or greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomers, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0063] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of such forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the 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.For example, 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 (EL Eliel, 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); See 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).

[0064] It should also be noted that the compounds disclosed herein may include E and Z isomers, or mixtures thereof, and cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are mixtures of E and Z isomers.

[0065] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentrations of isomers depend on the environment in which the compound is found, and may vary depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, which are called tautomers of each other: [ka]

[0066] As will be readily understood by one of ordinary skill in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present disclosure.

[0067] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S), or carbon-14 ( 14 They may be radiolabeled with deuterium (e.g., C) or 2 H), carbon-13 ( 13 C), or nitrogen-15( 15The compound may be isotopically enriched, such as with N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds disclosed herein are provided, e.g., isotopologues are deuterium-, carbon-13-, and / or nitrogen-15-enriched compounds. As used herein, "deuterated" refers to compounds in which at least one hydrogen (H) is replaced with deuterium (D or 2 H), meaning that the compound is enriched with deuterium at at least one position.

[0068] Regardless of stereoisomeric or isotopic composition, it is understood that each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts described herein.Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound described herein.Furthermore, the isotopic composition is limited to the elements present in each compound disclosed herein or its salt, but otherwise can vary independently of the choice of pharmaceutically acceptable salt of each compound.

[0069] It should be noted that if there is a discrepancy between a drawn structure and the name of that structure, the drawn structure should be given more weight.

[0070] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is a neurodegenerative disease described herein, or a symptom thereof.

[0071] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition; a method of preventing a subject from acquiring a disorder, disease, or condition; or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease described herein, or a symptom thereof.

[0072] The term "effective amount" in reference to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof.

[0073] As used herein, the term "subject" or "patient" includes animals, in one embodiment mammals, and in another embodiment humans, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. In one embodiment, the subject is a human having or at risk of having an S1P5-mediated disorder, or a symptom thereof.

[0074] While various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable subcombination. Conversely, while the invention may be described herein for clarity in the context of separate embodiments, the invention may also be implemented in a single embodiment.

[0075] compound In one embodiment, a compound of formula (I): [ka] [In the formula, Ring A is [ka] and; Z1 and Z2 are independently CR0 or N; L is azetidinyl optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl; R0 are each independently H, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C6 haloalkyl, or C1-C6 alkoxy; or two R groups together with the carbon atoms to which they are attached form a fused phenylene; R1 is C6-C 10 aryl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 R' groups, and the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen; R' are each independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; or two R' groups together with the carbon atoms to which they are attached form a fused phenylene; R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H; Alternatively, the dashed line between R2 and R3 represents a ring structure in which R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H; x is 1 to 5; Each R4 is independently -CO2H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; R5 and R6 are independently H or C1-C6 alkyl; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0077] In some embodiments, Z1 and Z2 are independently CR0 or N. In some embodiments, Z1 and Z2 are each independently CR0. In some embodiments, one of Z1 and Z2 is N and the other of Z1 and Z2 is CR0. In some embodiments, Z1 is N and Z2 is CR0. In some embodiments, Z1 is CR0 and Z2 is N. In some embodiments, Z1 and Z2 are each N. In some embodiments, Z1 and Z2 are each CH. In some embodiments, Z1 is CH and Z2 is CR0, where R0 is C1-C6 alkyl. In some embodiments, Z1 is CR0, where R0 is C1-C6 alkyl and Z2 is CH. In some embodiments, Z1 is CR0, where R0 is halo and Z2 is CH. In some embodiments, Z1 is CH and Z2 is CR0, where R0 is halo. In some embodiments, Z1 is N and Z2 is CH. In some embodiments, Z1 is CH and Z2 is N. In some embodiments, Z1 is N and Z2 is CR0, where R0 is C1-C6 alkyl. In some embodiments, Z2 is N and Z1 is CR0, where R0 is C1-C6 alkyl.

[0078] In some embodiments, each R is independently H, -CN, C-C alkyl, C-C cycloalkyl, halo, C-C haloalkyl, or C-C alkoxy. In some embodiments, each R is independently H, -CN, C-C alkyl, C-C cycloalkyl, halo, C-C haloalkyl, or C-C alkoxy. In some embodiments, each R is independently H, -CN, C-C alkyl, C-C cycloalkyl, halo, C-C haloalkyl, or C-C alkoxy. In some embodiments, each R is independently H, -CN, methyl, ethyl, isopropyl, cyclopropyl, Cl, F, -CF, or -OCH. In some embodiments, each R is independently H, methyl, or F. In some embodiments, two R groups together with their attached carbon atoms form a fused phenylene.

[0079] In some embodiments, R0 is H.

[0080] In some embodiments, R0 is -CN.

[0081] In some embodiments, R is C-C alkyl. In some embodiments, R is C-C alkyl. In some embodiments, R is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is n-propyl. In some embodiments, R is isopropyl.

[0082] In some embodiments, R is C-C cycloalkyl. In some embodiments, R is C-C cycloalkyl. In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R is cyclopropyl.

[0083] In some embodiments, R is halo. In some embodiments, R is Cl, F, or Br. In some embodiments, R is Cl. In some embodiments, R is F. In some embodiments, R is Br.

[0084] In some embodiments, R is C-C haloalkyl. In some embodiments, R is C-C haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R is C-C haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R is -CF, -CHF, -CHF, -CCl, -CHCl, -CHCl, -CFCl, -CHCF, -CHCHF, or -CHCCl. In some embodiments, R is -CF.

[0085] In some embodiments, R is C-C alkoxy. In some embodiments, R is C-C alkoxy. In some embodiments, R is -OCH, -OCHCH, -OCHCHCH, or -OCH(CH). In some embodiments, R is -OCH. In some embodiments, R is -OCHCH.

[0086] In some embodiments, two R0 groups together with their attached carbon atoms form a fused phenylene.

[0087] In some embodiments, ring A is [ka] is.

[0088] In some embodiments, ring A is [ka] is.

[0089] In some embodiments, L is azetidinyl optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl. In some embodiments, L is optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl. [ka] In some embodiments, L is optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl. [ka] In some embodiments, L is azetidinyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C6 alkyl. In some embodiments, L is unsubstituted azetidinyl. In some embodiments, L is azetidinyl substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl. In some embodiments, L is azetidinyl substituted with 1 to 3 substituents independently selected from halo and C1-C6 alkyl. In some embodiments, L is [ka] In some embodiments, L is: [ka] each of which may be optionally substituted with one F, Cl, or methyl. In some embodiments, L is [ka] is.

[0090] In some embodiments, R is C-C 10 In some embodiments, R1 is aryl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 R' groups, and the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R' groups, and the heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is phenyl, each of which is optionally substituted with 1-3 R' groups.

[0091] In some embodiments, R1 is a C6-C optionally substituted with 1 to 5 R' groups. 10 In some embodiments, R is a C-C alkyl group optionally substituted with 1 to 3 R' groups. 10 In some embodiments, R is an unsubstituted C-C 10 In some embodiments, R is a C-C aryl substituted with 1-5 R' groups. 10 In some embodiments, R is a C-C aryl substituted with 1-5 R' groups. 10 In some embodiments, R1 is aryl. In some embodiments, R1 is unsubstituted phenyl. In some embodiments, R1 is phenyl substituted with 1 to 3 R' groups.

[0092] In some embodiments, R1 is a 5- to 6-membered heteroaryl optionally substituted with 1-5 R' groups, where the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is an unsubstituted 5- to 6-membered heteroaryl, where the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is a 5- to 6-membered heteroaryl substituted with 1-5 R' groups, where the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is a 5- to 6-membered heteroaryl optionally substituted with 1-3 R' groups, where the heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is a 5-membered heteroaryl optionally substituted with 1-5 R' groups, where the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, or furanyl, each of which is optionally substituted with 1 to 5 R' groups. In some embodiments, R1 is a 6-membered heteroaryl, each of which is optionally substituted with 1 to 5 R' groups, where the heteroaryl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with 1 to 5 R' groups.

[0093] In some embodiments, each R' is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl. In some embodiments, each R' is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl. In some embodiments, each R' is independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl. In some embodiments, each R' is independently halo, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl. In some embodiments, each R' is independently F, Cl, methyl, ethyl, isopropyl, -CHF, or cyclopropyl. In some embodiments, two R' groups together with their bonding carbon atoms form a fused phenylene.

[0094] In some embodiments, R' is halo. In some embodiments, R' is F, Cl, or Br. In some embodiments, R' is F. In some embodiments, R' is Cl. In some embodiments, R' is Br.

[0095] In some embodiments, R' is C1-C6 alkyl. In some embodiments, R' is C1-C3 alkyl. In some embodiments, R' is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R' is methyl. In some embodiments, R' is ethyl. In some embodiments, R' is n-propyl. In some embodiments, R' is isopropyl.

[0096] In some embodiments, R' is C1-C6 haloalkyl. In some embodiments, R' is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R' is C1-C3 haloalkyl. In some embodiments, R' is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R' is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R' is -CF3. In some embodiments, R' is -CHF2.

[0097] In some embodiments, R' is C1-C6 alkoxy. In some embodiments, R' is C1-C3 alkoxy. In some embodiments, R' is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R' is -OCH3.

[0098] In some embodiments, R' is C3-C6 cycloalkyl. In some embodiments, R' is C3-C5 cycloalkyl. In some embodiments, R' is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R' is cyclopropyl. In some embodiments, R' is cyclobutyl.

[0099] In some embodiments, two R' groups together with their attached carbon atoms form a fused phenylene.

[0100] In some embodiments, R1 is [ka] is.

[0101] In some embodiments, R2 is H or C1-C6 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is C1-C3 alkyl. In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl.

[0102] In some embodiments, R3 is -(CH2) x -CO2H, where x is 1 to 5. In some embodiments, R3 is -(CH2) x In some embodiments, R3 is —CO2H, where x is 1 to 3. In some embodiments, R3 is —CH2CO2H. In some embodiments, R3 is —(CH2)2CO2H. In some embodiments, R3 is —(CH2)3CO2H.

[0103] 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.

[0104] In some embodiments, R2 is H or C1-C3 alkyl; R3 is -(CH2) x x is 1 to 3. In some embodiments, R is H; R is -(CH) x -COH; and x is 1 to 3. In some embodiments, R is C-C alkyl; and R is -(CH). x -CO2H; x is 1 to 3.

[0105] In some embodiments, [ka] teeth, [ka] is.

[0106] In some embodiments, R2 and R3, together with their attached nitrogen atom, form a 4- to 6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H. In some variations, the heterocyclyl is saturated and has no additional heteroatoms. In some embodiments, R2 and R3, together with their attached nitrogen atom, form a 4-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H. In some embodiments, R2 and R3, together with their attached nitrogen atom, form a 5-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H. In some embodiments, R2 and R3, together with their attached nitrogen atom, form a 6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl substituted with 1-3 R4 groups, where at least one R4 group is -CO2H. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1-5 R4 groups, where at least one R4 group is -CO2H.

[0107] In some embodiments, each R4 is independently -CO2H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. In some embodiments, each R4 is independently -CO2H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy. In some embodiments, each R4 is independently -CO2H, methyl, F, Cl, -CF3, or -OCH3.

[0108] In some embodiments, R4 is -CO2H.

[0109] In some embodiments, R4 is halo. In some embodiments, R4 is F, Cl, or Br. In some embodiments, R4 is F. In some embodiments, R4 is Cl.

[0110] In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl.

[0111] In some embodiments, R4 is C1-C6 haloalkyl. In some embodiments, R4 is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R4 is C1-C3 haloalkyl. In some embodiments, R4 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R4 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R4 is -CF3.

[0112] In some embodiments, R4 is C1-C6 alkoxy. In some embodiments, R4 is C1-C3 alkoxy. In some embodiments, R4 is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R4 is -OCH3.

[0113] In some embodiments, [ka] teeth, [ka] That is,

[0114] In some embodiments, n is 0. In some embodiments, n is 1.

[0115] In some embodiments, R5 and R6 are independently H or C1-C6 alkyl. In some embodiments, R5 and R6 are independently H or C1-C3 alkyl. In some embodiments, R5 and R6 are independently H or methyl.

[0116] In some embodiments, R5 is H. In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is C1-C3 alkyl. In some embodiments, R5 is methyl, ethyl, n-propyl, or isopropyl.

[0117] In some embodiments, R6 is H. In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is C1-C3 alkyl. In some embodiments, R6 is methyl, ethyl, n-propyl, or isopropyl.

[0118] In some embodiments, R5 and R6 are each H. In some embodiments, one of R5 and R6 is H and the other of R5 and R6 is C1-C6 alkyl. In some embodiments, one of R5 and R6 is H and the other of R5 and R6 is C1-C3 alkyl. In some embodiments, one of R5 and R6 is H and the other of R5 and R6 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, one of R5 and R6 is H and the other of R5 and R6 is methyl. In some embodiments, -CR5R6- is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0119] In some embodiments, the compound of formula (I) has formula (II): [ka] wherein L, R, R, R, and R are as described for formula (I). is a compound of

[0120] In some embodiments, the compound of formula (II) has formula (IIA) or (IIB): [ka] wherein L, R, R, R, R, and R are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl] is a compound of

[0121] In some embodiments, the compound of Formula (II) has the formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf): [ka] wherein R0, R1, R2, R3, and R4 are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl, and each R″ is independently selected from halo and C1-C6 alkyl. is a compound of

[0122] In some embodiments, the compound of Formula (II) has the formula (II-1), (II-2), or (II-3): [ka] wherein L, R, R, R, R, and R' are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl] is a compound of

[0123] In some embodiments, the compound of Formula (II) has the formula (II-1a), (II-1b), (II-2a), (II-2b), (II-3a), or (II-3b): [ka] wherein R, R, R, R, and R' are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl, and each R″ is independently selected from halo and C1-C6 alkyl. is a compound of

[0124] In some embodiments, the compound of formula (I) has formula (III): [ka] wherein L, R, Z, Z, R, R, and R are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl] is a compound of

[0125] In some embodiments, the compound of Formula (III) has the formula (IIIA), (IIIB), (IIIC), or (IIID): [ka] wherein L, R, R, R, R, and R are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl] is a compound of

[0126] In some embodiments, the compound of Formula (III) has the formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh): [ka] wherein R0, R1, R4, R5, and R6 are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl, and each R″ is independently selected from halo and C1-C6 alkyl. is a compound of

[0127] In some embodiments, the compound of Formula (III) has the formula (III-1), (III-2), (III-3), or (III-4): [ka] wherein L, R, R, R, R, and R' are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl] is a compound of

[0128] In some embodiments, the compound of Formula (III) has the formula (III-1a), (III-1b), (III-2a), (III-2b), (III-3a), (III-3b), (III-4a), or (III-4b): [ka] wherein R, R, R, R, and R' are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl, and each R″ is independently selected from halo and C1-C6 alkyl. is a compound of

[0129] In some embodiments, the compound of Formula (III) has the formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), or (IV-f): [ka] wherein R, R, R, R, and R' are as described for formula (I); [ka] is a 4- to 6-membered heterocyclyl, and each R″ is independently selected from halo and C1-C6 alkyl. In some variations, each R' is independently halo or C1-C6 alkyl and each R0 is independently halo or C1-C6 alkyl.

[0130] In the description herein, any description, variation, embodiment, or aspect of a part may be combined with any description, variation, embodiment, or aspect of other parts, and it is understood that any and all combinations of descriptions are the same as if specifically and individually described.For example, any description, variation, embodiment, or aspect provided herein for ring A of formula (I) may be combined with any description, variation, embodiment, or aspect of L, Z1, Z2, R0, R', R1, R2, R3, R4, R5, R6, x, and n, and any and all combinations are the same as if specifically and individually described.It is also understood that the descriptions, variations, embodiments, or aspects of all formula (I), where applicable, are similarly applied to and described in the same way for other formulas detailed herein, and any and all descriptions, variations, embodiments, or aspects are the same as if they were described separately and individually for all formulas. For example, all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, may be used in conjunction with the formulae as detailed herein (e.g., Formulas (II), (IIA), (IIB), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (II-1), (II-2), (II-3), (II-1a), (II-1b), (II-2a), (II-2b), (II-3a), (II-3b), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIa), (IIIb), (IIIc), (IIId), (IIIe)). , (IIIf), (IIIg), (IIIh), (III-1), (III-2), (III-3), (III-4), (III-1a), (III-1b), (III-2a), (III-2b), (III-3a), (III-3b), (III-4a), (III-4b), (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), and (IV-f), etc.), and any and all explanations, variations, embodiments, or aspects thereof are the same as if they were set forth separately and individually for all formulas.

[0131] In some embodiments, provided is a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof. While certain compounds described in this disclosure, including Table 1, are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any and all stereochemical forms (such as any enantiomeric or diastereomeric forms), and any tautomeric or other forms, of any of the compounds of this disclosure, including Table 1, are described herein. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] or a pharmaceutically acceptable salt thereof.

[0132] It is understood that combinations of substituents and / or variables within the depicted formulae herein are permissible only if such combinations result in stable compounds.

[0133] Furthermore, all compounds of formula (I) that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of formula (I) can be converted into their free base or acid form by standard techniques.

[0134] Synthesis method The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or the methods provided herein.By way of example, and not limitation, the compound of formula (I) can be prepared as outlined in Scheme 1 and the Examples described herein.It should be noted that those skilled in the art will know how to modify the procedures described in the illustrative Schemes and Examples to achieve their intended purpose. [ka]

[0135] As outlined in Scheme 1, compounds of general formula A can be synthesized from aryl bromides a or a-1 via Negishi coupling with azetidine b, followed by reductive amination with amino acid ester c, Buchwald coupling with an aryl bromide, and subsequent hydrolysis. Alternatively, compounds of general formula A can be synthesized from aryl bromides a or a-1 via coupling with amino acid ester c, followed by Negishi coupling with azetidine b, Buchwald coupling with an aryl bromide, and subsequent hydrolysis.

[0136] Compounds of general formula B can be obtained from aryl bromides a or a-1 via coupling with amino acid ester c, followed by Buchwald coupling with an aryl azetidine, and subsequent hydrolysis, as shown in Scheme 1.

[0137] How to use An embodiment of the present disclosure provides a method for modulating sphingosine 1-phosphate receptor 5 (S1P5) in a subject in need of treatment, characterized by administering to the subject an effective amount of a compound of formula (I). The modulation (e.g., inhibition or activation) of S1P5 can be evaluated and demonstrated by various methods 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).

[0138] In one aspect, provided herein is a method for modulating S1P5, comprising contacting S1P5 with an effective amount of a compound of formula (I) or any embodiment or variation 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.

[0139] 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 compound of formula (I) may reduce the activity of S1P5 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%, Adjust from 85-100%, 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%.

[0140] In another aspect, provided herein are methods for treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, provided herein are methods for preventing a neurological disorder in a subject in need thereof, 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-Barré 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.

[0141] 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 showing 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 treatment 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 treatment stabilizes the neurological disorder (prevents or slows the worsening of the neurological disorder). In some embodiments, administering a compound of Formula (I) to a subject in need of treatment delays the onset or recurrence of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment slows the progression of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment provides partial remission of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment provides complete remission of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment reduces the dosage of one or more other drugs required to treat the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment enhances the effectiveness of another drug used to treat the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment slows the progression of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment improves the quality of life of a subject with a neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment prolongs the survival of a subject with a neurological disorder.

[0142] In one aspect, provided herein is a method of preventing a subject susceptible to a neurological disorder from developing any symptoms of the neurological disorder, comprising administering to said subject a compound of Formula (I). In some embodiments, provided herein is a method of preventing a subject not yet exhibiting symptoms of a neurological disorder from developing any symptoms of the neurological disorder, comprising administering to said subject a compound of Formula (I).

[0143] In some aspects, provided herein are methods for reducing the extent of a neurological disorder in a subject, comprising administering to the subject a compound of Formula (I). In some embodiments, provided herein are methods for stabilizing a neurological disorder in a subject, comprising administering to the subject a compound of Formula (I). In some embodiments, the method prevents the neurological disorder from worsening. In some embodiments, the method delays the worsening of the neurological disorder.

[0144] In another aspect, provided herein is a method of delaying the onset or recurrence of a neurological disease in a subject, comprising administering to said subject a compound of formula (I).

[0145] In some embodiments, provided herein is a method for 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 partial remission of the neurological disorder. In some embodiments, the method provides complete remission of the neurological disorder.

[0146] In a further aspect, provided herein is a method of reducing the dosage of one or more other drugs required to treat a neurological disorder in a subject, comprising administering to said subject a compound of Formula (I). In some embodiments, provided herein is a method of enhancing the effect of another drug used to treat a neurological disorder in a subject, comprising administering to said subject a compound of Formula (I).

[0147] Also provided herein are methods for slowing the progression of a neurological disorder in a subject, comprising administering to the subject a compound of Formula (I). In some embodiments, the methods improve the quality of life of a subject with a neurological disorder. In some embodiments, the methods extend the survival of a subject with a neurological disorder.

[0148] In another aspect, provided herein is a method for treating neurological symptoms 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 neurological symptoms caused by a disease in a subject in need of prevention, 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 that causes neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject who does not yet exhibit neurological symptoms of a disease that causes neurological symptoms 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 extent of neurological symptoms caused by the disease in the subject. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment stabilizes neurological symptoms of the disease (prevents or delays the worsening of neurological symptoms). In some embodiments, administering a compound of Formula (I) to a subject in need of treatment delays the onset or recurrence of neurological symptoms caused by the disease. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment slows the progression of neurological symptoms caused by the disease. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment provides partial remission of the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment provides complete remission of the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment reduces the dose of one or more other drugs needed to treat the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment enhances the effect of another drug used to treat the neurological symptoms of the disease. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment slows the progression of the disease causing neurological symptoms.In some embodiments, administering a compound of Formula (I) to a subject in need of treatment improves the quality of life of the subject having a disease that causes neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject in need of treatment prolongs the survival of the subject having a disease that causes neurological symptoms. In some embodiments, the disease is Niemann-Pick disease.

[0149] In some embodiments, the compounds of formula (I) are useful in treating Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathies, 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, transplanted organ 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 vasculitis of the kidney, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, septic syndrome, kadzu ... Hexy, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, isolated polyglandular deficiency syndrome type I and polyglandular deficiency syndrome type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitis, enterocolitis synovitis, chlamydia, yersinia, and simian goiter. Monera-associated arthropathy, atherosclerosis / arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Royal-Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, autoimmune hepatitis of unknown cause, acquired immunodeficiency syndrome, acquired immunodeficiency-related disease, hepatitis B, hepatitis C, common variable immunodeficiency unclassifiable hypogammaglobulinemia, dilated cardiomyopathy, infertility, female infertility, ovarian insufficiency, premature ovarian failure, fibrotic lung disease, chronic wound healing, idiopathic interstitial pneumonia, post-inflammatory interstitial lung disease, fibrosis, interstitial pneumonia, interstitial lung disease associated with connective tissue 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,Ankylosing spondylitis-associated lung disease, vasculitic diffuse lung disease, hemosiderosis-associated lung disease, 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, type 1 autoimmune hepatitis (classic autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disorders due to organ transplantation, chronic immune disorders due to organ transplantation, osteoarthritis, primary sclerosing biliary tract disease Vasculitis, type 1 psoriasis, type 2 psoriasis, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidney, 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, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's disease / arteritis, autoimmune Thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lens-induced uveitis, primary vasculitis, leukoplakia, acute liver disease, chronic liver disease, alcoholic cirrhosis, alcohol-induced liver damage, cholestasis, idiosyncratic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, allergies and asthma, group B streptococcus (GBS) infection, psychiatric disorders (e.g., depression and schizophrenia) ), Th2- and ThI-mediated diseases, acute and chronic pain (various types of pain), and cancer (e.g., lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate, and rectal cancer, etc.) and hematopoietic malignancies (leukemia and lymphoma), and hematopoietic malignancies (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infections, acute pancreatitis, acute renal failure, adenocarcinoma, aerial ectopic beats, AIDS-dementia complex, alcoholic hepatitis, allergic conjunctivitis,Allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, 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 reactions to cardiopulmonary bypass, cartilage transplant rejection, cerebellar cortical degeneration, cerebellar disease, chaotic or multifocal atrial tachycardia, chemotherapy-related disorders, chronic myeloid leukemia (CML), chronic alcoholism, chronic inflammatory conditions, 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 sepsis, cystic fibrosis, cytokine therapy-related disorders, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, skin diseases, diabetes mellitus mellitus), diabetic atherosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's syndrome in middle age, drug-induced movement disorders induced by drugs that block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrine disorders, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal disorders and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymus graft rejection, Friedreich's ataxia, functional peripheral arterial disease, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, any organ or tissue transplant rejection, gram-negative sepsis, gram-positive sepsis, granulomas caused by intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, bleeding, hepatitis (type A), His bundle arrhythmias, HIV infection / HIV neuropathy, Hodgkin's disease,Hyperkinesia, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinesia, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, aortitis, influenza type A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's disease Sarcoma, renal transplant rejection, Legionella, leishmaniasis, leprosy, corticospinal system lesions, lipedema, liver transplant rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic, migraine, mitochondrial multisystem disease, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multisystem degeneration (Mencel Dejerine-Thomas) Shi-Drager and Machado-Joseph), myasthenia gravis, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic injury, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular atrophy, neutropenic fever, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disease, okt3 therapy, orchitis / epididymitis, orchitis / pi Pucca reconstruction, organomegaly, osteoporosis, pancreas graft rejection, pancreatic cancer, paraneoplastic syndrome / hypercalcemia associated with malignancy, parathyroid graft rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerosis, peripheral vascular disease, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrine abnormalities, monoclonal gammopathy, and skin manifestations syndrome), post-perfusion syndrome, post-pump syndrome pump syndrome, post-MI cardiotomy syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, senile chorea, senile dementia with Lewy bodies, seronegative arthropathy, shock, sickle cell anemia,Skin allograft rejection, skin lesion syndrome, small bowel graft rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degeneration, streptococcal myositis, organic lesions of the cerebellum, subacute sclerosing panencephalitis, syncope, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory response syndrome, systemic juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxicity, transplant, trauma / bleeding, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis / aseptic meningitis, virus-associated hemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, any organ or tissue xenograft rejection, acute pain, age-associated memory impairment (AAMI), anxiety and attention deficit disorder disorder), global attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, central neuropathic pain syndrome, central post-stroke pain, chemotherapy-induced neuropathy, agnosia and dysfunction in psychiatric disorders, agnosia associated with aging and neurodegeneration, agnosia associated with diabetes, agnosia in schizophrenia, complex regional pain syndrome, cognitive decline in Alzheimer's disease and related dementias, attention deficit dementia, dementia associated with Down syndrome, dementia with Lewy bodies, depression in Cushing's syndrome, CNS decline associated with traumatic brain injury, disorders with memory impairment, dizziness, substance abuse, epilepsy, HIV sensory neuropathy, Huntington's disease, hyperalgesia including neuropathic pain, inflammation and inflammatory diseases, inflammatory hyperalgesia, inflammatory pain, insulin resistance syndrome, jet lag, poor circulation, learning, major depressive disorder, medullary thyroid carcinoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, mood alterations, motion sickness, multiple sclerosis pain, narcolepsy, the need for angiogenesis and neovascularization of skin grafts due to poor circulation, the need for neovascularization associated with wound healing, neuropathic pain, neuropathy, neuropathy secondary to tumor invasion, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, pain in Parkinson's disease, pathological sleepiness, phantom limb pain, Pick's disease, polycystic ovary syndrome, post-traumatic stress disorder, post-herpetic neuralgia, post-mastectomy pain, post-operative pain,It is useful in the treatment of disorders selected from psychotic depression, schizoaffective disorder, seizures, senile dementia, sepsis syndrome, sleep disorders, smoking cessation, spinal cord injury pain, steroid-induced acute psychosis, subcategories of neuropathic pain such as peripheral neuropathic pain syndrome, substance abuse such as alcohol abuse, syndrome X, Tourette's syndrome, treatment-resistant depression, trigeminal neuralgia, type II diabetes, vertigo, and vestibular disorders.

[0150] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in the methods disclosed herein.

[0151] In a further aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the methods disclosed herein.

[0152] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered orally, topically, or parenterally to a subject 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.

[0153] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject 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 may contain conventional organic or inorganic additives, such as additives (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, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, The pharmaceutical composition can be prepared by a commonly used method using the following additives: sodium hydroxide, methylparaben, propylparaben, citric acid, menthol, glycine, or orange powder), flavoring agent (for example, citric acid, menthol, glycine, or orange powder), preservative (for example, sodium benzoate, sodium hydrogen sulfite, methylparaben, or propylparaben), stabilizer (for example, citric acid, sodium citrate, or acetic acid), suspending agent (for example, methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agent (for example, hydroxypropylmethylcellulose), diluent (for example, water), and base wax (for example, cocoa butter, white petrolatum, or polyethylene glycol).The effective amount of the compound of formula (I) in the pharmaceutical composition can be at the level that exerts desired effect, for example, in the unit dose of both oral and parenteral administration, it is about 0.005mg / kg (subject's body weight) to about 10mg / kg (subject's body weight).

[0154] The dose of the compound of formula (I) to be administered to a subject may vary considerably and depend on the judgment of a healthcare practitioner. Generally, the compounds disclosed herein may be administered at a dose of about 0.001 mg / kg (subject's body weight) to about 10 mg / kg (subject's body weight) 1 to 4 times a day, but the dose may vary appropriately depending on the subject's age, body weight, and medical condition, as well as the type of administration. In one embodiment, the dose is about 0.001 mg / kg (subject's body weight) to about 5 mg / kg (subject's body weight), about 0.01 mg / kg (subject's body weight) to about 5 mg / kg (subject's body weight), about 0.05 mg / kg (subject's body weight) to about 1 mg / kg (subject's body weight), about 0.1 mg / kg (subject's body weight) to about 0.75 mg / kg (subject's body weight), or about 0.25 mg / kg (subject's body weight) to about 0.5 mg / kg (subject's body weight). In one embodiment, one dose is given per day. The amount of a compound of formula (I) administered in any given case will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0155] In some embodiments, the compound of formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0156] In another embodiment, 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 mg 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).

[0157] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg or 100 mg of a compound of formula (I).

[0158] In another embodiment, provided herein is a unit dose formulation 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 the compound of Formula (I).

[0159] The compound of formula (I) may be administered once, twice, three times, four times, or more times daily. In certain embodiments, doses of 100 mg or less are administered as a single daily dose, and doses greater than 100 mg are administered twice daily in an amount equal to half the total daily dose.

[0160] 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.

[0161] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is left to the discretion of the healthcare practitioner and may depend in part on the site of the disease.

[0162] In one embodiment, provided herein is a capsule comprising a compound of formula (I) without any additional carriers, excipients, or vehicles.

[0163] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0164] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, injections, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing a compound of Formula (I) with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances (such as various types of starch), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose), flour, and similar edible powders.

[0165] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars (such as lactose, fructose, glucose, and the like). Natural and synthetic gums are also useful, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0166] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from sticking to the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, causing the tablet to disintegrate and release the compound. These include starch, clay, cellulose, algin, and gums. Among others, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavor and filler or with a film-forming protecting agent to modify the tablet's dissolution characteristics. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0167] 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 can be modified by adding wax to slightly raise its melting point.In particular, water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0168] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulation.For example, slowly dissolving pellets of the compound of formula (I) can be prepared and incorporated into tablets or capsules, or as sustained-release implantable devices.Techniques also include creating pellets with different dissolution rates and filling capsules with a mixture of pellets.Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time.Even parenteral formulations can be made long-acting by dissolving or suspending the compound of formula (I) in an oily or emulsifying vehicle that allows it to slowly disperse in serum.

[0169] Illustrative Embodiments The present disclosure is further described by the following embodiments, the features of each of which may be combined with any of the other embodiments as appropriate and practical.

[0170] Embodiment P1 Compounds of formula (I): [ka] [In the formula, Ring A is [ka] and; Z1 and Z2 are independently CR0 or N; L is azetidinyl optionally substituted with 1 to 5 substituents independently selected from halo and C1-C6 alkyl; R0 are each independently H, C1-C6 alkyl, halo, C1-C6 haloalkyl, or C1-C6 alkoxy; R1 is C6-C 10 aryl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 R' groups, and the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen; R' are each independently halo, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl; R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H; Alternatively, the dashed line between R2 and R3 represents a ring structure in which R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H; x is 1 to 5; Each R4 is independently -CO2H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy; R5 and R6 are independently H or C1-C6 alkyl; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

[0171] Embodiment P2 Ring A [ka] That is, A compound according to embodiment P1, or a pharmaceutically acceptable salt thereof.

[0172] Embodiment P3 Ring A [ka] That is, A compound according to embodiment P1, or a pharmaceutically acceptable salt thereof.

[0173] Embodiment P4 Z1 and Z2 are each independently CR0; A compound according to embodiment P3, or a pharmaceutically acceptable salt thereof.

[0174] Embodiment P5 Z1 is N; Z2 is CR0, A compound according to embodiment P3, or a pharmaceutically acceptable salt thereof.

[0175] Embodiment P6 Z1 is CR0; Z2 is N, A compound according to embodiment P3, or a pharmaceutically acceptable salt thereof.

[0176] Embodiment P7 R0 are each independently H, C1-C3 alkyl, halo, C1-C3 haloalkyl, or C1-C3 alkoxy; A compound according to any one of embodiments P1 to P6, or a pharmaceutically acceptable salt thereof.

[0177] Embodiment P8 R0 is, independently at each occurrence, H, methyl, Cl, F, -CF3, or -OCH3; A compound according to embodiment P7, or a pharmaceutically acceptable salt thereof.

[0178] Embodiment P9 Ring A is [ka] That is, A compound according to any one of embodiments P1, P2, P7, and P8, or a pharmaceutically acceptable salt thereof.

[0179] Embodiment P10 Ring A is [ka] That is, A compound according to any one of embodiments P1 and P3 to P8, or a pharmaceutically acceptable salt thereof.

[0180] Embodiment P11 L, [ka] each of which is optionally substituted with 1 to 2 substituents independently selected from halo and C1-C3 alkyl; A compound according to any one of embodiments P1 to P10, or a pharmaceutically acceptable salt thereof.

[0181] Embodiment P12 L, [ka] each of which may be optionally substituted with one F, Cl, or methyl; A compound according to embodiment P11, or a pharmaceutically acceptable salt thereof.

[0182] Embodiment P13 L, [ka] That is, A compound according to embodiment P12, or a pharmaceutically acceptable salt thereof.

[0183] Embodiment P14 R1 is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R' groups, and the heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen; A compound according to any one of embodiments P1 to P13, or a pharmaceutically acceptable salt thereof.

[0184] Embodiment P15 R1 is phenyl optionally substituted with 1 to 3 R' groups; A compound according to embodiment P14, or a pharmaceutically acceptable salt thereof.

[0185] Embodiment P16 each R' is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl; A compound according to any one of embodiments P1 to P15, or a pharmaceutically acceptable salt thereof.

[0186] Embodiment P17 R' are each independently halo or C3-C6 cycloalkyl; A compound according to embodiment P16, or a pharmaceutically acceptable salt thereof.

[0187] Embodiment P18 R' is, independently at each occurrence, F, Cl, or cyclopropyl; A compound according to embodiment P17, or a pharmaceutically acceptable salt thereof.

[0188] Embodiment P19 R1, [ka] That is, A compound according to any one of embodiments P1 to P18, or a pharmaceutically acceptable salt thereof.

[0189] Embodiment P20 R2 is H or C1-C3 alkyl; R3 is -(CH2) x -CO2H; x is 1 to 3; A compound according to any one of embodiments P1 to P19, or a pharmaceutically acceptable salt thereof.

[0190] Embodiment P21 [ka] but, [ka] That is, A compound according to embodiment P20, or a pharmaceutically acceptable salt thereof.

[0191] Embodiment P22 R2 and R3 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl substituted with 1 to 3 R4 groups, wherein at least one R4 group is -CO2H; A compound according to any one of embodiments P1 to P19, or a pharmaceutically acceptable salt thereof.

[0192] Embodiment P23 each R4 is independently -CO2H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; A compound according to embodiment P22, or a pharmaceutically acceptable salt thereof.

[0193] Embodiment P24 R4 is, independently at each occurrence, -CO2H, methyl, Cl, -CF3, or -OCH3; A compound according to embodiment P23, or a pharmaceutically acceptable salt thereof.

[0194] Embodiment P25 [ka] but, [ka] That is, A compound according to any one of embodiments P1 to P19 and P22 to P24, or a pharmaceutically acceptable salt thereof.

[0195] Embodiment P26 n is 0, A compound according to any one of embodiments P1 to P25, or a pharmaceutically acceptable salt thereof.

[0196] Embodiment P27 n is 1, A compound according to any one of embodiments P1 to P25, or a pharmaceutically acceptable salt thereof.

[0197] Embodiment P28 R5 and R6 are independently H or C1-C3 alkyl; A compound according to embodiment P27, or a pharmaceutically acceptable salt thereof.

[0198] Embodiment P29 R5 and R6 are independently H or methyl; A compound according to embodiment P28, or a pharmaceutically acceptable salt thereof.

[0199] Embodiment P30 -CR5R6- is -CH2- or -CH(CH3)-; A compound according to embodiment P29, or a pharmaceutically acceptable salt thereof.

[0200] Embodiment P31 Formula (II): [ka] is expressed as A compound according to any one of embodiments P1, P2, P7-P9, and P11-P26, or a pharmaceutically acceptable salt thereof.

[0201] Embodiment P32 Formula (III): [ka] [In the formula, [ka] is a 4- to 6-membered heterocyclyl and at least one R group is —COH] is expressed as A compound according to any one of embodiments P1, P3 to P8, P10 to P19, P22 to P25, and P27 to P30, or a pharmaceutically acceptable salt thereof.

[0202] Embodiment P33 A compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0203] Embodiment P34 A pharmaceutical composition comprising a compound according to any one of embodiments P1 to P33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0204] Embodiment P35 A method for modulating sphingosine 1-phosphate receptor 5 (S1P5), comprising contacting S1P5 with an effective amount of a compound of any one of embodiments P1 to P33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment P34.

[0205] Embodiment P36 A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments P1 to P33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment P34.

[0206] Embodiment P37 The method of embodiment P36, wherein said neurological disease is Alzheimer's disease or multiple sclerosis. [Example]

[0207] The following examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures while adhering to the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art can modify the procedures described in the examples to achieve their goals.

[0208] Salts of the compounds described herein can 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 a solution of the acid (e.g., aqueous HCl).

[0209] As used in some of the chemical structures provided in the Examples below, the designation of a particular atom by "*" or "or1" indicates that the absolute stereochemistry of the indicated atom has not been determined.

[0210] The following abbreviations may be relevant to this application: Abbreviation [Table 22]

[0211] Synthesis Example Example S1. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (1a and 1b) [ka]

[0212] Synthesis of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of NaBH3CN (3.64 g, 56.9 mmol, 4.00 equiv.) in methanol (20 mL) was added ZnCl2 (2 M in 2-Me-THF, 14.2 mL, 28.4 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 15 minutes. Then, methyl piperidine-4-carboxylate (4.07 g, 28.4 mmol, 2.00 equiv.) and 5-bromo-2,3-dihydro-1H-inden-1-one (3.00 g, 14.2 mmol, 1.00 equiv.) were added. The resulting mixture was stirred at 80 °C overnight. LCMS showed that the reaction was complete. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3 * 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using PE:EA=3:1 to give methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (2.84 g, 59%) as an oil. LCMS (ESI, m / z): 338 [M+H] + .

[0213] Synthesis of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.0 g, 7.06 mmol, 1.00 equiv.) in DMF (15 mL) was added zinc powder (693 mg, 10.6 mmol, 1.50 equiv.). The resulting mixture was stirred at 60 °C for 3 h under a N atmosphere. Next, Pd(dba) (104 mg, 0.110 mmol, 0.016 equiv.), tris-(o-tolyl)phosphine (69 mg, 0.230 mmol, 0.032 equiv.), and methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (383 mg, 1.130 mmol, 0.160 equiv.) were added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (60 mL) and extracted with EtOAc (3*40 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 64%) as a yellow oil. LCMS (ESI, m / z): 415 [M+H] +

[0214] Synthesis of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (800 mg, 1.93 mmol, 1.00 equiv.) in DCM (10 mL) was added TBSOTf (1.33 mL, 5.79 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (500 mg, 82.4%) as a yellow oil. LCMS (ESI, m / z): 315 [M+H] +

[0215] Synthesis of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (1.6 g, 5.09 mmol, 1.00 equiv.), 2-bromo-1,3-dichlorobenzene (1.7 g, 7.63 mmol, 1.50 equiv.), RuPhos Pd G3 (639 mg, 0.763 mmol, 0.15 equiv.), and RuPhos (357 mg, 0.763 mmol, 0.15 equiv.) in 1,4-dioxane (25 mL), Cs2CO3 (4.9 g, 15.3 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 1 / 3) to give the crude product, which was then repurified by prep-HPLC (Column: X-select CSH OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 52% B in 7 min; 210 / 254 nm; RT: 5.77 min) to give methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (160 mg, 6.8%) as a colorless oil. LCMS (ESI, m / z): 459 [M+H] +

[0216] Chiral Separation of Methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] Racemic methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate was separated by Chiral HPLC (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 5% B to 5% B in 20 min; 220 / 254 nm; RT1: 10.089 min; RT2: 13.625 min; Injection volume: 3 ml; Run number: 1) to give Isomer 1 (60 mg, 100% ee) and Isomer 2 (60 mg, 99.9% ee), respectively.

[0217] Synthesis of 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1, 1a) [ka] To a stirred solution of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 mg, 0.130 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (10 mg, 0.390 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 3 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 5-6 with acetic acid and 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: 30% B to 50% B in 8 min, hold at 50% B for 1 min; 254 / 210 nm; RT: 8.26 min) to give 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (13.3 mg, 23%) as a white solid.

[0218] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (br, 1H), 7.29-7.23 (m, 5H), 6.74 (t, J = 8.0 Hz, 1H), 4.82 (t, J = 8.0 Hz, 2H), 4.36-4.32 (m, 2H), 4.29-4.23 (m, 1H), 3.78-3.71 (m, 1H), 2.88-2.72 (m, 3H), 2.49-2.45 (m, 1H), 2.28-2.10 (m, 3H), 2.01-1.95 (m, 2H), 1.82-1.73 (m, 2H), 1.62-1.43 (m, 2H)

[0219] LCMS (ESI, m / z): 445 [M+H] + Analysis conditions: Shim-pack XR-ODS, 3.0*50 mm, 2.2 μm; mobile phase A: water (0.05% TFA), mobile phase B: アセトニトリル (0.05% TFA); flow rate: 1.20 mL / min; グラジエント: 2.0 minutes, 5% B, 100% B, 100% B, 0.7 minutes, 0.05 minutes, 100% B, 5% B; 254 nm; RT: 1.720 min

[0220] Synthesis of 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 1b)

change

[0221] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (br, 1H), 7.29-7.22 (m, 5H), 6.75 (t, J = 8.0 Hz, 1H), 4.82 (t, J = 8.0 Hz, 2H), 4.36-4.32 (m, 2H), 4.26 (t, J = 7.2 Hz, 1H), 3.78-3.71 (m, 1H), 2.88-2.70 (m, 3H), 2.49-2.45 (m, 1H), 2.28-2.10 (m, 3H), 2.01-1.95 (m, 2H), 1.82-1.73 (m, 2H), 1.62-1.40 (m, 2H)

[0222] LCMS (ESI, m / z): 445 [M+H] +Analysis conditions: 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 in 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.729 min

[0223] Example S2. 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (2a and 2b) [ka]

[0224] Synthesis of methyl 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (800 mg, 2.54 mmol, 1.00 equiv.), 2-bromo-1,3-difluorobenzene (737 mg, 3.82 mmol, 1.50 equiv.), RuPhos Pd G3 (356 mg, 0.382 mmol, 0.150 equiv.), and RuPhos (178 mg, 0.382 mmol, 0.150 equiv.) in anhydrous 1,4-dioxane (20 mL), Cs2CO3 (2.48 g, 7.62 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with ethyl acetate / petroleum ether, 1 / 1) to give methyl 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (140 mg, 13%) as a yellow oil. LCMS (ESI, m / z): 427 [M+H] +This racemic mixture was then resolved by Chiral-HPLC (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 11 min; 220 / 254 nm; RT1: 7.437 min, RT2: 8.632 min; Injection volume: 0.7 mL; Run number: 10) to give the desired enantiomers (60 mg each).

[0225] Synthesis of 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1 and 2a) [ka] To a stirred solution of methyl 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 mg, 0.140 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (11 mg, 0.420 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 17% B to 47% B in 7 min; 210 / 254 nm; RT: 6.4 min) to give 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26.6 mg, 45.7%) as a white solid.

[0226] LCMS (ESI, m / z): 413 [M+H] +Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.624 min

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (br, 1H), 7.30-7.22 (m, 3H), 6.98-6.92 (m, 2H), 6.75-6.68 (m, 1H), 4.54-4.48 (m, 2H), 4.30-4.23 (m, 1H), 4.13-4.09 (m, 2H), 3.94-3.87 (m, 1H), 2.88-2.72 (m, 3H), 2.49-2.46 (m, 1H), 2.27-2.12 (m, 3H), 2.02-1.94 (m, 2H), 1.83-1.73 (m, 2H), 1.64-1.52 (m, 1H), 1.50-1.42 (m, 1H)

[0228] Synthesis of 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 2b) [ka] To a stirred solution of methyl 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 mg, 0.140 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (11 mg, 0.420 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 16% B to 46% B in 7 min; 210 / 254 nm; RT: 6.7 min) to give 1-(5-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (27.5 mg, 47.2%) as a white solid.

[0229] LCMS (ESI, m / z): 413 [M+H] + Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.614 min

[0230] 11H NMR (400 MHz, DMSO-d6) δ 12.06 (broad, 1H), 7.28 (singlet, 1H), 7.23 - 7.21 (multiplet, 2H), 6.96 - 6.92 (multiplet, 2H), 6.75 - 6.67 (multiplet, 1H), 4.53 - 4.48 (multiplet, 2H), 4.25 (triplet, J = 6.8 Hz, 1H), 4.13 - 4.08 (multiplet, 2H), 3.94 - 3.86 (multiplet, 1H), 2.89 - 2.70 (multiplet, 3H), 2.47 - 2.44 (multiplet, 1H), 2.29 - 2.09 (multiplet, 3H), 2.01 - 1.95 (multiplet, 2H), 1.82 - 1.73 (multiplet, 2H), 1.63 - 1.53 (multiplet, 1H), 1.50 - 1.40 (multiplet, 1H)

[0231] Example S3. 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (3a and 3b)

Chem.

[0232] Synthesis of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate

Chem.

[0233] Synthesis of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (800 mg, 1.93 mmol, 1.00 equiv.) in DCM (10 mL) was added TBSOTf (1.33 mL, 5.79 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (500 mg, 82.4%) as a yellow oil. LCMS (ESI, m / z): 315 [M+H] +

[0234] Synthesis of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.640 mmol, 1.00 equiv.) and (3-fluorophenyl)boronic acid (178 mg, 1.28 mmol, 2.00 equiv.) in ACN (8 mL) was added Cu(OAc)2 (58 mg, 0.320 mmol, 0.500 equiv.) and TEA (193 mg, 1.92 mmol, 3.00 equiv.). The resulting mixture was stirred at 80° C. overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified on a flash silica gel column (eluted with PE / EA, 1 / 3) to give methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (130 mg, 0.318 mmol) as a yellow oil. LCMS (ESI, m / z): 409 [M+H] +The racemic mixture was then resolved by Chiral HPLC (column: Chiralpak IA, 2*25 cm, 5 μm; mobile phase A: Hex (8 mM NH3·MeOH), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 10% B to 10% B in 20 min; 220 / 254 nm; RT1: 6.351 min; RT2: 9.977 min) to give the desired enantiomers (40 mg each).

[0235] Synthesis of 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1, 3a) [ka] To a stirred solution of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (40 mg, 0.100 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (8 mg, 0.300 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 20% B to 39% B in 10 min; 210 / 254 nm; RT: 9.10 min) to give 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (15.5 mg, 39.8%) as a white solid.

[0236] LCMS (ESI, m / z): 395 [M+H] +Analysis 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 in 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.112 min

[0237] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (br, 1H), 7.25-7.17 (m, 4H), 6.49-6.44 (m, 1H), 6.32-6.26 (m, 2H), 4.28-4.22 (m, 3H), 3.96-3.89 (m, 1H), 3.81-3.78 (m, 2H), 2.89-2.70 (m, 3H), 2.49-2.46 (m, 1H), 2.26-2.14 (m, 3H), 2.02-1.91 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.50 (m, 1H), 1.47-1.41 (m, 1H)

[0238] Synthesis of 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 3b) [ka] To a stirred solution of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (40 mg, 0.100 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (8 mg, 0.300 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 20% B to 37% B in 10 min; 210 / 254 nm; RT: 9.58 min) to give 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (7.3 mg, 18.8%) as a white solid.

[0239] LCMS (ESI, m / z): 395 [M+H] + Analysis 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 in 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.115 min

[0240] 11H NMR (400 MHz, DMSO-d6) δ 12.07 (broad, 1H), 7.26 - 7.17 (multiplet, 4H), 6.49 - 6.44 (multiplet, 1H), 6.32 - 6.26 (multiplet, 2H), 4.28 - 4.22 (multiplet, 3H), 3.97 - 3.90 (multiplet, 1H), 3.81 - 3.78 (multiplet, 2H), 2.89 - 2.71 (multiplet, 3H), 2.49 - 2.46 (multiplet, 1H), 2.29 - 2.14 (multiplet, 3H), 2.02 - 1.91 (multiplet, 2H), 1.84 - 1.75 (multiplet, 2H), 1.63 - 1.50 (multiplet, 1H), 1.47 - 1.41 (multiplet, 1H)

[0241] Example S4. 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (4a and 4b)

Chem.

[0242] Synthesis of methyl 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate

Chem.

[0243] Synthesis of 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1, 4a) [ka] To a stirred solution of methyl 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 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 overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. 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: 14% B to 44% B in 7 min; 254 / 210 nm; RT: 6.53 min) to give 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (24.4 mg, 42.7% yield) as a white solid.

[0244] LCMS (ESI, m / z): 395 [M+H] + Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.542 min

[0245] 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br, 1H), 7.26-7.19 (m, 3H), 7.09-7.01 (m, 2H), 6.77-6.71 (m, 1H), 6.64-6.59 (m, 1H), 4.34-4.29 (m, 2H), 4.25 (t, J = 7.6 Hz, 1H), 3.97-3.85 (m, 3H), 2.89-2.70 (m, 3H), 2.49-2.45 (m, 1H), 2.28-2.22 (m, 1H), 2.19-2.09 (m, 2H), 2.01-1.96 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.53 ​​(m, 1H), 1.50-1.40 (m, 1H)

[0246] Synthesis of 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 4b) [ka] To a stirred solution of methyl 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 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 overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. 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: 14% B to 44% B in 7 min; 254 / 210 nm; RT: 6.20 min) to give 1-(5-(1-(2-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (30.9 mg, 53.3% yield) as a white solid.

[0247] LCMS (ESI, m / z): 395 [M+H] +Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.536 min

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 7.25-7.18 (m, 3H), 7.09-7.02 (m, 2H), 6.77-6.71 (m, 1H), 6.64-6.59 (m, 1H), 4.33-4.29 (m, 2H), 4.25 (t, J = 7.6 Hz, 1H), 3.96-3.85 (m, 3H), 2.88-2.70 (m, 3H), 2.49-2.45 (m, 1H), 2.28-2.21 (m, 1H), 2.17-2.08 (m, 2H), 2.01-1.95 (m, 2H), 1.81-1.71 (m, 2H), 1.62-1.52 (m, 1H), 1.49-1.40 (m, 1H)

[0249] Example S5. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (5) [ka]

[0250] Synthesis of 5-bromo-7-methyl-2,3-dihydro-1H-inden-1-ol [ka] To a stirred solution of 5-bromo-7-methyl-2,3-dihydro-1H-inden-1-one (800 mg, 3.55 mmol, 1.00 equiv.) in methanol (10 mL) was added NaBH4 (202 mg, 5.33 mmol, 1.50 equiv.). The resulting mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction was quenched with water (50 mL) and extracted with EtOAc (3*20 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with 100% EtOAc) to give 5-bromo-7-methyl-2,3-dihydro-1H-inden-1-ol (800 mg, 99.1% yield) as a yellow oil. LCMS (ESI, m / z): 227 [M+H] +

[0251] Synthesis of 5-bromo-1-chloro-7-methyl-2,3-dihydro-1H-indene [ka] To a stirred solution of 5-bromo-7-methyl-2,3-dihydro-1H-inden-1-ol (800 mg, 3.52 mmol, 1.00 equiv.) in DCM (10 mL) was added SOCl (4.19 g, 35.2 mmol, 10.0 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step without further purification.

[0252] Synthesis of methyl 1-(5-bromo-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 5-bromo-1-chloro-7-methyl-2,3-dihydro-1H-indene (800 mg, 3.26 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (700 mg, 4.89 mmol, 1.50 equiv.) in ACN (10 mL) was added K2CO3 (1.35 g, 9.77 mmol, 3.00 equiv.). The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with PE / EtOAc, 4 / 1) to afford methyl 1-(5-bromo-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (850 mg, 74.1% yield) as a yellow oil. LCMS (ESI, m / z): 352 [M+H] +

[0253] Synthesis of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of (1-tert-butoxycarbonylazetidin-3-yl)-iodozinc (791 mg, 2.27 mmol, 2.00 equiv.) in DMF (10 mL) was added Pd(dba) (156 mg, 0.170 mmol, 0.150 equiv.), tris-(o-tolyl)phosphine (104 mg, 0.340 mmol, 0.300 equiv.), and methyl 1-(5-bromo-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (400 mg, 1.14 mmol, 1.00 equiv.). The resulting mixture was stirred at 80 °C overnight under a N atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NHCl (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with PE / EA, 4 / 1) to give methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (400 mg, 82.2% yield) as a yellow oil. LCMS (ESI, m / z): 429 [M+H] +

[0254] Synthesis of methyl 1-(5-(azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (400 mg, 0.930 mmol, 1.00 equiv.) in DCM (8 mL) was added TBSOTf (0.5 mL, 2.80 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash C18 silica chromatography (eluting with ACN / water (0.05% TFA), 5 / 95) to give methyl 1-(5-(azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 98.0% yield) as a yellow oil. LCMS (ESI, m / z): 329 [M+H] +

[0255] Synthesis of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 0.910 mmol, 1.00 equiv.), 2-bromo-1,3-dichlorobenzene (248 mg, 1.10 mmol, 1.20 equiv.) in 1,4-dioxane (8 mL), CsCO (891 mg, 2.73 mmol, 3.00 equiv.), RuPhos Pd G (115 mg, 0.140 mmol, 0.150 equiv.), and RuPhos (64 mg, 0.140 mmol, 0.150 equiv.) were added. The resulting mixture was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with PE / EtOAc, 5 / 1) to give methyl methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 23.1% yield) as a yellow oil. LCMS (ESI, m / z): 473 [M+H] +

[0256] Synthesis of 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (5) [ka] To a stirred solution of methyl 1-[5-[1-(2,6-dichlorophenyl)azetidin-3-yl]-7-methyl-indan-1-yl]piperidine-4-carboxylate (100 mg, 0.210 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH (26 mg, 1.05 mmol, 5.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction was acidified to pH 4 by the addition of acetic acid and 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 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min; 254 / 210 nm; RT: 6.32 min) to give 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-methyl-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (23.3 mg, 23.8% yield) as a white solid.

[0257] LCMS (ESI, m / z): 459 [M+H] + Analysis conditions: Column: HALO C18, 3.0*30 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 in 1.30 min, hold at 100% for 0.50 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.030 min

[0258] 11H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 6.99 (s, 1H), 6.74 (t, J = 8.0 Hz, 1H), 4.83 - 4.79 (m, 2H), 4.35 - 4.31 (m, 3H), 3.75 - 3.67 (m, 1H), 2.81 - 2.76 (m, 3H), 2.34 (s, 3H), 2.33 - 2.31 (m, 1H), 2.18 - 2.09 (m, 3H), 2.03 - 1.97 (m, 1H), 1.82 - 1.74 (m, 2H), 1.67 - 1.63 (m, 1H), 1.57 - 1.50 (m, 1H), 1.36 - 1.24 (m, 1H)

[0259] Example S6. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (6)

Chem.

[0260] Synthesis of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate

Chem.

[0261] Synthesis of methyl 1-(5-(azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (450 mg, 1.04 mmol, 1.00 equiv.) in DCM (5 mL) was added TBSOTf (0.5 mL, 3.120 mmol, 3.00 equiv.). The mixture was stirred at 0° C. for 1 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl 1-(5-(azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (450 mg, 96% yield) as a pale yellow oil. LCMS (ESI, m / z): 333 [M+H] +

[0262] Synthesis of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.600 mmol, 1.00 equiv.) and 2-bromo-1,3-dichlorobenzene (136 mg, 0.600 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL), Pd(dba) (55 mg, 0.060 mmol, 0.10 equiv.), CPhos (18 mg, 0.120 mmol, 0.20 equiv.), and CsCO (586 mg, 1.80 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 3) to give methyl methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (50 mg, 17% yield) as a pale yellow oil. LCMS (ESI, m / z): 477 [M+H] +

[0263] Synthesis of 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (6) [ka] To a stirred solution of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (50 mg, 0.100 mmol, 1.00 equiv.) in THF (2 mL) and water (0.2 mL) was added LiOH·HO (13 mg, 0.310 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 20% B to 39% B in 10 min; 210 / 254 nm; RT: 9.10 min) to give 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (25.9 mg, 52% yield) as an off-white solid.

[0264] LCMS (ESI, m / z): 463 [M+H] + Analysis 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 in 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.307 min

[0265] 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.16 (s, 1H), 7.06-7.03 (m, 1H), 6.76 (t, J = 7.8 Hz, 1H), 4.82 (t, J = 8.1 Hz, 2H), 4.39-4.34 (m, 3H), 3.82-3.72 (m, 1H), 3.01-2.90 (m, 1H), 2.84-2.71 (m, 2H), 2.60-2.55 (m, 1H), 2.24-2.05 (m, 5H), 1.78-1.74 (m, 2H), 1.58-1.40 (m, 2H)

[0266] Example S7. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (7) [ka]

[0267] Synthesis of 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one [ka] To a solution of tert-butyl 3-(1-oxo-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate (600 mg, 1.50 mmol, 1.00 equiv.) in DCM (5 mL) was added TBSOTf (0.4 mL, 2.25 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 1 hour. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 77%) as a white solid. LCMS (ESI, m / z): 188 [M+H] +

[0268] Synthesis of 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one [ka] A solution of 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.60 mmol, 1.00 equiv.), 2-bromo-1,3-dichlorobenzene (358 mg, 1.60 mmol, 1.00 equiv.), Pd(dba) CHCl (166 mg, 0.160 mmol, 0.10 equiv.), t-BuONa (470 mg, 4.80 mmol, 3.00 equiv.), and XPhos (152 mg, 3.200 mmol, 0.20 equiv.) in toluene (10 mL) was stirred at 90 °C for 2 h under a N atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (150 mg, 28%) as a yellow oil. LCMS (ESI, m / z): 332 [M+H] +

[0269] Synthesis of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] A solution of 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (150 mg, 0.452 mmol, 1.00 equiv.), methyl piperidine-3-carboxylate (58 mg, 0.452 mmol, 1.00 equiv.), ZnCl (120 mg, 0.904 mmol, 2.00 equiv.), and NaBHCN (114 mg, 1.808 mmol, 4.00 equiv.) in methanol (10 mL) was stirred at 60 °C for 15 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified on a flash silica gel column (eluted with PE / EA, 7 / 3) to give methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (30 mg, 20%) as a yellow oil. LCMS (ESI, m / z): 445 [M+H] +

[0270] Synthesis of 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (7) [ka] A solution of methyl 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (30.0 mg, 0.070 mmol, 1.00 equiv.) and LiOH (5.00 mg, 0.210 mmol, 3.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 ExRS. 30*250, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 50% B in 7 min; 254 / 210 nm; RT: 5.65 min) to give 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (1.9 mg, 6%) as a white solid.

[0271] LCMS (ESI, m / z): 431 [M+H] + Analysis 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 60% B in 1.85 min, 60% B to 95% B in 0.45 min, hold at 95% for 0.50 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 1.566 min

[0272] 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.27 (m, 3H), 7.25-7.21 (m, 2H), 6.75 (t, J = 8.0 Hz, 1H), 4.83 (t, J = 8.0 Hz, 2H), 4.35 (t, J = 8.0 Hz, 1H), 4.19-4.13 (m, 1H), 3.79-3.72 (m, 2H), 2.99-2.88 (m, 2H), 2.84-2.72 (m, 3H), 2.67-2.59 (m, 2H), 2.10-2.04 (m, 2H), 1.96-1.90 (m, 2H)

[0273] Example S8a. 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (8a)

change

[0274] Synthesis of tert-butyl 3-(1-(3-(methoxycarbonyl)azetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate

change

[0275] Synthesis of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a stirred solution of tert-butyl 3-(1-(3-(methoxycarbonyl)azetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate (400 mg, 1.03 mmol, 1.00 equiv.) in DCM (6 mL) was added TBSOTf (820 mg, 3.09 mmol, 1.00 equiv.) dropwise. The resulting mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with ACN:HO, 1 / 10) to give methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (280 mg, 94.5% yield) as a yellow oil. LCMS (ESI, m / z): 287 [M+H] +

[0276] Synthesis of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (280 mg, 0.980 mmol, 1.00 equiv.), 1-bromo-3-fluorobenzene (171 mg, 0.980 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL), RuPhos (68 mg, 0.150 mmol, 0.150 equiv.), RuPhos Pd G3 (137 mg, 0.150 mmol, 0.150 equiv.), and Cs2CO3 (956 mg, 2.94 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with PE / EtOAc, 1 / 1) to give methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (40 mg, 10.7% yield) as a yellow oil. LCMS (ESI, m / z): 381 [M+H] +

[0277] Synthesis of 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (enantiomers 1, 8a) [ka] To a stirred solution of ethyl methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (40 mg, 0.110 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (8 mg, 0.330 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. 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: 14% B to 44% B in 8 min; 254 / 210 nm; RT: 7.45 min) to give 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (19.8 mg, 51.3% yield) as a white solid.

[0278] LCMS (ESI, m / z): 413 [M+H] + Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.556 min

[0279] 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.15-7.13 (m, 2H), 6.49-6.44 (m, 1H), 6.31-6.26 (m, 2H), 4.24 (t, J = 7.6 Hz, 1H), 3.96-3.89 (m, 1H), 3.80-3.77 (m, 3H), 3.51-3.47 (m, 1H), 3.39-3.35 (m, 2H), 3.25-3.22 (m, 1H), 3.18-3.11 (m, 1H), 2.95-2.87 (m, 1H), 2.76-2.69 (m, 1H), 2.06-1.97 (m, 1H), 1.85-1.78 (m, 1H)

[0280] Example S8b. 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (Enantiomers 2, 8b) [ka]

[0281] Synthesis of tert-butyl 3-(1-(3-(methoxycarbonyl)azetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate [ka] A solution of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (2.00 g, 7.06 mmol, 6.24 equiv.) and Zn (693 mg, 10.6 mmol, 9.36 equiv.) in DMF (15 mL) was stirred at 60 °C for 3 h under a N atmosphere. Pd(dba) (104 mg, 0.110 mmol, 0.010 equiv.), tris-(o-tolyl)phosphine (69 mg, 0.230 mmol, 0.020 equiv.), and methyl 1-(5-bromoindan-1-yl)azetidine-3-carboxylate (350 mg, 1.13 mmol, 1.00 equiv.) were then added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3*20 mL). The organic layers were combined and concentrated. The residue was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give tert-butyl 3-(1-(3-(methoxycarbonyl)azetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate (130 mg, 26.1%) as a yellow oil. LCMS (ESI, m / z): 387 [M+H] +

[0282] Synthesis of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a stirred solution of tert-butyl 3-(1-(3-(methoxycarbonyl)azetidin-1-yl)-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate (400 mg, 1.03 mmol, 1.00 equiv.) in DCM (6 mL) was added TBSOTf (820 mg, 3.09 mmol, 1.00 equiv.) dropwise. The resulting mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with ACN:HO, 1 / 10) to give methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (280 mg, 94.5% yield) as a yellow oil. LCMS (ESI, m / z): 287 [M+H] +

[0283] Synthesis of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a stirred solution of methyl 1-(5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (280 mg, 0.980 mmol, 1.00 equiv.), 1-bromo-3-fluorobenzene (171 mg, 0.980 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL), RuPhos (68 mg, 0.150 mmol, 0.150 equiv.), RuPhos Pd G3 (137 mg, 0.150 mmol, 0.150 equiv.), and Cs2CO3 (956 mg, 2.94 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with PE / EtOAc, 1 / 1) to give methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (40 mg, 10.7% yield) as a yellow oil. LCMS (ESI, m / z): 381 [M+H] +

[0284] Synthesis of 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a stirred solution of methyl 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (40 mg, 0.110 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH (8 mg, 0.330 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. 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: 20% B to 38% B in 10 min, hold at 38% B for 2 min; 254 / 210 nm; RT: 10.45 min) to give 1-(5-(1-(3-fluorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (28.5 mg, 73.0% yield) as a white solid.

[0285] LCMS (ESI, m / z): 413 [M+H] + Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.551 min

[0286] 11H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.22 (m, 2H), 7.21 - 7.17 (m, 1H), 7.14 - 7.12 (m, 2H), 6.49 - 6.44 (m, 1H), 6.31 - 6.26 (m, 2H), 4.24 (t, J = 7.6 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.80 - 3.73 (m, 3H), 3.45 (t, J = 7.2 Hz, 1H), 3.33 - 3.30 (m, 2H), 3.21 - 3.18 (m, 1H), 3.15 - 3.08 (m, 1H), 2.94 - 2.86 (m, 1H), 2.75 - 2.67 (m, 1H), 2.04 - 1.98 (m, 1H), 1.84 - 1.77 (m, 1H)

[0287] Example S9. 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (9a and 9b)

Chem.

[0288] Synthesis of tert-butyl 3-(2,6-difluorophenyl)-3-hydroxyazetidine-1-carboxylate

Chem.

[0289] Synthesis of tert-butyl 3-(2,6-difluorophenyl)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-(2,6-difluorophenyl)-3-hydroxy-azetidine-1-carboxylate (2.4 g, 8.41 mmol, 1.00 equiv.) in toluene (10 mL) was added Burgess reagent (4.2 g, 17.67 mmol, 2.10 equiv.). The reaction was stirred at 110° C. for 12 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and Pd / C (200 mg, 1.880 mmol, 0.250 equiv.) was added. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluting with water (5 mM NH4HCO3) / ACN, 3 / 7) to give tert-butyl 3-(2,6-difluorophenyl)azetidine-1-carboxylate (800 mg, 39%) as an off-white solid. LCMS (ESI, m / z): 270 [M+H] +

[0290] Synthesis of 3-(2,6-difluorophenyl)azetidine [ka] To a stirred solution of tert-butyl 3-(2,6-difluorophenyl)azetidine-1-carboxylate (200 mg, 0.740 mmol, 1.00 equiv.) in DCM (10.0 mL) was added TBSOTf (0.1 mL, 0.820 mmol, 1.10 equiv.). The resulting mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude 3-(2,6-difluorophenyl)azetidine was used directly in the next step without further purification. LCMS (ESI, m / z): 170 [M+H] +

[0291] Synthesis of methyl 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 3-(2,6-difluorophenyl)azetidine (240 mg, 1.42 mmol, 1.00 equiv.) and methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (527 mg, 1.56 mmol, 1.10 equiv.) in 1,4-dioxane (10 mL), Pd(dba) CHCl (146 mg, 0.14 mmol, 0.10 equiv.), CPhos (43 mg, 0.28 mmol, 0.20 equiv.), and CsCO (1.4 g, 4.26 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3 / ACN, 1 / 9) to give methyl 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (240 mg, 39%) as an off-white solid. LCMS (ESI, m / z): 427 [M+H] +

[0292] Chiral Separation of Methyl 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] The racemate (300 mg) was separated by chiral HPLC (column: CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase A: Hex (0.1% IPA), mobile phase B: EtOH; flow rate: 30 mL / min; gradient: 50% B to 50% B in 32 min; 220 / 254 nm; RT1: 22.3 min; RT2: 27.6 min) to give isomer 1 (120 mg) and isomer 2 (120 mg), respectively.

[0293] Synthesis of 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1, 9a) [ka] To a stirred solution of methyl 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (120 mg, 0.280 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL), LiOH·HO (35 mg, 0.840 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was complete. The reaction was acidified to pH 5-6 by dropwise addition of acetic acid and concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluting with water (10 mM NH4HCO3) / ACN, 1 / 1) to give 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (30 mg, 25%) as an off-white solid.

[0294] 1 H NMR (300 MHz, DMSO-d6) δ 7.37-7.32 (m, 1H), 7.11-7.04 (m, 3H), 6.34-6.32 (m, 2H), 4.34-4.25 (m, 3H), 4.16-4.13 (m, 1H), 3.88-3.82 (m, 2H), 2.78-2.66 (m, 3H), 2.24-2.07 (m, 4H), 1.97-1.90 (m, 2H), 1.80-1.71 (m, 2H), 1.60-1.40 (m, 2H)

[0295] LCMS (ESI, m / z): 413 [M+H] + Analysis conditions: Column: EVO C18 Column 3.0*50 mm, 2.6 mm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.097 min

[0296] Synthesis of 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 9b) [ka] To a stirred solution of methyl 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (120 mg, 0.280 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL), LiOH·HO (35 mg, 0.840 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was complete. The reaction was acidified to pH 5-6 by dropwise addition of acetic acid and concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluting with water (10 mM NH4HCO3) / ACN, 1 / 1) to give 1-(5-(3-(2,6-difluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (28.4 mg, 24%) as an off-white solid.

[0297] 1 H NMR (300 MHz, DMSO-d6) δ 7.40-7.30 (m, 1H), 7.11-7.04 (m, 3H), 6.34-6.32 (m, 2H), 4.34-4.25 (m, 3H), 4.17-4.13 (m, 1H), 3.88-3.82 (m, 2H), 2.78-2.63 (m, 3H), 2.27-2.05 (m, 4H), 1.97-1.90 (m, 2H), 1.80-1.71 (m, 2H), 1.60-1.41 (m, 2H)

[0298] LCMS (ESI, m / z): 413 [M+H] + Analysis conditions: Column: EVO C18 Column 3.0*50 mm, 2.6 mm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.101 min

[0299] Example S10. 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (10a and 10b) [ka]

[0300] Synthesis of methyl 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.590 mmol, 1.00 equiv.), 3-(2-fluorophenyl)azetidine (89.4 mg, 0.590 mmol, 1.00 equiv.), CPhos (51.6 mg, 0.120 mmol, 0.200 equiv.), Pd(dba) (108 mg, 0.120 mmol, 0.200 equiv.), and cesium carbonate (385 mg, 1.18 mmol, 2.00 equiv.) in anhydrous 1,4-dioxane (2 mL) was stirred at 90 °C under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 56% B to 72% B in 10 min, hold at 72% B for 5 min; 210 / 254 nm; RT: 12.68 min) to give methyl 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (60 mg, 24.8%) as a pale yellow solid. LCMS (ESI, m / z): 409 [M+H] +The racemic product was then resolved by chiral-HPLC (column: Chiralpak IA, 2*25 cm, 5 mm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 20 min; 220 / 254 nm) to give chiral separated 1 enantiomer (22 mg) with a retention time of 8.894 min and chiral separated 2 enantiomer (20 mg) with a retention time of 10.086 min.

[0301] Synthesis of 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 1, 10a) [ka] A mixture of chirally separated 1-enantiomer methyl 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (22.0 mg, 0.050 mmol, 1.00 equiv.) and lithium hydroxide (2.58 mg, 0.110 mmol, 2.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction was acidified to pH 4 by the addition of acetic acid and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B in 8 min; 254 / 210 nm; RT: 7.52 min) to give 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (11.2 mg, 51.5%) as a white solid.

[0302] LCMS (ESI, m / z): 393 [MH] -Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.538 min

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 11.9 (br, 1H), 7.53-7.49 (m, 1H), 7.34-7.28 (m, 1H), 7.24-7.16 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.35-6.33 (m, 2H), 4.26-4.23 (m, 2H), 4.18-4.11 (m, 2H), 3.82-3.78 (m, 2H), 2.83-2.75 (m, 2H), 2.71-2.63 (m, 1H), 2.49-2.43 (m, 1H), 2.25-2.06 (m, 3H), 1.98-1.91 (m, 2H), 1.81-1.72 (m, 2H), 1.61-1.51 (m, 1H), 1.48-1.38 (m, 1H)

[0304] Synthesis of 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (enantiomers 2, 10b) [ka] A mixture of the chiral separated two enantiomers of methyl 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (20.0 mg, 0.050 mmol, 1.00 equiv.) and lithium hydroxide (2.58 mg, 0.110 mmol, 2.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction was acidified to pH 4 by the addition of acetic acid and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 mm; 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 in 8 min; 254 / 210 nm; RT: 6.16 min) to give 1-(5-(3-(2-fluorophenyl)azetidin-1-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (4.4 mg, 22.1%) as a white solid.

[0305] LCMS (ESI, m / z): 393 [MH] - Analysis 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 in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.537 min

[0306] 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br, 1H), 7.53-7.49 (m, 1H), 7.34-7.28 (m, 1H), 7.24-7.16 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.35-6.33 (m, 2H), 4.26-4.23 (m, 2H), 4.18-4.11 (m, 2H), 3.82-3.78 (m, 2H), 2.83-2.75 (m, 2H), 2.71-2.63 (m, 1H), 2.49-2.43 (m, 1H), 2.24-2.08 (m, 3H), 1.98-1.91 (m, 2H), 1.80-1.71 (m, 2H), 1.61-1.51 (m, 1H), 1.48-1.38 (m, 1H)

[0307] Example S11. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (11) [ka]

[0308] Synthesis of methyl 1-(4-bromobenzyl)piperidine-4-carboxylate [ka] To a stirred solution of 1-bromo-4-(chloromethyl)benzene (10.0 g, 48.67 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (13.9 g, 97.33 mmol, 2.00 equiv.) in ACN (100 mL) was added K2CO3 (20.1 g, 146 mmol, 3.00 equiv.). The resulting mixture was stirred at 60 °C for 2 h. LCMS showed the reaction was complete. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3*100 mL). The organic layers were combined and washed with brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash silica gel column chromatography (eluted with EtOAc / PE, 1 / 3) to give methyl 1-(4-bromobenzyl)piperidine-4-carboxylate (12.0 g, 78%) as a pale yellow oil. LCMS (ESI, m / z): 312 [M+H] +

[0309] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (40.8 g, 144.14 mmol, 10.00 equiv.) in DMF (100 mL) was added zinc powder (2.8 g, 43.24 mmol, 3.00 equiv.). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. Methyl 1-(4-bromobenzyl)piperidine-4-carboxylate (4.5 g, 14.41 mmol, 1.00 equiv.), Pd(dba) (1.3 g, 1.44 mmol, 0.10 equiv.), and tri-m-tolylphosphane (876 mg, 2.88 mmol, 0.20 equiv.) were then added. The resulting mixture was stirred at 80 °C under nitrogen for 16 hours. LCMS indicated the reaction was complete. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (3*150 mL). The combined organic layers were washed with brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 120 mL / min; gradient: 77% B to 85% B in 7 min; 254 / 210 nm) to give methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (5.2 g, 92%) as an off-white solid. LCMS (ESI, m / z): 389 [M+H] +

[0310] Synthesis of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (5.2 g, 13.38 mmol, 1.00 equiv.) in DCM (100 mL) was added TBSOTf (7.1 mL, 40.15 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 120 mL / min; gradient: 10% B to 20% B in 5 min; 254 / 210 nm) to give methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (5.2 g, 96%) as a pale yellow oil. LCMS (ESI, m / z): 289 [M+H] +

[0311] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (4.3 g, 14.91 mmol, 1.00 equiv.) and 2-bromo-1,3-dichloro-benzene (5.0 g, 22.37 mmol, 1.50 equiv.) in 1,4-dioxane (100 mL), Pd(dba) (1.4 g, 1.49 mmol, 0.10 equiv.), CPhos (1.3 g, 2.98 mmol, 0.20 equiv.), and CsCO (14.5 g, 44.73 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated the reaction was complete. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (3 x 150 mL). The organic layers were combined and washed with brine, then dried over anhydrous NaSO and concentrated. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 120 mL / min; gradient: 80% B to 90% B in 7 min; 254 / 210 nm) to give methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (750 mg, 11%) as an off-white solid. LCMS (ESI, m / z): 433 [M+H] +

[0312] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (11) [ka] To a stirred solution of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (750 mg, 1.73 mmol, 1.00 equiv.) in THF (10 mL) and water (1 mL) was added LiOH·HO (217 mg, 5.19 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was complete. The reaction was acidified to pH 5-6 by dropwise addition of acetic acid and subsequently concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 45% B to 50% B in 4 min; 254 / 210 nm) to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (558.8 mg, 75%) as an off-white solid.

[0313] 1 H NMR (300 MHz, Chloroform-d) δ 7.41 (s, 4H), 7.15 (d, J = 7.8 Hz, 2H), 6.65 (t, J = 7.8 Hz, 1H), 4.92 (t, J = 8.1 Hz, 2H), 4.49-4.44 (m, 2H), 3.93 (s, 2H), 3.79-3.69 (m, 1H), 3.26 (d, J = 11.1 Hz, 2H), 2.45-2.25 (m, 3H), 2.10-2.06 (m, 2H), 1.99-1.91 (m, 2H)

[0314] LCMS (ESI, m / z): 419 [M+H] + Analysis conditions: Column: YMC Meteoric Core C18 BIO Column 2.1*30 mm, 2.7 m; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 1.19 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 0.758 min

[0315] Example S12a. (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (12a) [ka]

[0316] Synthesis of methyl (S)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of 1-bromo-4-(chloromethyl)benzene (3 g, 14.6 mmol, 1.00 equiv.) and methyl rac-(3S)-pyrrolidine-3-carboxylate (2.83 g, 21.9 mmol, 1.50 equiv.) in ACN (10 mL) was added K2CO3 (4.03 g, 29.2 mmol, 2.00 equiv.). The resulting mixture was stirred at 80 °C for 5 h. LCMS showed the reaction was complete. The solvent was removed by evaporation. The residue was diluted with water (20 mL) and then extracted with ethyl acetate (3 * 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with water (0.05% TFA) / ACN, 3 / 7) to give methyl (S)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate (2.78 g, 63.9%) as a yellow oil. LCMS (ESI, m / z): 298 [M+H] +

[0317] Synthesis of methyl (S)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)-pyrrolidine-3-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.3 g, 40.2 mmol, 6.00 equiv.) in DMF (30 mL) was added zinc powder (2.6 g, 40.2 mmol, 6.00 equiv.). The resulting mixture was stirred at 60 °C for 3 h under a N atmosphere. Pd(dba) (921 mg, 1.01 mmol, 0.15 equiv.), tris-(o-tolyl)phosphine (612 mg, 2.01 mmol, 0.30 equiv.), and methyl (S)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate (2.00 g, 6.71 mmol, 1.00 equiv.) were then added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3*40 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give methyl (S)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (2 g, 79.6%) as a yellow oil. LCMS (ESI, m / z): 375 [M+H] +

[0318] Synthesis of methyl (S)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (S)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)-pyrrolidine-3-carboxylate (2 g, 5.34 mmol, 1.00 equiv.) in DCM (3 mL) was added TBSOTf (2.5 mL, 14.1 mmol, 2.64 equiv.) dropwise. The resulting mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl (S)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (970 mg, 66.2%) as an orange oil. LCMS (ESI, m / z): 275 [M+H] +

[0319] Synthesis of methyl (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (S)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (600 mg, 2.19 mmol, 1.00 equiv.) and 2-bromo-1,3-dichlorobenzene (988 mg, 4.37 mmol, 2.00 equiv.) in 1,4-dioxane (6 mL), RuPhos Pd G3 (183 mg, 0.220 mmol, 0.10 equiv.), CsCO3 (2.13 g, 6.56 mmol, 3.00 equiv.), and RuPhos (204 mg, 0.440 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 3) to give methyl (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-benzyl)pyrrolidine-3-carboxylate (120 mg, 13.1%) as a yellow oil. LCMS (ESI, m / z): 419 [M+H] +

[0320] Synthesis of (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (12a) [ka] To a stirred solution of methyl (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-pyrrolidine-3-carboxylate (120 mg, 0.290 mmol, 1.00 equiv.) in THF (1.5 mL) and water (1.5 mL) was added LiOH (21 mg, 0.860 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 mm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 45% B in 9 min; Wavelength: 254 / 220 nm; RT: 8.85 min) to give (S)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (71.6 mg, 61.2%) as a white solid.

[0321] LCMS (ESI, m / z): 405 [M+H] + Analysis conditions: Column: YMC Meteoric Core C18 BIO, 2.1*30 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 in 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 0.749 min

[0322] 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.72 (t, J = 8.0 Hz, 1H), 4.90 (t, J = 8.0 Hz, 2H), 4.44-4.41 (m, 2H), 4.13 (q, J = 8.8 Hz, 2H), 3.82-3.76 (m, 1H), 3.30-3.25 (m, 2H), 3.17-3.13 (m, 3H), 3.07-3.01 (m, 2H)

[0323] Example S12b. (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (12b) [ka]

[0324] Synthesis of methyl (R)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of 1-bromo-4-(chloromethyl)benzene (3 g, 14.6 mmol, 1.00 equiv.) and methyl (R)-pyrrolidine-3-carboxylate (2.83 g, 21.9 mmol, 1.50 equiv.) in ACN (10 mL) was added K2CO3 (4.03 g, 29.2 mmol, 2.00 equiv.). The resulting mixture was stirred at 80 °C for 5 h. LCMS showed the reaction was complete. The solvent was removed by evaporation. The residue was diluted with water (20 mL) and then extracted with ethyl acetate (3 * 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with water (0.05% TFA) / ACN, 3 / 7) to give methyl (R)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate (4.13 g, 94.9%) as a yellow oil. LCMS (ESI, m / z): 298 [M+H] +

[0325] Synthesis of methyl (R)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.3 g, 40.2 mmol, 6.00 equiv.) in DMF (30 mL) was added zinc powder (2.6 g, 40.2 mmol, 6.00 equiv.). The resulting mixture was stirred at 60 °C for 3 h under a N atmosphere. Pd(dba) (921 mg, 1.01 mmol, 0.15 equiv.), tris-(o-tolyl)phosphine (612 mg, 2.01 mmol, 0.30 equiv.), and methyl (R)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate (2.00 g, 6.71 mmol, 1.00 equiv.) were then added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3*40 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give methyl (R)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (1.9 g, 75.6%) as a yellow oil. LCMS (ESI, m / z): 375 [M+H] +

[0326] Synthesis of methyl (R)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (R)-1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzyl)-pyrrolidine-3-carboxylate (2 g, 5.34 mmol, 1.00 equiv.) in DCM (3 mL) was added TBSOTf (2.5 mL, 14.1 mmol, 2.64 equiv.) dropwise. The resulting mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl (R)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (990 mg, 70.8%) as an orange oil. LCMS (ESI, m / z): 275 [M+H] +

[0327] Synthesis of methyl (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (R)-1-(4-(azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (600 mg, 2.19 mmol, 1.00 equiv.) and 2-bromo-1,3-dichlorobenzene (988 mg, 4.37 mmol, 2.00 equiv.) in 1,4-dioxane (6 mL), Pd(dba) (200 mg, 0.220 mmol, 0.10 equiv.), CsCO (2.13 g, 6.56 mmol, 3.00 equiv.), and CPhos (190 mg, 0.440 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 3) to give methyl (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (120 mg, 13.1%) as a yellow oil. LCMS (ESI, m / z): 419 [M+H] +

[0328] Synthesis of (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (12b) [ka] To a stirred solution of methyl (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylate (120 mg, 0.290 mmol, 1.00 equiv.) in THF (1.5 mL) and water (1.5 mL) was added LiOH (21 mg, 0.860 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 mm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50% B in 7 min; Wavelength: 254 / 220 nm; RT: 6.32 min) to give (R)-1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)pyrrolidine-3-carboxylic acid (56.6 mg, 48.3%) as a white solid.

[0329] LCMS (ESI, m / z): 405 [M+H] + Analysis conditions: Column: YMC Meteoric Core C18 BIO, 2.1*30 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 in 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 0.757 min

[0330] 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.72 (t, J = 8.0 Hz, 1H), 4.90 (t, J = 8.0 Hz, 2H), 4.44-4.41 (m, 2H), 4.13 (q, J = 8.8 Hz, 2H), 3.82-3.75 (m, 1H), 3.28-3.18 (m, 2H), 3.16-3.00 (m, 3H), 2.25-2.17 (m, 2H)

[0331] Example S13. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)azetidine-3-carboxylic acid (13) [ka]

[0332] Synthesis of ethyl 1-(4-bromobenzyl)azetidine-3-carboxylate [ka] To a stirred solution of 1-bromo-4-(chloromethyl)benzene (2.12 g, 10.32 mmol, 1.00 equiv.) and ethyl azetidine-3-carboxylate (2.00 g, 15.48 mmol, 1.50 equiv.) in ACN (10 mL) was added K2CO3 (2.85 g, 20.63 mmol, 3.00 equiv.). The resulting mixture was stirred at 80 °C for 2 h. LCMS showed the reaction was complete. The solvent was removed by evaporation. The residue was diluted with water (20 mL) and then extracted with ethyl acetate (3 * 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with water (0.05% TFA) / ACN, 3 / 7) to give ethyl 1-(4-bromobenzyl)azetidine-3-carboxylate (2.50 g, 8.38 mmol, 81.3%) as a yellow oil. LCMS (ESI, m / z): 298 [M+H] +

[0333] Synthesis of tert-butyl 3-(4-((3-(ethoxycarbonyl)azetidin-1-yl)methyl)phenyl)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (22.8 g, 80.4 mmol, 10.0 equiv.) in DMF (100 mL) was added zinc powder (5.22 g, 80.4 mmol, 10.0 equiv.). The resulting mixture was stirred at 60 °C for 3 h under a N atmosphere. Pd(dba) (1.47 g, 1.62 mmol, 0.20 equiv.), tris-(o-tolyl)phosphine (1.72 g, 12.0 mmol, 0.70 equiv.), and ethyl 1-(4-bromobenzyl)azetidine-3-carboxylate (2.40 g, 8.04 mmol, 1.00 equiv.) were then added. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3*80 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give tert-butyl 3-(4-((3-(ethoxycarbonyl)azetidin-1-yl)methyl)-phenyl)azetidine-1-carboxylate (1.00 g, 33.2%) as a yellow oil. LCMS (ESI, m / z): 375 [M+H] +

[0334] Synthesis of ethyl 1-(4-(azetidin-3-yl)benzyl)azetidine-3-carboxylate [ka] To a stirred solution of tert-butyl 3-(4-((3-(ethoxycarbonyl)azetidin-1-yl)methyl)-phenyl)azetidine-1-carboxylate (1.00 g, 2.67 mmol, 1.00 equiv.) in DCM (5 mL) was added TBSOTf (1.32 mL, 7.48 mmol, 2.80 equiv.). The resulting mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give ethyl 1-(4-(azetidin-3-yl)benzyl)azetidine-3-carboxylate (600 mg, 2.19 mmol, 82%) as a yellow oil. LCMS (ESI, m / z): 275 [M+H] +

[0335] Synthesis of ethyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)azetidine-3-carboxylate [ka] To a stirred solution of ethyl 1-(4-(azetidin-3-yl)benzyl)azetidine-3-carboxylate (600 mg, 2.19 mmol, 1.00 equiv.) and 2-bromo-1,3-dichloro-benzene (494 mg, 2.19 mmol, 1.00 equiv.) in 1,4-dioxane (2 mL), RuPhos (102 mg, 0.220 mmol, 0.100), RuPhos Pd G3 (183 mg, 0.220 mmol, 0.100 equiv.), and Cs2CO3 (2.13 g, 6.56 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified on a flash silica gel column (eluted with PE / EA, 1 / 1) to give ethyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-benzyl)azetidine-3-carboxylate (120 mg, 13.1%) as a yellow oil. LCMS (ESI, m / z): 420 [M+H] +

[0336] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)azetidine-3-carboxylic acid (13) [ka] To a stirred solution of ethyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)azetidine-3-carboxylate (120 mg, 0.290 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added NaOH (34 mg, 0.860 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50% B in 10 min, 254 / 220 nm; RT: 9.67 min) to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-benzyl)azetidine-3-carboxylic acid (36.3 mg, 31.9%) as a white solid.

[0337] LCMS (ESI, m / z): 391 [M+H] + Analysis conditions: Column: YMC Meteoric Core C18 BIO, 2.1*30 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 55% B in 1.85 min, 55% B to 95% B in 0.45 min, hold at 95% for 0.50 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 0.389 min

[0338] 1H NMR (400 MHz, CD3OD) δ 7.55 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.73 (t, J = 8.0 Hz, 1H), 4.91 (t, J = 8.0 Hz, 2H), 4.44-4.41 (m, 2H), 4.24 (s, 2H), 4.11-4.03 (m, 4H), 3.83-3.76 (m, 1H), 3.41-3.35 (m, 1H)

[0339] Example S14. Synthesis of 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (14) [ka]

[0340] Synthesis of methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (200 mg, 0.690 mmol, 1.00 equiv.) and 2-bromo-1,3-difluorobenzene (133 mg, 0.690 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL), RuPhos Pd G3 (64 mg, 0.070 mmol, 0.10 equiv.), RuPhos (64 mg, 0.140 mmol, 0.20 equiv.), and Cs2CO3 (676 mg, 2.080 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 2) to give methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (100 mg, 36% yield) as an off-white solid. LCMS (ESI, m / z): 401 [M+H] +

[0341] Synthesis of 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (80 mg, 0.200 mmol, 1.00 equiv.) in THF (2 mL) and water (0.2 mL) was added LiOH·HO (25 mg, 0.600 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 66% B to 80% B in 7 min; 254 / 210 nm; RT: 6.12 min) to give 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (33 mg, 42% yield) as an off-white solid.

[0342] LCMS (ESI, m / z): 387 [M+H] + Analysis 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 in 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.106 min

[0343] 1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.98-6.92 (m, 2H), 6.76-6.7 (m, 1H), 4.56-4.49 (m, 2H), 4.15-4.09 (m, 2H), 3.97-3.87 (m, 1H), 3.42 (s, 2H), 2.77-2.71 (m, 2H), 2.24-2.14 (m, 1H), 2.01-1.92 (m, 2H), 1.81-1.75 (m, 2H), 1.60-1.47 (m, 2H)

[0344] Example S15. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (15) [ka]

[0345] Synthesis of methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] A solution of ZnCl2 (1.9 M in Me-THF, 19.8 mL, 37.54 mmol, 2.00 equiv.) and NaBH3CN (4.72 g, 75.09 mmol, 4.00 equiv.) in methanol (8 mL) was stirred at room temperature for 10 min. Then, 4-bromo-2,6-dimethyl-benzaldehyde (4 g, 18.77 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (5.38 g, 37.55 mmol, 2.00 equiv.) were added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was poured into DCM / H2O (1 / 1, 100 mL). The separated organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluted with PE / EA, 3 / 1) to give methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (3.5 g, 54.8%) as a pale yellow oil. LCMS (ESI, m / z): 340 [M+H] +

[0346] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (13.24 g, 46.75 mmol, 10.0 equiv.) in DMF (75 mL) was added zinc powder (4.41 g, 67.48 mmol, 15.0 equiv.). The resulting mixture was stirred at 60 °C for 5 hours. Then, methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.5 g, 4.41 mmol, 1.00 equiv.), Pd(dba) (807 mg, 0.88 mmol, 0.20 equiv.), and tri(o-tolyl)phosphine (1.34 g, 4.41 mmol, 1.00 equiv.) were added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash C18 silica chromatography (eluting with 100% ACN) to give methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.8 g, 98.0%) as a pale yellow oil. LCMS (ESI, m / z): 417 [M+H] +

[0347] Synthesis of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde [ka] To a stirred solution of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.8 g, 4.32 mmol, 1.00 equiv.) in DCM (2 mL) was added TBSOTf (1.53 mL, 8.64 mmol, 2.00 equiv.) dropwise at room temperature. The resulting solution was stirred at room temperature for 1 hour. LCMS showed complete conversion. The reaction mixture was concentrated in vacuo. The residue was purified by flash C18 silica chromatography (eluting with 22% ACN (0.05% TFA) in water) to give methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde (1.3 g, 95.1%) as a pale yellow oil. LCMS (ESI, m / z): 317 [M+H] +

[0348] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde (2 g, 6.32 mmol, 1.00 equiv.), 2-bromo-1,3-dichloro-benzene (2.86 g, 12.64 mmol, 2.00 equiv.) in 1,4-dioxane (2 mL), RuPhos Pd G3 (884 mg, 0.95 mmol, 0.15 equiv.), RuPhos (442 mg, 0.95 mmol, 0.15 equiv.), and CsCO3 (6.16 g, 18.96 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc (20 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash C18 silica chromatography (eluting with 90% ACN (10 mM NH4HCO3) in water) to give methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (500 mg, 17.1%) as a pale yellow oil. LCMS (ESI, m / z): 461 [M+H] +

[0349] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (15) [ka] A mixture of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (25 mg, 0.54 mmol, 1.00 equiv.) and LiOH (39 mg, 1.63 mmol, 1.00 equiv.) in THF (2.5 mL) and water (2.5 mL) was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 5-6 by the addition of acetic acid and then concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B in 7 min; Wavelength: 254 / 220 nm; RT: 5.92 min) to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (165.1 mg, 66.7%) as a white solid.

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 7.6 Hz, 2H), 7.03 (s, 2H), 6.74 (t, J = 7.6 Hz, 1H), 4.80 (t, J = 8.0 Hz, 2H), 4.34 (t, J = 8.0 Hz, 2H), 3.71-3.64 (m, 1H), 3.38 (s, 2H), 2.69-2.66 (m, 2H), 2.33 (s, 6H), 2.20-2.14 (m, 1H), 2.08-2.02 (m, 2H), 1.76-1.72 (m, 2H), 1.48-1.40 (m, 2H)

[0351] LCMS (ESI, m / z): 447 [M+H] +Analysis conditions: Column: YMCMeteoric C18 BIO, 2.1*30 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 in 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 0.849 min

[0352] Example S16. 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylic acid (16a and 16b) [ka]

[0353] Synthesis of methyl 1-(1-(4-bromo-2-methylphenyl)ethyl)piperidine-4-carboxylate [ka] To a stirred solution of NaCNBH3 (3.55 g, 93.87 mmol) in methanol (25 mL), ZnCl2 (1 M in THF, 23 mL, 23.47 mmol) was added. The mixture was stirred at room temperature for 0.5 h. A solution of 1-(4-bromo-2-methyl-phenyl)ethanone (5.00 g, 23.47 mmol) and methyl piperidine-4-carboxylate (6.72 g, 46.93 mmol) in methanol (25 mL) was added dropwise. The resulting mixture was stirred at 60 °C for 12 h. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluted with PE / EtOAc, 1 / 1) to give methyl 1-(1-(4-bromo-2-methylphenyl)ethyl)piperidine-4-carboxylate (5.5 g, 68.9% yield) as a yellow oil. LCMS (ESI, m / z): 340[M+H] +

[0354] Synthesis of methyl 1-(1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (24.6 g, 70.53 mmol, 4.00 equiv.) in DMF (30 mL) was added zinc powder (5.76 g, 88.2 mmol, 5.00 equiv.). The resulting mixture was stirred at 60 °C for 3 h under a N atmosphere. Pd(dba) (1.61 g, 1.76 mmol, 0.010 equiv.), tris-(o-tolyl)phosphine (1.07 g, 3.53 mmol, 0.020 equiv.), and methyl 1-(1-(4-bromo-2-methylphenyl)ethyl)piperidine-4-carboxylate (6.00 g, 17.6 mmol, 1.00 equiv.) were then added. The resulting mixture was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3*80 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 4 / 1) to give methyl 1-(1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-methyl-phenyl)ethyl)piperidine-4-carboxylate (1.9 g, 25.9% yield) as a yellow solid. LCMS (ESI, m / z): 417 [M+H] +

[0355] Synthesis of methyl 1-(1-(4-(azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde [ka] To a stirred solution of methyl 1-(1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate (1.9 g, 4.56 mmol) in DCM (10 mL) was added TBSOTF (5 mL, 56.44 mmol). The resulting solution was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl 1-(1-(4-(azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde (900 mg, 62.4% yield) as a yellow oil. LCMS (ESI, m / z): 317 [M+H] +

[0356] Synthesis of methyl 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(1-(4-(azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde (900 mg, 2.84 mmol) in 1,4-dioxane (10 mL) was added 2-bromo-1,3-dichloro-benzene (1.28 g, 5.69 mmol), RuPhos Pd G3 (530 mg, 0.570 mmol), RuPhos (133 mg, 0.280 mmol), and Cs2CO3 (2.78 g, 8.53 mmol). The resulting solution was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 3) to give methyl 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate (139 mg, 10.6% yield) as a yellow oil. LCMS (ESI, m / z): 461 [M+H] +

[0357] Chiral Separation of Methyl 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate [ka] The racemate was resolved by chiral HPLC (column: CHIRALPAK IG-3, 3.0*50 mm, 3 μm; mobile phase B: MeOH (1% 2M NH3-MeOH); flow rate: 2 mL / min; gradient: isocratic 20% B; wavelength: 220 nm) to give 65 mg of the first enantiomer and 50 mg of the second enantiomer.

[0358] Synthesis of 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylic acid (enantiomers 1, 16a) [ka] A mixture of methyl 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate (Enantiomer 1, 65 mg, 0.140 mmol) and LiOH (18 mg, 0.420 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 64% B in 8 min; Wavelength: 254 / 220 nm; RT: 7.08 min) to give 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)-ethyl)piperidine-4-carboxylic acid (22.8 mg, 35.9% yield) as a white solid.

[0359] LCMS (ESI, m / z): 447 [M+H] +Analysis conditions: Column: HALO C18, 3.0*30 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 in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.035 min

[0360] 1 H NMR (300 MHz, CD3OD) δ 7.52-7.37 (m, 3H), 7.26 (d, J = 7.8 Hz, 2H), 6.73 (t, J = 7.8 Hz, 1H), 4.89 (t, J = 8.1 Hz, 2H), 4.51-4.40 (m, 3H), 3.80-3.73 (m, 1H), 3.65-3.55 (m, 1H), 3.21-3.16 (m, 1H), 2.92-2.84 (m, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 1H), 2.12-1.81 (m, 4H), 1.64 (d, J = 6.9 Hz, 3H)

[0361] Synthesis of 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)-ethyl)piperidine-4-carboxylic acid (chiral separation 2, 16b) [ka] A mixture of methyl 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)ethyl)piperidine-4-carboxylate (enantiomer 2, 50 mg, 0.110 mmol) and LiOH (14 mg, 0.330 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 39% B to 64% B in 8 min; Wavelength: 254 / 220 nm; RT: 7.10 min) to give 1-(1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-methylphenyl)-ethyl)piperidine-4-carboxylic acid (25.4 mg, 51.9% yield) as a white solid.

[0362] LCMS (ESI, m / z): 447 [M+H] + Analysis conditions: Column: HALO C18, 3.0*30 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 in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.033 min

[0363] 1H NMR (300 MHz, CD3OD) δ 7.52-7.38 (m, 3H), 7.19 (d, J = 7.8 Hz, 2H), 6.72 (t, J = 7.8 Hz, 1H), 4.90 (t, J = 8.1 Hz, 2H), 4.53-4.41 (m, 3H), 3.80-3.71 (m, 1H), 3.65-3.55 (m, 1H), 3.21-3.16 (m, 1H), 2.94-2.85 (m, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 1H), 2.12-1.85 (m, 4H), 1.64 (d, J = 6.9 Hz, 3H)

[0364] Example S17. 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylic acid (17) [ka]

[0365] Synthesis of methyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate [ka] To a stirred solution of methyl cyclopent-3-ene-1-carboxylate (2.00 g, 15.9 mmol, 1.00 equiv.) in DCM (15 mL) was added m-CPBA (3.50 g, 20.3 mmol, 1.30 equiv.). The resulting mixture was stirred at 0 °C for 3 h. GCMS indicated the reaction was complete. The reaction was quenched with aqueous NaSO, filtered, and the filtrate was diluted with DCM (50 mL), washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. This afforded methyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (2 g, 88.7%) as a crude pale yellow oil, which was used directly in the next step.

[0366] Synthesis of methyl 4-oxo-2-(2-oxoethyl)butanoate [ka] To a stirred solution of methyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (2 g, 14.07 mmol, 1.00 equiv.) in ethyl acetate (3 mL) was added HIO (2.96 g, 15.48 mmol, 1.10 equiv.). The resulting mixture was stirred at 0 °C for 3.5 h. The reaction mixture was filtered. The reaction mixture was poured into EA / HO, and the organic layer was washed with brine and dried over anhydrous NaSO. This afforded methyl 4-oxo-2-(2-oxoethyl)butanoate (2 g, 89.9%) as a crude pale yellow oil, which was used directly in the next step.

[0367] Synthesis of methyl 1-(2-(4-bromophenyl)propan-2-yl)piperidine-4-carboxylate [ka] A solution of ZnCl (2.0 M in THF, 8.5 mL, 19.0 mmol, 2.00 equiv.) and NaBHCN (2.43 g, 37.9 mmol, 4.00 equiv.) in methanol (20 mL) was stirred at room temperature for 10 minutes. Methyl 4-oxo-2-(2-oxoethyl)butanoate (1.50 g, 9.48 mmol, 1.00 equiv.) and 2-(4-bromophenyl)propan-2-amine (1.62 g, 7.59 mmol, 0.80 equiv.) were then added. The resulting reaction was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 20 / 80) to give methyl 1-(2-(4-bromophenyl)propan-2-yl)piperidine-4-carboxylate (600 mg, 18.6%) as a pale yellow oil. LCMS (ESI, m / z): 340 [M+H] +

[0368] Synthesis of methyl 1-(2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (5.29 g, 18.7 mmol, 10.0 equiv.) in DMF (30 mL) was added zinc (1.76 g, 26.99 mmol, 15.0 equiv.). The resulting mixture was stirred at 60° C. for 5 hours. Then methyl 1-(2-(4-bromophenyl)propan-2-yl)piperidine-4-carboxylate (600 mg, 1.76 mmol, 1.00 equiv.), Pd(bda) (323 mg, 0.35 mmol, 0.20 equiv.), and tri(o-tolyl)phosphine (536 mg, 1.76 mmol, 1.00 equiv.) were added. The resulting mixture was stirred at 80° C. overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with saturated aqueous NH4Cl (60 mL) and extracted with EtOAc (3*40 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude was purified by flash silica gel chromatography (eluted with PE / EtOAc, 2 / 1) to give methyl 1-(2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate (730 mg, 99.4%) as a pale yellow oil. LCMS (ESI, m / z): 417 [M+H] +

[0369] Synthesis of methyl 1-(2-(4-(azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(2-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)-propan-2-yl)piperidine-4-carboxylate (730 mg, 1.75 mmol, 1.00 equiv.) in DCM (2 mL) was added TBSOTf (0.62 mL, 3.5 mmol, 2.00 equiv.) dropwise. The resulting mixture was stirred at room temperature for 1 h. LCMS showed complete conversion. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give methyl 1-(2-(4-(azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate (550 mg, 99.2%) as a pale yellow oil. LCMS (ESI, m / z): 317 [M+H] +

[0370] Synthesis of methyl 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate [ka] A solution of methyl 1-(2-(4-(azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate (550 mg, 1.74 mmol, 1.00 equiv.), 2-bromo-1,3-dichloro-benzene (785 mg, 3.48 mmol, 2.00 equiv.), RuPhos Pd G3 (243 mg, 0.26 mmol, 0.15 equiv.), RuPhos (122 mg, 0.26 mmol, 0.15 equiv.), and Cs2CO3 (1.69 g, 5.21 mmol, 3.00 equiv.) in 1,4-dioxane (2 mL) was stirred at 90 °C under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give methyl 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate (170 mg, 21.2%) as a pale yellow oil. LCMS (ESI, m / z): 461 [M+H] +

[0371] Synthesis of 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylic acid (17) [ka] A mixture of methyl 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylate (175 mg, 0.38 mmol, 1.00 equiv.) and LiOH (27 mg, 1.14 mmol, 3.00 equiv.) in THF (2 mL) and water (2 mL) was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 10 min, hold at 45% B for 2 min; Wavelength: 254 / 220 nm; RT: 10.38 min) to give 1-(2-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)propan-2-yl)piperidine-4-carboxylic acid (108.5 mg, 62.5%) as a white solid.

[0372] LCMS (ESI, m / z): 447 [M+H] + Analysis conditions: Column: YMC Meteoric Core C18 BIO, 2.1*30 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 in 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 0.803 min

[0373] 1H NMR (400 MHz, DMSO-d6) δ 12.0 (br, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 8.0 Hz, 1H), 4.83 (t, J = 8.0 Hz, 2H), 4.37-4.34 (m, 2H), 3.79-3.71 (m, 1H), 2.72-2.69 (m, 2H), 2.18-2.04 (m, 3H), 1.77-1.73 (m, 2H), 1.55-1.45 (m, 2H), 1.27 (s, 6H)

[0374] Example S18. 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (18) General Route: [ka]

[0375] Synthesis of methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (18-a) [ka] To a solution of 5-bromopicolinaldehyde (3 g, 16.13 mmol) in anhydrous 1,2-DCE (10 mL) was added methyl piperidine-4-carboxylate (2.309 g, 16.13 mmol), and the reaction mixture was stirred at ambient temperature. After 10 min, sodium triacetoxyborohydride (3.42 g, 16.13 mmol) was added, and the reaction mixture was stirred at room temperature. After 4 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography eluting with 0–100% ethyl acetate in petroleum ether to give methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (1.8 g, 35.6% yield) as a colorless oil. LCMS (ESI, m / z): 313.0, 315.0 [M, M+2H] +

[0376] Synthesis of methyl 1-((5-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (18-b) [ka] To a stirred solution of activated zinc (1.044 g, 15.96 mmol) in anhydrous DMF (20 mL) was added 1,2-dibromoethane (0.028 mL, 0.319 mmol) and heated to 60°C. After 30 minutes, the mixture was cooled to ambient temperature and chlorotrimethylsilane (0.1 mL, 0.782 mmol) was added. The reaction mixture was then stirred at ambient temperature for an additional 30 minutes. Next, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (4.52 g, 15.96 mmol) in anhydrous DMF (15 mL) was added to the mixture and heated to 60°C for 2 hours to give (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide.

[0377] In a separate two-necked round-bottom flask, to a solution of methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (1.0 g, 3.19 mmol) in anhydrous DMF (20 mL) was added XPhos Pd G4 (0.549 g, 0.639 mmol). Freshly prepared (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide was then added to the mixture via cannula under a nitrogen atmosphere. The reaction mixture was then heated to 80 °C under a nitrogen atmosphere, and the reaction progress was monitored by LCMS. After 16 h, LCMS analysis indicated complete conversion of the starting material. The reaction mixture was cooled to ambient temperature, filtered through a Celite pad, and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel, washed with cold water (300 mL), followed by brine solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-5% methanol in dichloromethane to afford methyl 1-((5-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (1.4 g, 78% yield) as a yellow oil. LCMS (ESI, m / z): 390.2 [M+H] +

[0378] Synthesis of methyl 1-((5-(azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (18-c) [ka] To a stirred solution of methyl 1-((5-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (1.3 g, 3.34 mmol) in anhydrous dichloromethane (40 mL), tert-butyldimethylsilyl trifluoromethanesulfonate (2.302 mL, 10.01 mmol) was added, and the resulting mixture was stirred at room temperature. After 1 h, LCMS analysis indicated complete conversion of the starting material. The reaction mixture was concentrated in vacuo, and the residue was purified by C18 silica column chromatography (mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 120 mL / min; gradient: 10% B to 20% B in 5 min; 254 / 210 nm). The required fractions were collected and concentrated under reduced pressure to give methyl 1-((5-(azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate.TFA (850 mg, 61.2% yield) as a brown gum. LCMS (ESI, m / z): 290.2 [M+H] +

[0379] Synthesis of methyl 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (18-d) [ka] To a solution of methyl 1-((5-(azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (400 mg, 1.382 mmol) and 1,3-dichloro-2-iodobenzene (453 mg, 1.659 mmol) in anhydrous 1,4-dioxane (20 mL) was added cesium carbonate (1.3 g, 4.15 mmol). The reaction mixture was then degassed under vacuum and filled with nitrogen. RuPhos Pd G3 (116 mg, 0.138 mmol) was added to the mixture and heated to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite, and washed with dichloromethane. The filtrate was then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-70% ethyl acetate in petroleum ether to afford methyl 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (140 mg, 21.22% yield) as a yellow oil. LCMS (ESI, m / z): 434.0 [M+H] +

[0380] Synthesis of 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (18) [ka] To a stirred solution of methyl 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (140 mg, 0.322 mmol) in tetrahydrofuran (5 mL) and HO (0.5 mL), lithium hydroxide (23.16 mg, 0.967 mmol) was added, and the resulting mixture was stirred at ambient temperature. After 2 h, TLC analysis indicated complete conversion of the starting material. The volatiles were removed under reduced pressure, and the aqueous layer was acidified with acetic acid to maintain a pH of 5. The resulting mixture was then purified by C18 silica column chromatography (mobile phase A: water (10 mM ammonium formate), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 45% B to 50% B in 4 min; 254 / 210 nm). The desired fractions were collected and lyophilized to give 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid, formate salt (45 mg, 28.1% yield) as a white solid. LCMS (ESI, m / z): 420.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.49-8.48 (m, 1H), 7.92-7.90 (m, 1H), 7.43 (d, J = 8.00 Hz, 1H), 7.24 (d, J = 8.00 Hz, 2H), 6.76 (t, J = 8.00 Hz, 1H), 4.85 (t, J = 8.00 Hz, 2H), 4.37 (t, J = 6.80 Hz, 2H), 3.83-3.78 (m, 1H), 3.55 (s, 2H), 2.78-2.55 (m, 2H), 2.34-2.33 (m, 1H), 2.46-2.47 (m, 1H), 2.20-2.18 (m, 2H), 1.75 (m, 2H), 1.60-1.52 (m, 2H)

[0381] Example S19. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylic acid (19)

[0382] Synthesis of methyl 1-(4-bromo-2,5-dimethylbenzyl)piperidine-4-carboxylate (19-a) [ka] The title compound was synthesized according to the general synthetic procedure of 18-a. LCMS (ESI, m / z): 342.0 [M+2H] +

[0383] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylate (19-b) [ka] The title compound was synthesized according to the general synthetic procedure of 18-b. LCMS (ESI, m / z): 417.3 [M+H] +

[0384] Synthesis of methyl 1-(4-(azetidin-3-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylate (19-c) [ka] The title compound was synthesized according to the general synthetic procedure of 18-c. LCMS (ESI, m / z): 317.2 [M+H] +

[0385] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylate (19-d) [ka] The title compound was synthesized according to the general synthetic procedure of 18-d. LCMS (ESI, m / z): 461.2 [M+H] +

[0386] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylic acid (19) [ka] The title compound was synthesized according to the general synthetic procedure of 18. LCMS (ESI, m / z): 447.0 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz): δ 7.23 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 6,98 (s, 1H), 6.74 (t, J = 7.6 Hz, 1H), 4.84 (t, J = 8.4 Hz, 2H), 4.33 (t, J = 7.6 Hz, 2H), 3.92-3.88 (m, 1H), 3.31 (s, 3H), 2.72-2.69 (m, 2H), 2.28 (s, 3H), 2.18 (s, 3H), 2.16-2.14 (m, 1H), 1.98-1.93 (m, 2H), 1.76-1.73 (m, 2H), 1.49-1.47 (m, 2H)

[0387] Example S20. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylic acid (20)

[0388] Synthesis of methyl 1-(4-bromo-3,5-dimethylbenzyl)piperidine-4-carboxylate (20-a) [ka] The title compound was synthesized according to the general synthetic procedure of 18-a. LCMS (ESI, m / z): 340.0, 342.0 [M+2H] +

[0389] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (20-b) [ka] The title compound was synthesized according to the general synthetic procedure of 18-b. LCMS (ESI, m / z): 417.0 [M+H] +

[0390] Synthesis of methyl 1-(4-(azetidin-3-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (20-c) [ka] The title compound was synthesized according to the general synthetic procedure of 18-c. LCMS (ESI, m / z): 317.2 [M+H] +

[0391] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (20-d) [ka] The title compound was synthesized according to the general synthetic procedure of 18-d. LCMS (ESI, m / z): 461.2 [M+H] +

[0392] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylic acid (20) [ka] The title compound was synthesized according to the general synthetic procedure of 18. LCMS (ESI, m / z): 447.0 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 12.12 (bs, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.87 (s, 2H), 6.73 (t, J = 8.0 Hz, 1H), 4.96 (t, J = 8.4 Hz, 2H), 4.44-4.40 (m, 2H), 4.19-4.15 (m, 1H), 3.33 (s, 2H), 2.72-2.67 (m, 2H), 2.26 (s, 6H), 2.19-2.13 (m, 1H), 1.95-1.90 (m, 2H), 1.76-1.74 (m, 2H), 1.56-1.50 (m, 2H)

[0393] Example S21. 1-((6-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-3-yl)methyl)piperidine-4-carboxylic acid (21)

[0394] Synthesis of methyl 1-((6-bromopyridin-3-yl)methyl)piperidine-4-carboxylate (21-a) [ka] The title compound was synthesized according to the general synthetic procedure of 18-a. LCMS (ESI, m / z): 313.1, 315.0 [M, M+2H] +

[0395] Synthesis of methyl 1-((6-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridin-3-yl)methyl)piperidine-4-carboxylate (21-b) [ka] The title compound was synthesized according to the general synthetic procedure of 18-b. LCMS (ESI, m / z): 390.2 [M+H] +

[0396] Synthesis of methyl 1-((6-(azetidin-3-yl)pyridin-3-yl)methyl)piperidine-4-carboxylate (21-c) [ka] The title compound was synthesized according to the general synthetic procedure of 18-c. LCMS (ESI, m / z): 290.2 [M+H] +

[0397] Synthesis of methyl 1-((6-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-3-yl)methyl)piperidine-4-carboxylate (21-d) [ka] The title compound was synthesized according to the general synthetic procedure of 18-d. LCMS (ESI, m / z): 434.1 [M+H] +

[0398] Synthesis of 1-((6-(1-(2,6-dichlorophenyl)azetidin-3-yl)pyridin-3-yl)methyl)piperidine-4-carboxylic acid (21) [ka] The title compound was synthesized according to the general synthetic procedure of 18. LCMS (ESI, m / z): 420.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.56 (m, 1H), 7.88-7.85 (m, 1H), 7.54 (d, J = 8.00 Hz, 1H), 7.18 (d, J = 8.00 Hz, 2H), 6.71 (t, J = 8.00 Hz, 2H), 4.91 (m, 2H), 4.63-4.59 (m, 2H), 3.96 (m, 1H), 3.87 (s, 2H), 3.17-3.08 (m, 2H), 2.50 (m, 2H), 2.35 (m, 1H), 2.00-1.96 (m, 2H), 1.82-1.80 (m, 2H)

[0399] Example S22. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3-fluorobenzyl)piperidine-4-carboxylic acid (22)

[0400] Synthesis of methyl 1-(4-bromo-3-fluorobenzyl)piperidine-4-carboxylate (22-a) [ka] The title compound was synthesized according to the general synthetic procedure of 18-a. LCMS (ESI, m / z): 331.2 [M+2H] +

[0401] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-fluorobenzyl)piperidine-4-carboxylate (22-b) [ka] The title compound was synthesized according to the general synthetic procedure of 18-b. Light yellow oil; LCMS (ESI, m / z): 407.1 [M+H] +

[0402] Synthesis of methyl 1-(4-(azetidin-3-yl)-3-fluorobenzyl)piperidine-4-carboxylate (22-c) [ka] The title compound was synthesized according to the general synthetic procedure of 18-c. LCMS (ESI, m / z): 307.1 [M+H] +

[0403] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3-fluorobenzyl)piperidine-4-carboxylate (22-d) [ka] The title compound was synthesized according to the general synthetic procedure of 18-d. LCMS (ESI, m / z): 451.0 [M+H] +

[0404] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3-fluorobenzyl)piperidine-4-carboxylic acid (22) [ka] The title compound was synthesized according to the general synthetic procedure of 18. LCMS (ESI, m / z): 437.0 [M+H] + ;1 H NMR (400 MHz, DMSO-d6): (400 MHz, DMSO-d6) d 7.49 (t, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 2H), 7.15-7.07 (m, 2H), 6.75 (t, J = 8 Hz, 1H), 4.85 (t, J = 8 Hz, 2H), 4.40 (t, J = 7.2 Hz, 2H), 3.98-3.94 (m, 1H), 3.44 (s, 2H), 2.74-2.71 (m, 2H), 2.21-2.15 (m, 1H), 2.01-1.98 (m, 2H), 1.80-1.70 (m, 2H), 1.59-1.49 (m, 2H)

[0405] Example S23. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluorobenzyl)piperidine-4-carboxylic acid (23)

[0406] Synthesis of methyl 1-(4-bromo-2-fluorobenzyl)piperidine-4-carboxylate (23-a) [ka] The title compound was synthesized according to the general synthetic procedure of 18-a. LCMS (ESI, m / z): 331.2 [M+2H] +

[0407] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-fluorobenzyl)piperidine-4-carboxylate (23-b) [ka] The title compound was synthesized according to the general synthetic procedure of 18-b. Pale yellow liquid; LCMS (ESI, m / z): 407.1 [M+H] +

[0408] Synthesis of methyl 1-(4-(azetidin-3-yl)-2-fluorobenzyl)piperidine-4-carboxylate (23-c) [ka] The title compound was synthesized according to the general synthetic procedure of 18-c. LCMS (ESI, m / z): 307.1 [M+H] +

[0409] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluorobenzyl)piperidine-4-carboxylate (23-d) [ka] The title compound was synthesized according to the general synthetic procedure of 18-d. LCMS (ESI, m / z): 451.0 [M+H] +

[0410] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluorobenzyl)piperidine-4-carboxylic acid (23) [ka] The title compound was synthesized according to the general synthetic procedure of 18. LCMS (ESI, m / z): 437.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ 7.53-7.49 (m, 1H), 7.40-7.48 (m, 2H), 7.21 (d, J = 8.00 Hz, 2H), 6.75 (t, J = 8.00 Hz, 1H), 4.93-4.91 (m, 2H), 4.45-4.41 (m, 2H), 4.15 (s, 2H), 3.79-3.83 (m, 2H), 2.86 (m, 2H), 2.45 (m, 2H), 2.05-2.09 (m, 2H), 1.87-1.90 (m, 2H)

[0411] Example S24. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (24) [ka]

[0412] Synthesis of tert-butyl 3-(2,6-dichlorophenyl)-3-hydroxyazetidine-1-carboxylate [ka] To a solution of 2-bromo-1,3-dichlorobenzene (3.0 g, 13.28 mmol, 1.00 equiv.) in dry THF (20 mL) was added iPrMgCl-LiCl (1.3 M in THF, 20.4 mL, 26.56 mmol, 2.00 equiv.) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 3 h. Next, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4.5 g, 26.56 mmol, 2.00 equiv.) in dry THF (5.0 mL) was added. The reaction was allowed to warm slowly to room temperature and stirred at room temperature for an additional 12 h. The reaction was quenched with aq. NH4Cl (20 mL) and extracted with ether (2*25 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3) / ACN, 80 / 20) to give tert-butyl 3-(2,6-dichlorophenyl)-3-hydroxyazetidine-1-carboxylate (2.0 g, 47%) as a yellow solid. LCMS (ESI, m / z): 318 [M+H] +

[0413] Synthesis of tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-(2,6-dichlorophenyl)-3-hydroxy-azetidine-1-carboxylate (2.0 g, 6.290 mmol, 1.00 equiv.) in toluene (10 mL) was added Burgess reagent (2.2 g, 9.430 mmol, 1.50 equiv.). The reaction was stirred at 110 °C for 12 hours. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and Rh(PPh3)3Cl (1.1 g, 1.250 mmol, 2.00 equiv.) was added. The resulting mixture was stirred at 50 °C under a hydrogen atmosphere for 12 hours. LCMS showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3 / ACN, 30 / 70) to give tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate (560 mg, 30%) as a yellow solid. LCMS (ESI, m / z): 302 [M+H] +

[0414] Synthesis of 3-(2,6-dichlorophenyl)azetidine [ka] To a stirred solution of tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate (300 mg, 0.990 mmol, 1.00 equiv.) in DCM (5.0 mL) was added TBSOTf (0.3 mL, 1.99 mmol, 2.00 equiv.). The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude 3-(2,6-dichlorophenyl)azetidine was used directly in the next step without further purification. LCMS (ESI, m / z): 202 [M+H] +

[0415] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of 3-(2,6-dichlorophenyl)azetidine (150 mg, 0.740 mmol, 1.00 equiv.) in 1,4-dioxane (5.0 mL), 1-(4-bromobenzyl)piperidine-4-carboxylic acid (278 mg, 0.890 mmol, 1.20 equiv.), CPhos (22 mg, 0.150 mmol, 0.20 equiv.), Pd(dba) (67 mg, 0.070 mmol, 0.10 equiv.), and CsCO (725 mg, 2.230 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3 / ACN, 10 / 90) to give methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate (230 mg, 71%) as a yellow solid. LCMS (ESI, m / z): 433 [M+H] +

[0416] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (24) [ka] To a solution of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate (220 mg, 0.510 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was added LiOH·HO (42 mg, 1.02 mmol, 2.00 equiv.). The reaction was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction was acidified to pH 5-6 by dropwise addition of acetic acid and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 ExRS, 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: 15% B to 45% B in 8 min, 254 / 220 nm; RT: 7.82 min) to give 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (54.6 mg, 25%) as an off-white solid.

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 4.59-4.50 (m, 1H), 4.42 (t, J = 7.6 Hz, 2H), 3.98 (t, J = 7.6 Hz, 2H), 3.31 (s, 2H), 2.73-2.69 (m, 2H), 2.18-2.10 (m, 1H), 1.94-1.87 (m, 2H), 1.77-1.72 (m, 2H), 1.58-1.45 (m, 2H)

[0418] LCMS (ESI, m / z): 419 [M+H] +Analysis conditions: L-column 3 C18, 3.0*30 mm, 2.0 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 1.50 mL / min; Gradient: 10% B to 60% B in 1.85 min, 60% B to 95% B in 0.45 min, hold at 95% B for 0.5 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 1.587 min

[0419] Example S25. (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylic acid [ka]

[0420] Synthesis of methyl (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylate [ka] To a stirred solution of 3-(2,6-dichlorophenyl)azetidine (50 mg, 0.250 mmol, 1.00 equiv.) in tBuOH (5 mL) was added methyl (R)-1-(4-bromobenzyl)pyrrolidine-3-carboxylate (148 mg, 0.490 mmol, 2.00 equiv.), BrettPhos Pd G3 (23 mg, 0.020 mmol, 0.10 equiv.), and K2CO3 (171 mg, 1.24 mmol, 5.00 equiv.). The resulting mixture was stirred at 80 °C for 3 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give methyl (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylate (31 mg, 29% yield) as an off-white solid. LCMS (ESI, m / z): 419 [M+H] +

[0421] Synthesis of (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylic acid (25) [ka] To a stirred solution of methyl (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylate (31 mg, 0.070 mmol, 1.00 equiv.) in THF (3 mL) and water (0.6 mL) was added LiOH·HO (9 mg, 0.220 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 3 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 67% B in 7 min; Wavelength: 254 / 220 nm; RT: 6.53 min) to give (R)-1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)pyrrolidine-3-carboxylic acid (7.6 mg, 25% yield) as an off-white solid.

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 8.0 Hz, 2H), 4.60-4.52 (m, 1H), 4.42 (t, J = 7.6 Hz, 2H), 3.99 (t, J = 7.8 Hz, 2H), 3.43 (d, J = 2.8 Hz, 2H), 2.92-2.84 (m, 1H), 2.70-2.63 (m, 2H), 2.50-2.35 (m, 2H), 1.94-1.89 (m, 2H)

[0423] LCMS (ESI, m / z): 405 [M+H] +Analysis conditions: Column: HALO C18 3.0*30 mm, 2.7 mm; Mobile phase A: Water (0.05% TFA), Mobile phase B: Acetonitrile (0.05% TFA); Flow rate: 1.50 mL / min; Gradient: 5% B to 60% B in 2.10 min, 60% B to 100% B in 0.30 min, hold at 100% for 0.40 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.704 min

[0424] Example S26. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylic acid (26) [ka]

[0425] Synthesis of ethyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylate [ka] To a stirred solution of ethyl 1-(4-bromobenzyl)azetidine-3-carboxylate (120 mg, 0.400 mmol, 1.00 equiv.) and 3-(2,6-dichlorophenyl)azetidine (81 mg, 0.400 mmol, 1.00 equiv.) in tBuOH (4 mL) was added BrettPhos Pd G3 (36 mg, 0.040 mmol, 0.10 equiv.) and K2CO3 (166 mg, 1.210 mmol, 3.00 equiv.). The resulting mixture was stirred at 80 °C for 3 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give ethyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylate (60 mg, 35% yield) as an off-white solid. LCMS (ESI, m / z): 405 [M+H] +

[0426] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylic acid (26) [ka] To a stirred solution of ethyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylate (60 mg, 0.140 mmol, 1.00 equiv.) in THF (2 mL) and water (0.2 mL) was added LiOH·HO (18 mg, 0.430 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 45% B in 8 min; Wavelength: 254 / 220 nm; RT: 7.93 min) to give 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)azetidine-3-carboxylic acid (20.5 mg, 36% yield) as an off-white solid.

[0427] 1 H NMR (300 MHz, CD3OD) δ 7.40 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.60 (d, J = 7.8 Hz, 2H), 4.75-4.66 (m, 1H), 4.50 (t, J = 8.1 Hz, 2H), 4.23-4.14 (m, 4H), 4.07-4.04 (m, 4H), 3.44-3.35 (m, 1H)

[0428] LCMS (ESI, m / z): 391 [M+H] + Analysis conditions: Column: HALO C18 Column 3.0*30 mm, 2.0 mm; 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 in 1.80 min, 60% B to 100% B in 0.15 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.15 min; 254 nm; RT: 1.483 min

[0429] Example S27. 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (27) [ka]

[0430] Synthesis of methyl 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate [ka] To a stirred solution of 3-(2,6-difluorophenyl)azetidine (80 mg, 0.470 mmol, 1.00 equiv.) and methyl 1-(4-bromobenzyl)piperidine-4-carboxylate (162 mg, 0.520 mmol, 1.10 equiv.) in 1,4-dioxane (2 mL), Pd(dba) (43 mg, 0.050 mmol, 0.10 equiv.), CPhos (41 mg, 0.090 mmol, 0.20 equiv.), and CsCO (153 mg, 0.470 mmol, 3.00 equiv.) were added. The mixture was stirred at 80 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give methyl 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate (150 mg, 79% yield) as a pale yellow oil. LCMS (ESI, m / z): 401 [M+H] +

[0431] Synthesis of 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (27) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylate (150 mg, 0.370 mmol, 1.00 equiv.) in THF (2 mL) and water (0.2 mL) was added LiOH·HO (47 mg, 1.12 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic 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: 57% B to 66% B in 7 min; 254 / 210 nm; RT: 5.68 min) to give 1-(4-(3-(2,6-difluorophenyl)azetidin-1-yl)benzyl)piperidine-4-carboxylic acid (55.9 mg, 38% yield) as an off-white solid.

[0432] LCMS (ESI, m / z): 387 [M+H] + Analysis 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 45% B in 1.70 min, 45% B to 95% B in 0.30 min, hold at 95% for 0.70 min, 95% B to 10% B in 0.10 min; 254 nm; RT: 1.607 min

[0433] 1 H NMR (300 MHz, DMSO-d6) δ 7.40-7.30 (m, 1H), 7.10-7.03 (m, 4H), 6.46-6.42 (m, 2H), 4.35-4.27 (m, 3H), 3.90-3.85 (m, 2H), 3.31 (s, 2H), 2.74-2.68 (m, 2H), 2.21-2.16 (m, 1H), 1.96-1.88 (m, 2H), 1.78-1.72 (m, 2H), 1.57-1.44 (m, 2H)

[0434] Example S28. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (28) [ka]

[0435] Synthesis of tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate [ka] To a stirred solution of 2-bromo-1,3-dichloro-benzene (1.05 g, 4.65 mmol) in DMF (15 mL) was added (1-tert-butoxycarbonylazetidin-3-yl)-iodozinc (7.29 g, 20.9 mmol), (o-tolu)P (245 mg, 0.930 mmol), and Pd(dba) (267 mg, 0.460 mmol). The resulting mixture was stirred at 80 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was diluted with saturated aqueous NHCl (60 mL) and extracted with EtOAc (3*40 mL). The organic layers were combined, dried over MgSO, and concentrated. The crude material was purified by flash silica gel chromatography (eluting with PE / EtOAc, 2 / 1) to give tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate (320 mg, 22.8% yield) as an off-white solid. LCMS (ESI, m / z): 302 [M+H] +

[0436] Synthesis of 3-(2,6-dichlorophenyl)azetidine [ka] To a stirred solution of tert-butyl 3-(2,6-dichlorophenyl)azetidine-1-carboxylate (320 mg, 1.06 mmol, 1.00 equiv.) in DCM (3 mL) was added TBSOTf (0.2 mL). The reaction was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified on a flash C18 column (eluted with water / ACN, 5 / 95) to give 3-(2,6-dichlorophenyl)azetidine (170 mg, 78.4%) as a yellow oil. LCMS (ESI, m / z): 202 [M+H] +

[0437] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] To a stirred solution of 3-(2,6-dichlorophenyl)azetidine (50 mg, 0.250 mmol, 1.00 equiv.) in tBuOH (3 mL) was added methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (168 mg, 0.490 mmol, 2.00 equiv.), BrettPhos Pd G3 (23 mg, 0.020 mmol, 0.10 equiv.), and K2CO3 (171 mg, 1.24 mmol, 5.00 equiv.). The resulting mixture was stirred at 80 °C for 3 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated and purified by flash silica gel column (eluted with PE / EA, 1 / 1) to give methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (33 mg, 28% yield) as an off-white solid. LCMS (ESI, m / z): 461 [M+H] +

[0438] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (28) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (33 mg, 0.070 mmol, 1.00 equiv.) in THF (1 mL) and water (0.2 mL) was added LiOH·HO (9 mg, 0.210 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 with acetic acid and then concentrated. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 45% B in 8 min; Wavelength: 254 / 220 nm; RT: 7.93 min) to give 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (10.9 mg, 34% yield) as an off-white solid.

[0439] 1 H NMR (300 MHz, DMSO-d6) δ 7.47 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 8.1 Hz, 1H), 6.18 (s, 2H), 4.55-4.48 (m, 1H), 4.40 (t, J = 7.5 Hz, 2H), 3.96 (t, J = 7.5 Hz, 2H), 3.30 (s, 2H), 2.69-2.65 (m, 2H), 2.26 (s, 6H), 2.22-2.14 (m, 1H), 2.03-1.96 (m, 2H), 1.75-1.71 (m, 2H), 1.49-1.40 (m, 2H)

[0440] LCMS (ESI, m / z): 447 [M+H] +Analysis conditions: Column: HALO C18 3.0*30 mm, 2.7 mm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.273 min

[0441] Example S29. 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (29) General scheme: [ka]

[0442] Synthesis of methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (29-a) [ka] To a solution of 5-bromopicolinaldehyde (3 g, 16.13 mmol) in anhydrous 1,2-DCE (10 mL) was added methyl piperidine-4-carboxylate (2.309 g, 16.13 mmol), and the reaction mixture was stirred at ambient temperature. After 10 min, sodium triacetoxyborohydride (3.42 g, 16.13 mmol) was added, and the reaction mixture was stirred at room temperature. After 4 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography eluting with 0–100% ethyl acetate in petroleum ether to give methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (1.8 g, 35.6% yield) as a colorless oil. LCMS (ESI, m / z): 313.0, 315.0 [M, M+2H] +

[0443] Synthesis of methyl 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (29-b) [ka] To a solution of methyl 1-((5-bromopyridin-2-yl)methyl)piperidine-4-carboxylate (250 mg, 0.798 mmol) and 3-(2,6-dichlorophenyl)azetidine (194 mg, 0.958 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (2.395 mmol). The reaction mixture was then degassed with nitrogen for 10 min, followed by the addition of XPhos Pd G4 (68.7 mg, 0.080 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature, filtered through a Celite pad, and washed with a DCM:MeOH (1:1) mixture. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-100% ethyl acetate in petroleum ether to afford methyl 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (180 mg, 41.5% yield) as a yellow liquid. LCMS (ESI, m / z): 434.0 [M+H] +

[0444] Synthesis of 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (29) [ka] To a stirred solution of methyl 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylate (180 mg, 0.414 mmol) in tetrahydrofuran (5 mL) and HO (0.5 mL) was added LiOH (29.8 mg, 1.243 mmol). The resulting mixture was stirred at room temperature, and the reaction progress was monitored by TLC analysis. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then acidified with acetic acid to maintain a pH of 4 and concentrated under reduced pressure. The resulting residue was purified by reverse-phase C18 silica preparative HPLC (mobile phase A: water (10 mM ammonium formate), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 45% B to 50% B in 4 min; 254 / 210 nm). The desired fractions were collected and lyophilized to give 1-((5-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (63 mg, 31.8% yield) as an off-white solid. LCMS (ESI, m / z): 420.0 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.55 (s, 1H), 7.95 (m, 1H), 7.41-7.33 (m, 3H), 7.26-7.22 (m, 1H), 7.01-6.98 (m, 1H), 4.86-4.78 (m, 2H), 4.58-4.54 (m, 2H), 4.13 (s, 2H), 3.45-3.30 (m, 1H), 2.94-2.88 (m, 2H), 2.41-2.36 (m, 1H), 2.08-2.03 (m, 2H), 1.95-1.90 (m, 2H)

[0445] Example S30. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylic acid (30)

[0446] Synthesis of methyl 1-(4-bromo-2,5-dimethylbenzyl)piperidine-4-carboxylate (30-a) [ka] The title compound was synthesized according to the general synthetic procedure of 29-a. LCMS (ESI, m / z): 342.0 [M+2H]+

[0447] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylate (30-b) [ka] The title compound was synthesized according to the general synthetic procedure of 29-b. LCMS (ESI, m / z): 462.1 [M+H] +

[0448] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,5-dimethylbenzyl)piperidine-4-carboxylic acid (30) [ka] The title compound was synthesized according to the general synthetic procedure of 29. LCMS (ESI, m / z): 445.0 [M−H] - . 1 H NMR (400 MHz, CD3OD): δ 7.38 (d, J = 8 Hz, 2H), 7.24-7.20 (m, 1H), 7.09 (s, 1H), 6.49 (s, 1H), 4.59-4.56 (m, 3H), 4.22-4.16 (m, 4H), 3.50-3.43 (m, 2H), 3.04 (m, 2H), 2.45-2.42 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.09-2.06 (m, 2H), 1.91 (m, 2H)

[0449] Example S31. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylic acid (31)

[0450] Synthesis of methyl 1-(4-bromo-3,5-dimethylbenzyl)piperidine-4-carboxylate (31-a) [ka] The title compound was synthesized according to the general synthetic procedure of 29-a. LCMS (ESI, m / z): 342.0 [M+2H] +

[0451] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (31-b) [ka] The title compound was synthesized according to the general synthetic procedure of 29-b. LCMS (ESI, m / z): 462.1 [M+H] +

[0452] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylic acid (31) [ka] The title compound was synthesized according to the general synthetic procedure of 29. LCMS (ESI, m / z): 445.1 [M−H] - ; 1 H-NMR (400 MHz, DMSO-d6): δ 7.43 (d, J = 8 Hz, 2H), 7.30-7.26 (m, 1H), 6.72 (s, 2H), 4.68 (s, 2H), 4.31-4.28 (m, 3H), 3.34 (s, 2H), 2.71-2.67 (m, 2H), 2.26 (s, 6H), 2.15-2.14 (m, 1H), 1.91-1.86 (m, 2H), 1.75-1.72 (m, 2H), 1.54-1.44 (m, 2H)

[0453] Example S32. 1-((6-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-3-yl)methyl)piperidine-4-carboxylic acid (32)

[0454] Synthesis of methyl 1-((6-bromopyridin-3-yl)methyl)piperidine-4-carboxylate (32-a) [ka] The title compound was synthesized according to the general synthetic procedure of 29-a. LCMS (ESI, m / z): 313.1, 315.0 [M, M+2H] +

[0455] Synthesis of methyl 1-((6-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-3-yl)methyl)piperidine-4-carboxylate (32-b) [ka] To a solution of 3-(2,6-dichlorophenyl)azetidine, TFA (120 mg, 0.380 mmol) in anhydrous 1,4-dioxane (5 mL) was added methyl 1-((6-bromopyridin-3-yl)methyl)piperidine-4-carboxylate (119 mg, 0.380 mmol) and cesium carbonate (371 mg, 1.139 mmol). The reaction mixture was then heated to 100 °C, and the progress of the reaction was monitored by TLC and LCMS analysis. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography eluting with 0 to 100% ethyl acetate in petroleum ether to give methyl 1-((6-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-3-yl)methyl)piperidine-4-carboxylate (60 mg, 21.1% yield). LCMS (ESI, m / z): 434.0 [M+H] +

[0456] Synthesis of 1-((6-(3-(2,6-dichlorophenyl)azetidin-1-yl)pyridin-3-yl)methyl)piperidine-4-carboxylic acid (32) [ka] The title compound was synthesized according to the general synthetic procedure of 29. LCMS (ESI, m / z): 418.0 [M−H] - ; 1 H NMR: (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.65 (d, J = 8.4 Hz,1H), 7.42 (m, 2H), 7.27-7.23 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.88 (m, 2H), 4.57-4.49 (m, 4H), 4.01 (s, 2H), 2.81 (m, 2H), 2.36 (m, 1H), 2.05-2.04 (m, 2H), 1.88-1.85 (m, 2H)

[0457] Example S33. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2-fluorobenzyl)piperidine-4-carboxylic acid (33)

[0458] Synthesis of methyl 1-(4-bromo-2-fluorobenzyl)piperidine-4-carboxylate (33-a) [ka] The title compound was synthesized according to the general synthetic procedure of 29-a. LCMS (ESI, m / z): 331.2 [M+2H] +

[0459] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2-fluorobenzyl)piperidine-4-carboxylate (33-b) [ka] The title compound was synthesized according to the general synthetic procedure of 29-b. LCMS (ESI, m / z): 452.0 [M+H] +

[0460] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2-fluorobenzyl)piperidine-4-carboxylic acid (33) [ka] The title compound was synthesized according to the general synthetic procedure of 29. LCMS (ESI, m / z): 436.0 [M−H] - ; 1 H NMR: (400 MHz, CD3OD): δ 7.41 (d, J = 8 Hz, 2H), 7.33-7.22 (m, 2H), 6.43-6.34 (m, 2H), 4.81-4.77 (m, 1H), 4.50-4.46 (m, 2H), 4.32-4.28 (m, 2H), 4.19 (s, 2H), 3.42 (m, 2H), 3.02 (m, 2H), 2.44 (m, 1H), 2.17-2.12 (m, 2H), 1.91 (m, 2H)

[0461] Example S34. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylic acid (34) [ka]

[0462] Synthesis of 4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzaldehyde [ka] To a solution of 4-bromo-3-fluorobenzaldehyde (100 mg, 0.493 mmol) and 3-(2,6-dichlorophenyl)azetidine (119 mg, 0.591 mmol) in anhydrous 1,4-dioxane in a microwave vial, cesium carbonate (1.478 mmol) was added, followed by Ruphos Pd G3 (41.2 mg, 0.049 mmol) under a nitrogen atmosphere. The vial was sealed and irradiated in a microwave reactor at 110 °C. After 4 h, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with dichloromethane. The filtrate was then concentrated in vacuo, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-10% ethyl acetate in petroleum ether to afford 4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzaldehyde (80 mg, 19.04% yield) as a yellow oil. LCMS (ESI, m / z): 324.0 [M+H] +

[0463] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylate [ka] To a stirred solution of 4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzaldehyde (80 mg, 0.247 mmol) and methyl piperidine-4-carboxylate (35.3 mg, 0.247 mmol) in anhydrous methanol (10 mL), acetic acid (0.014 mL, 0.247 mmol) was added, and the mixture was stirred at ambient temperature. After 1 h, MP-cyanoborohydride resin (78 mg, 0.370 mmol) was added to the reaction mixture, which was stirred at the same temperature. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then filtered and washed with dichloromethane. The filtrate was then washed with water (20 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-30% ethyl acetate in petroleum ether to afford methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylate (60 mg, 37.5% yield) as a yellow oil. LCMS (ESI, m / z): 452.0 [M+H] +

[0464] Synthesis of 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylic acid (34) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylate (80 mg, 0.177 mmol) in tetrahydrofuran (5 mL) and HO (0.5 mL), lithium hydroxide (12.73 mg, 0.532 mmol) was added, and the resulting mixture was stirred at room temperature. After 16 h, LCMS analysis indicated complete conversion of the starting material. The reaction mixture was acidified with acetic acid to maintain a pH of 4-5, followed by concentration under reduced pressure. The resulting residue was purified by preparative HPLC (Method: Column: Xselect C18 (250 x 19) mm, 5 micron; Mobile Phase A: 0.1% formic acid in water; Mobile Phase B: acetonitrile). The desired fractions were collected and lyophilized to give 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-3-fluorobenzyl)piperidine-4-carboxylic acid, formate (22.8 mg, 26.5% yield) as a white solid. LCMS (ESI, m / z): 435.2 [M−H] - ; 1 H NMR: (400 MHz, CD3OD): δ 7.39 (d, J = 8 Hz, 2H), 7.25-7.21 (m, 1H), 7.16-7.12 (m, 2H), 6.68 (t, J = 8.8 Hz, 1H), 4.63-4.59 (m, 4H), 4.33-4.29 (m, 2H), 4.05 (s, 2H), 2.86 (m, 2H), 2.37 (m, 1H), 2.07-2.04 (m, 2H), 1.89 (m, 2H)

[0465] LCMS conditions: Column: Kinetex XB - C18 (75 x 3.0) mm, 2.6 μm; Mobile phase: A: 5 mM ammonium formate pH 3.3:ACN (98:02); Mobile phase: B: 5 mM ammonium formate pH 3.3:ACN (98:02); Flow rate: 1.0 mL / min

[0466] LCMS Methods in the Examples Below Method 1:Column: Kinetex XB - C18 (75 x 3.0) mm, 2.6 μm; Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02); Mobile phase B: ACN:buffer (98:02); Flow rate: 1.0 ml / min Method 2: Column: XBridge C8 (50x4.6mm) 5 μm; Mobile phase A: 0.1% TFA in H2O; Mobile phase B: 0.1% TFA in ACN; Flow rate: 1.5ml / min Method 3: Column: Aquity Uplc BEH C18 (50 x 3.0)mm, 1.7 μm; Mobile phase: A: 0.1% FA in water; Mobile phase: B: 0.1% TFA in CAN; Flow rate: 1.0 ml / min Method 4: Column: Aquity BEH C18 (50 x 3.0) mm, 1.7 μm; Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02); Mobile phase B: ACN:buffer (98:02); Flow rate: 0.7 ml / min Method 5: Column: XSELECT CSH C18 (50 x 4.6 mm) 5 μm, Mobile phase A: 0.1% FA in H2O, Mobile phase B: ACN, Flow rate: 1.5 ml / min Method 6: Column: XBridge C8 (50x4.6mm) 3.5 μm, mobile phase A: 0.1% FA in H2O, mobile phase B: ACN, flow rate: 1.5 ml / min

[0467] General route to compounds 35-37 [ka]

[0468] Synthesis of tert-butyl 3-(2,6-dichlorophenyl)-3-fluoroazetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(2,6-dichlorophenyl)-3-hydroxyazetidine-1-carboxylate (1.8 g, 5.66 mmol) in anhydrous DCM (20 mL) at -75 °C, Deoxo-Fluor (4.99 mL, 8.49 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was then quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water (3 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give tert-butyl 3-(2,6-dichlorophenyl)-3-fluoroazetidine-1-carboxylate (1.1 g, 3.44 mmol, 60.7% yield). LCMS Method 1; LCMS (ESI, m / z): 220.0 [M-100]. +

[0469] Synthesis of 3-(2,6-dichlorophenyl)-3-fluoroazetidine [ka] To a stirred solution of tert-butyl 3-(2,6-dichlorophenyl)-3-fluoroazetidine-1-carboxylate (1 g, 3.12 mmol) in anhydrous DCM (10 mL) at 0 °C was added TFA (2.390 mL, 31.2 mmol). The mixture was warmed and stirred at ambient temperature, and the reaction progress was monitored by TLC. After 1 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with diethyl ether to give the TFA salt of 3-(2,6-dichlorophenyl)-3-fluoroazetidine (690 mg, 70% yield) as a white solid. LCMS Method 1; LCMS (ESI, m / z): 220.0 [M+H] +

[0470] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-bromobenzyl)piperidine-4-carboxylate (148 mg, 0.475 mmol) and 3-(2,6-dichlorophenyl)-3-fluoroazetidine (150 mg, 0.475 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (387 mg, 1.186 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of XPhos Pd G2 (37.3 mg, 0.47 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The combined filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-100% ethyl acetate in petroleum ether to afford methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylate (90 mg, 42% yield) as a yellow solid. LCMS Method 1; LCMS (ESI, m / z): 309.0 [M-142] +

[0471] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-bromo-3,5-dimethylbenzyl)piperidine-4-carboxylate (250 mg, 0.735 mmol) and 1-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,2,2-trifluoroethan-1-one (232 mg, 0.735 mmol) in anhydrous 1,4-dioxane (4 mL) was added cesium carbonate (718 mg, 2.204 mmol). The reaction mixture was degassed with nitrogen for 10 min, followed by the addition of XPhos Pd G4 (63.2 mg, 0.073 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-100% ethyl acetate in petroleum ether to afford methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (150 mg, 42.6% yield) as a yellow semi-solid. LCMS Method 1, LCMS (ESI, m / z): 336.0 [M-142] +

[0472] Synthesis of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (200 mg, 0.588 mmol) and 1-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,2,2-trifluoroethan-1-one (186 mg, 0.588 mmol) in anhydrous 1,4-dioxane (4 mL) was added cesium carbonate (575 mg, 1.763 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of XPhos Pd G4 (25.3 mg, 0.029 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-100% ethyl acetate in petroleum ether to afford methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (170 mg, 60.3% yield) as a yellow solid. LCMS Method 1, LCMS (ESI, m / z): 336.0 [M-142] +

[0473] Example S35. 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylic acid (35) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylate (80 mg, 0.177 mmol) in THF (2 mL) and HO (0.5 mL) was added LiOH (22.31 mg, 0.532 mmol). The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by TLC. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC. Prep. HPLC method: Diluent: THF:acetonitrile (30:70), Column: Symmetry C8 (300 x 19) mm, 7 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylic acid (11 mg, 12.67% yield, 99.2% purity) as a white solid. 1 H NMR: (400 MHz, MeOD) δ 7.50 (d, J = 7.50 Hz, 2H), 7.40 (t, J = 7.40 Hz, 1H), 7.32 (d, J = 7.34 Hz, 2H), 6.69 (d, J = 6.72 Hz, 2H), 4.82-4.69 (m, 2H), 4.51-4.42 (m, 2H), 4.08 (s, 2H), 2.88 (s, 2H), 2.34 (s, 1H), 2.03 (d, J = 2.06 Hz, 2H), 1.87 (s, 2H). 2H is merged with the MeOD solvent signal peak. LCMS Method 1, LCMS (ESI, m / z): 435.3 [M] -

[0474] Example S36. 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylic acid (36) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-3,5-dimethylbenzyl)piperidine-4-carboxylate (150 mg, 0.313 mmol) in THF (4 mL) and HO (1 mL) was added LiOH (39.4 mg, 0.939 mmol). The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by TLC. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was acidified with acetic acid and concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC. Prep. HPLC method: Diluent: THF:acetonitrile (50:50), Column: Xselect C18 (250 x 19) mm, 5 micron, Mobile phase A: 10 mM ammonium formate in water, Mobile phase B: acetonitrile. The desired fractions were collected and lyophilized to give 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)benzyl)piperidine-4-carboxylic acid (11 mg, 12.67% yield, 99.5% purity) as a white solid. 1 H NMR (400 MHz, MeOD): δ 7.49-7.47 (m, 2H), 7.41-7.37 (m, 1H), 6.99 (s, 2H), 5.03-4.94 (m, 2H), 4.78-4.75 (m, 1H), 4.71-4.68 (m, 1H), 4.07 (s, 2H), 2.96 (m, 2H), 2.40 (s, 7H), 2.05 (s, 2H), 1.84 (s, 1H). 2H is merged with the MeOD solvent signal peak. LCMS Method 1, LCMS (ESI, m / z): 465.2 [M] -

[0475] Example S37. 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (37) [ka] To a stirred solution of methyl 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (150 mg, 0.313 mmol) in THF (4 mL) and HO (1 mL) was added LiOH (39.4 mg, 0.939 mmol). The resulting mixture was stirred at room temperature, and the progress of the reaction was monitored by TLC. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC. Prep. HPLC method: Diluent: THF:acetonitrile (50:50), Column: Xselect C18 (250 x 19) mm, 5 micron, Mobile phase A: 10 mM ammonium formate in water, Mobile phase B: acetonitrile. The desired fractions were collected and lyophilized to give 1-(4-(3-(2,6-dichlorophenyl)-3-fluoroazetidin-1-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid, formate salt (32 mg, 0.062 mmol, 19.77% yield, 98.4% purity) as a white solid. 1 H NMR: (400 MHz, MeOD) δ 7.48 (d, J = 7.50 Hz, 2H), 7.40 (m, 1H), 6.43 (s, 2H), 4.69 (m, 2H), 4.44 (d, J = 4.47 Hz, 1H), 4.38 (d, J = 4.40 Hz, 1H), 4.24 (s, 2H), 3.44 (m, 2H), 3.08 (s, 2H), 2.42 (s, 7H), 2.05 (d, J = 2.08 Hz, 2H), 1.89 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 465.0 [M] -

[0476] General route to compounds 38–43 [ka]

[0477] Synthesis of methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (300 mg, 1.040 mmol) and 1,3-difluoro-2-iodobenzene (225 mg, 0.936 mmol) in anhydrous 1,4-dioxane (5 mL) was added CsCO (847 mg, 2.60 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G (87 mg, 0.104 mmol) and heating to 95 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 20-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (100 mg, 23% yield) as a yellow semi-solid. LCMS Method 5, LCMS (ESI, m / z): 400.6 [M+H] +

[0478] Synthesis of methyl 1-(4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] Under nitrogen, to a solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate, TFA (300 mg, 0.746 mmol), and iodobenzene (152 mg, 0.746 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (607 mg, 1.864 mmol), followed by iodobenzene (152 mg, 0.746 mmol). The reaction mixture was then heated to 95° C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to ambient temperature and filtered through a pad of Celite, which was washed with ethyl acetate. The filtrate was then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate (110 mg, 37.2%) as a light brown gum. LCMS Method 1, LCMS (ESI, m / z): 365.2 [M+H] +

[0479] Synthesis of methyl 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (200 mg, 0.694 mmol) and 1-fluoro-2-iodobenzene (139 mg, 0.624 mmol) in anhydrous 1,4-dioxane (10 mL) was added CsCO (565 mg, 1.734 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G (58.1 mg, 0.069 mmol) and heating to 95 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (60-120 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (50 mg, 18% yield) as a yellow semi-solid. LCMS Method 1, LCMS (ESI, m / z): 382.8.0 [M+2H] +

[0480] Synthesis of methyl 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (300 mg, 1.040 mmol) and 1-fluoro-3-iodobenzene (208 mg, 0.936 mmol) in anhydrous 1,4-dioxane (5 mL) was added CsCO (847 mg, 2.60 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G (87 mg, 0.104 mmol) and heating to 95 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 20-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (142 mg, 35% yield) as a white solid. LCMS Method 2, LCMS (ESI, m / z): 383.2 [M+H] +

[0481] Synthesis of methyl 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-benzyl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate (207 mg, 0.718 mmol) in 1,4-dioxane (5 mL) was added 2-chloro-1-cyclopropyl-4-iodobenzene (200 mg, 0.718 mmol) and cesium carbonate (468 mg, 1.436 mmol). The reaction mixture was degassed under vacuum and filled with nitrogen. After 10 minutes, Ruphos Pd G3 (60.1 mg, 0.072 mmol) was added, and the mixture was heated to 100 °C. After 16 hours, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to ambient temperature and filtered through a Celite pad, washing with ethyl acetate. The filtrate was then concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (10 mL) and washed with ice-cold water. The organic layer was dried over sodium sulfate and concentrated. The crude material was then purified by flash silica gel column chromatography (230-400 mesh) eluting with 30-70% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (90 mg, 28% yield) as a yellow semi-solid. LCMS Method 1, LCMS (ESI, m / z): 439.3 [M+H] +

[0482] Synthesis of methyl 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)benzyl)piperidine-4-carboxylate, TFA (150 mg, 0.373 mmol), and 1-bromo-4-cyclopropylbenzene (66.1 mg, 0.335 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (304 mg, 0.932 mmol), followed by Ruphos Pd G3 (31.2 mg, 0.037 mmol). The reaction mixture was degassed under vacuum, filled with nitrogen, and then heated to 90 °C under a nitrogen atmosphere. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate. The filtrate was then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (53 mg, 34.1%) as a colorless oil. LCMS Method 1, LCMS (ESI, m / z): 405.3 [M+H] +

[0483] Example S38. 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (38) [ka] To a solution of methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (40 mg, 0.100 mmol) in THF (3 mL) and water (1 mL) was added LiOH (12.57 mg, 0.300 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC analysis. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified to pH 5-6 with acetic acid. The resulting solid was filtered and washed with diethyl ether to give 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (15 mg, 38.2% yield, 98.3% purity) as a white solid. 1H NMR (400 MHz, MeOD): δ 7.54-7.52 (m, 2H), 7.47-7.45 (m, 2H), 6.86-6.79 (m, 2H), 6.73-6.66 (m, 1H), 4.63-4.57 (m, 2H), 4.20-4.15 (m, 2H), 4.11 (s, 1H), 4.00-3.94 (m, 1H), 3.33-3.32 (m, 1H), 2.84 (s, 2H), 2.37-2.35 (m, 1H), 2.06-2.03 (m, 2H), 1.89-1.86 (m, 2H) LCMS method 2; LCMS (ESI, m / z): 386.8 [M+H] +

[0484] Example S39. 1-(4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylic acid (39) To a solution of methyl 1-(4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate (110 mg, 0.278 mmol) in THF (5 mL) and water (1 mL) was added LiOH (26.6 mg, 1.111 mmol). The reaction mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC analysis. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure, and the aqueous layer was then acidified to pH 4 with acetic acid. The precipitate was filtered, rinsed with diethyl ether, and dried in vacuo to afford 1-(4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylic acid (40 mg, 40.2%) as a beige solid. 1H NMR (400 MHz, CD3OD) δ 7.33 (d, J = 8Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.21 - 7.17 (m, 2H), 6.72 - 6.68 (m, 1H), 6.49 (d, J = 7.6 Hz), 4.25 - 4.21 (m, 2H), 3.95 - 3.92 (m, 1H), 3.78 - 3.75 (m, 2H), 3.42 (s, 2H), 2.74 - 2.67 (m, 2H), 2.21-2.17 (m, 1H), 1.99 - 1.93 (m, 2H), 1.78 - 1.75 (m, 2H), 1.57 - 1.51 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 351.2 [M+H] +

[0485] Example S40. 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (40) [ka] To a solution of methyl 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (45 mg, 0.118 mmol) in THF (4 mL) and water (1 mL) was added LiOH (14.81 mg, 0.353 mmol). The resulting mixture was stirred at ambient temperature, and the progress of the reaction was monitored by TLC analysis. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:acetonitrile (30:70). Column: Symmetry C8 (300 x 19) mm, 7 micron. Mobile phase A: 5 mM ammonium formate in water. Mobile phase B: acetonitrile. The desired fractions were collected and lyophilized to give 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid, formate salt (14 mg, 0.034 mmol, 28.5% yield, 99.1% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.33 (m, 2H), 7.27-7.25 (m, 2H), 7.08-7.02 (m, 2H), 6.76-6.71 (m, 1H), 6.64-6.59 (m, 1H), 4.33-4.30 (m, 2H), 3.95-3.85 (m, 3H), 3.49-3.48 (m, 2H), 2.74-2.67 (m, 2H), 2.17-2.11 (m, 1H), 1.97-1.92 (t, J=11.2 Hz, 2H), 1.77-1.74 (m, 2H), 1.56-1.48 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 367.2 [M+H] +

[0486] Example S41. 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (41) [ka] To a solution of methyl 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (140 mg, 0.366 mmol) in THF (3 mL) and water (1 mL) was added LiOH (46.1 mg, 1.098 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC analysis. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified to pH 5-6 with acetic acid. The resulting solid was filtered and washed with diethyl ether to give 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (38 mg, 0.102 mmol, 27.9% yield, 99.18% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.33-7.31 (m, 2H), 7.27-7.25 (m, 2H), 7.22-7.16 (m, 1H), 6.49-6.44 (m, 1H), 6.31-6.26 (m, 2H), 4.26-4.22 (m, 2H), 3.96-3.92 (m, 1H), 3.81-3.78 (m, 2H), 3.41 (s, 2H), 2.74-2.67 (m, 2H), 2.20-2.14 (m, 1H), 1.98-1.90 (m, 2H), 1.77-1.75 (m, 2H), 1.53-1.51 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 369.2 [M+H] +

[0487] Example S42. 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (42) [ka] To a solution of methyl 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (90 mg, 0.205 mmol) in THF (4 mL) and water (1 mL) was added LiOH (14.73 mg, 0.615 mmol). The resulting mixture was stirred at ambient temperature, and the progress of the reaction was monitored by TLC analysis. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:20:30). Column: Xselect C18 (150 x 19) mm, 5 micron. Mobile phase A: 0.1% formic acid in water. Mobile phase B: acetonitrile. The desired fractions were collected and lyophilized to give 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid, formate salt (17.8 mg, 0.037 mmol, 18.00% yield, 97.7% purity) as a white solid. 1H NMR: (400 MHz, MeOD): δ 12.05 (s, 1H), 7.25-7.33 (m, 4H), 6.88 (d, J = 8.40 Hz, 1H), 6.53 (d, J = 2.40 Hz, 1H), 6.37-6.39 (m, 1H), 4.20-4.24 (m, 2H), 3.78-3.94 (m, 1H), 2.68-3.76 (m, 2H), 2.53-2.68 (m, 2H), 2.50-2.51 (m, 2H), 1.99-2.00 (m, 1H), 1.95-1.98 (m, 3H), 1.77 (d, J = 10.40 Hz, 2H), 1.53 (d, J = 9.60 Hz, 2H), 0.87-0.91 (m, 2H), 0.55-0.58 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 425.2 [M+H] +

[0488] Example S43. 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (43) [ka] To a solution of methyl 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylate (50 mg, 0.124 mmol) in THF (5 mL) and water (1 mL) was added LiOH (8.88 mg, 0.371 mmol), and the reaction mixture was stirred at room temperature. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then concentrated under reduced pressure, and the aqueous layer was extracted with diethyl ether (15 mL). The aqueous layer was then acidified to pH 4 with acetic acid, and the precipitate was collected by filtration, rinsed with diethyl ether, and dried in vacuo to give 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)benzyl)piperidine-4-carboxylic acid (24 mg, 47.9%) as a beige solid. 11H NMR (400 MHz, CD3OD); δ 7.50 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.98 - 6.95 (m, 2H), 6.50 - 6.48 (m, 2H), 4.29 - 4.25 (m, 2H), 4.12 (s, 2H), 4.09 - 3.97 (m, 1H), 3.83 - 3.80 (m, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.06 - 2.03 (m, 2H), 1.89 - 1.79 m, 3H), 0.89 - 0.85 (m, 2H), 0.59 - 0.56 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 391.2 [M+H] +

[0489] General route to compounds 44-49 [Chemical formula] ​​​​​​​​​To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate, TFA (300 mg, 0.697 mmol), and 1,3-difluoro-2-iodobenzene (201 mg, 0.836 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (1135 mg, 3.48 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (58.3 mg, 0.070 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (190 mg, 41.7% yield) as a light brown semi-solid. LCMS Method 1, LCMS (ESI, m / z): 429.2 [M+H] +

[0491] Synthesis of methyl 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate, TFA (300 mg, 0.697 mmol), and iodobenzene (171 mg, 0.836 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (1135 mg, 3.48 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos-Pd-G3 (58.3 mg, 0.070 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-35% ethyl acetate in petroleum ether to afford methyl 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate (170 mg, 59.0% yield) as a light brown semi-solid. LCMS Method 1, LCMS (ESI, m / z): 393.3 [M+H] +

[0492] Synthesis of methyl 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethyl-benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (300 mg, 0.948 mmol) and 1-ethyl-2-iodo-3-methylbenzene (467 mg, 1.896 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (2.84 mmol). The reaction mixture was then degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (79 mg, 0.095 mmol) and heating to 80 °C. After 12 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (60-120 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2-ethyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (170 mg, 41.0% yield) as a brown liquid. LCMS Method 1, LCMS (ESI, m / z): 435.2 [M+H] +

[0493] Synthesis of methyl 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethyl-benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (500 mg, 1.580 mmol) and 1,3-diethyl-2-iodobenzene (493 mg, 1.896 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (4.74 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (132 mg, 0.158 mmol) and heating to 80 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (60-120 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2,6-diethylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (300 mg, 42% yield) as a yellow solid. LCMS Method 3, LCMS (ESI, m / z): 449.2 [M+H] +

[0494] Synthesis of methyl 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethyl-benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate, TFA (500 mg, 1.162 mmol), and 1-cyclopropyl-2-iodobenzene (354 mg, 1.452 mmol) in anhydrous 1,4-dioxane (8 mL) was added cesium carbonate (1135 mg, 3.48 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (97 mg, 0.116 mmol) and heating to 80 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 5-30% ethyl acetate in petroleum ether to afford methyl 1-((5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-3-methylpyridin-2-yl)methyl)piperidine-4-carboxylate (210 mg, 31.6% yield) as a light brown semi-solid. LCMS Method 1, LCMS (ESI, m / z): 433.2 [M+H] +

[0495] Synthesis of methyl 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethyl-benzyl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate, TFA (300 mg, 0.697 mmol), and 1-cyclopropyl-2-iodo-3-methylbenzene (198 mg, 0.767 mmol) in anhydrous 1,4-dioxane (10 mL) was added cesium carbonate (681 mg, 2.091 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (58.4 mg, 0.070 mmol) and heating to 100 °C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(2-cyclopropyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (50 mg, 16% yield) as a colorless semi-solid. LCMS Method 1, LCMS (ESI, m / z): 447.2 [M+H] +

[0496] Example S44. 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (44) [ka] To a solution of methyl 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (190 mg, 0.291 mmol) in THF (4 mL) and water (1 mL) was added LiOH (34.8 mg, 1.454 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:20:30), Column-1: Xselect C18 (150 x 19) mm, 5 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(4-(1-(2-fluoro-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (55 mg, 0.130 mmol, 26.4% yield, 97.3% purity) as a white solid. 1 H NMR (MeOD, 400 MHz): δ 6.86 (s, 2H), 6.89-6.78 (m, 2H), 6.73-6.66 (m, 1H), 4.58-4.53 (m, 2H), 4.17-4.12 (m, 4H), 3.86-3.84 (m, 1H), 2.96-2.91 (m, 2H), 2.46 (s, 6H), 2.43-2.39 (m, 2H), 2.06-2.01 (m, 2H), 1.91-1.86 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 415.2 [M+H] +

[0497] Example S45. 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylic acid (45) [ka] To a solution of methyl 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylate (170 mg, 0.411 mmol) in THF (4 mL) and water (1 mL) was added LiOH (49.3 mg, 2.057 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:20:30), Column-1: Xselect C18 (150 x 19) mm, 5 micron, Mobile phase A: water, 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)piperidine-4-carboxylic acid, formate salt (82 mg, 0.193 mmol, 46.9% yield, 99.9% purity) as an off-white solid. 1 H NMR (MeOD, 400 MHz): δ 7.24-7.17 (m, 4H), 6.77 (t, J = 8 Hz, 1H), 6.56 (dd, J = 8.4, 8.8 Hz, 2H), 4.28-4.25 (m, 2H), 4.14 (s, 2H), 3.92-3.81 (m, 3H), 2.94-2.89 (m, 2H), 2.45 (s, 6H), 2.43-2.38 (m, 2H), 2.05-2.00 (m, 2H), 1.90-1.85 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 427.2 [M+H] +

[0498] Example S46. 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (46) [ka] To a solution of methyl 1-(4-(1-(2-ethyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (160 mg, 0.368 mmol) in THF (4 mL) and water (1 mL) was added LiOH (26.4 mg, 1.104 mmol). The resulting mixture was stirred at ambient temperature and the reaction progress was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:20:30), Column-1: Xselect C18 (150 x 19) mm, 5 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(4-(1-(2-ethyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid, formate salt (90.2 mg, 0.180 mmol, 49.0% yield, 93.3% purity) as a white solid. 1 H NMR: (400 MHz,MeOD): δ 7.26 (m, 2H), 6.90-6.95 (m, 2H), 6.76-6.80 (m, 1H), 4.45-4.75 (m, 2H), 4.04-4.20 (m, 4H), 3.76-3.80 (m, 1H), 2.71-2.99 (m, 4H), 2.48 (m, 8H), 2.38 (m, 4H), 2.04-2.07 (m, 2H), 1.91 (s, 2H), 1.20-1.24 (m, 3H) LCMS method 1; LCMS (ESI, m / z): 421.2 [M+H] +

[0499] Example S47. 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (47) [ka] To a solution of methyl 1-(4-(1-(2,6-diethylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (300 mg, 0.669 mmol) in THF (4 mL) and water (1 mL) was added LiOH (48.0 mg, 2.006 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:10:40), Column-1: Xbridge C8 (150 x 19) mm, 5 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(4-(1-(2,6-diethylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid, formate salt (106.6 mg, 0.213 mmol, 31.9% yield, 96.2% purity) as a white solid. 1 H-NMR (400 MHz, MeOD): δ 7.30 (bs, 2H), 6.97-6.99 (m, 2H), 6.87-6.91 (m, 1H), 4.50-4.53 (m, 2H), 4.20 (s, 2H), 4.01-4.04 (m, 2H), 3.79-3.83 (m, 1H), 3.33-3.38 (m, 2H), 2.98 (bs, 2H), 2.76-2.82 (m, 4H), 2.40-2.49 (m, 8H), 2.04-2.07 (m, 2H), 1.87-2.03 (m, 2H), 1.23-1.27 (m, 6H) LCMS method 1; LCMS (ESI, m / z): 435.2 [M+H] +

[0500] Example S48. 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (48) [ka] To a solution of methyl 1-(4-(1-(2-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (160 mg, 0.370 mmol) in THF (4 mL) and water (1 mL) was added LiOH (46.6 mg, 1.110 mmol). The resulting mixture was stirred at ambient temperature and the progress of the reaction was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:10:40), Column-1: Sunfire C18 (150 x 19) mm, 5 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The required fractions were collected and lyophilized to give 1-(4-(1-(2-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid, formate salt (62 mg, 0.133 mmol, 35.8% yield, 99.3% purity) as a white solid. 1 H NMR (400 MHz, MeOD); δ 7.21 (s, 2H), 7.09-7.21 (m, 1H), 6.99 (d, J = 7.60 Hz, 1H), 6.77 (dt, J = 1.20, 10.27 Hz, 1H), 6.59 (dd, J = 0.80, 8.00 Hz, 1H), 4.41-4.45 (m, 2H), 4.13 (s, 2H), 3.95-3.99 (m, 2H), 3.84-3.86 (m, 1H), 3.29 (m, 1H), 2.90 (m, 2H), 2.46 (s, 6H), 2.04 (m, 1H), 2.00-2.04 (m, 2H) LCMS method 1; LCMS (ESI, m / z): 419.2 [M+H] +

[0501] Example S49. 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (49) [ka] To a solution of methyl 1-(4-(1-(2-cyclopropyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (50 mg, 0.112 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (14.09 mg, 0.336 mmol). The resulting mixture was stirred at ambient temperature, and the reaction progress was monitored by TLC. Upon completion of the reaction, the volatiles were concentrated under reduced pressure, and the residue was dissolved in water and acidified with acetic acid. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by prep. HPLC. Prep. HPLC method: Diluent: THF:water:ACN (50:20:30) Column: Xselect C18 (150 x 19) mm, 5 micron, Mobile phase A: water with 0.1% formic acid, Mobile phase B: acetonitrile. The desired fractions were collected and lyophilized to give 1-(4-(1-(2-cyclopropyl-6-methylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid, formate salt (4.50 mg, 9.06 μmol, 8.09% yield, 96.3% purity) as an off-white solid. 1 H NMR (400 MHz, MeOD): δ 7.22 (s, 2H), 6.90-6.86 (m, 2H), 6.70-6.66 (m, 1H), 4.71-4.67 (m, 2H), 4.21-4.17 (m, 4H), 2.95 (bs, 2H), 2.46 (s, 8H), 2.31 (s, 3H), 2.09-2.01 (m, 4H), 1.88 (bs, 2H), 0.91-0.88 (m, 2H), 0.39-0.11 (m, 2H) LCMS method 2; LCMS (ESI, m / z): 453.2 [M+H] +

[0502] General route to compounds 50-54 [ka]

[0503] Synthesis of methyl 1-(4-bromo-2-fluoro-6-methylbenzyl)piperidine-4-carboxylate [ka] To a stirred solution of 4-bromo-2-fluoro-6-methylbenzaldehyde (750 mg, 3.46 mmol) and methyl piperidine-4-carboxylate (495 mg, 3.46 mmol) in DCE (15 mL) was added AcOH (0.1 mL) and stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (1099 mg, 5.18 mmol) was added at ice-cold temperature, and the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with DCM (2 x 20 mL), and the combined organic phase was washed with water (30 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 30-50% ethyl acetate in petroleum ether to give methyl 1-(4-bromo-2-fluoro-6-methylbenzyl)piperidine-4-carboxylate (660 mg, 55% yield) as a yellow semi-solid. LCMS Method 1, LCMS (ESI, m / z): 344.0 [M+H] +

[0504] Synthesis of methyl 1-(4-bromo-2-chloro-6-methylbenzyl)piperidine-4-carboxylate [ka] To a stirred solution of 4-bromo-2-chloro-6-methylbenzaldehyde (500 mg, 2.141 mmol) and methyl piperidine-4-carboxylate (307 mg, 2.141 mmol) in DCE (15 mL) was added acetic acid (0.123 mL, 2.141 mmol) and stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (681 mg, 3.21 mmol) was added at ice-cold temperature, allowed to warm to room temperature, and stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with DCM (2 x 20 mL), and the combined organic phase was washed with water (30 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 30-50% ethyl acetate in petroleum ether to give methyl 1-(4-bromo-2-chloro-6-methylbenzyl)piperidine-4-carboxylate (200 mg, 27% yield) as a yellow liquid. LCMS Method 1, LCMS (ESI, m / z): 360.0 [M+H] +

[0505] Synthesis of methyl 1-(4-bromo-2,6-diethylbenzyl)piperidine-4-carboxylate [ka] To a solution of 4-bromo-2,6-diethylbenzaldehyde (1.405 g, 5.83 mmol) and methyl piperidine-4-carboxylate (1.001 g, 6.99 mmol) in anhydrous 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (1.605 g, 7.57 mmol), and the reaction mixture was then heated to 60 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography eluting with 0–50% ethyl acetate in petroleum ether to afford methyl 1-(4-bromo-2,6-diethylbenzyl)piperidine-4-carboxylate (905 mg, 40.9%) as a yellow gum. LCMS Method 1, LCMS (ESI, m / z): 369.9 [M+H]+

[0506] Synthesis of methyl 1-(4-bromo-2,6-diisopropylbenzyl)piperidine-4-carboxylate [ka] To a solution of 4-bromo-2,6-diisopropylbenzaldehyde (0.7 g, 2.60 mmol) and methyl piperidine-4-carboxylate (0.372 g, 2.60 mmol) in anhydrous 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.661 g, 3.12 mmol), and the reaction mixture was then heated to 60 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether to give methyl 1-(4-bromo-2,6-diisopropylbenzyl)piperidine-4-carboxylate (400 mg, 36.9%). LCMS Method 1, LCMS (ESI, m / z): 396.2 [M+H] +

[0507] Synthesis of methyl 1-((4-bromonaphthalen-1-yl)methyl)piperidine-4-carboxylate [ka] To a stirred solution of 4-bromo-1-naphthaldehyde (2 g, 8.51 mmol) and methyl piperidine-4-carboxylate (1.218 g, 8.51 mmol) in DCE (30 mL) was added acetic acid (0.0487 mL, 0.851 mmol) and stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (2.70 g, 12.76 mmol) was added at ice-cold temperature, and the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with DCM (2 × 30 mL), and the combined organic phase was washed with water (50 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give methyl 1-((4-bromonaphthalen-1-yl)methyl)piperidine-4-carboxylate (2.255 g, 73.2% yield) as a yellow liquid. LCMS Method 1, LCMS (ESI, m / z): 362.0 [M+H] +

[0508] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)piperidine-4-carboxylate [ka] To a suspension of activated zinc (1852 mg, 28.3 mmol) in anhydrous DMF (10 mL) was added 1,2-dibromoethane (0.016 mL, 0.189 mmol), and the mixture was heated to 75 °C. After 15 min, the reaction mixture was cooled to room temperature, trimethylchlorosilane (0.024 mL, 0.189 mmol) was added, and the mixture was stirred at ambient temperature for an additional 30 min. Next, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1336 mg, 4.72 mmol) in 2 mL of anhydrous DMF was added to the reaction mixture, which was stirred at room temperature for an additional 30 min, followed by the addition of methyl 1-(4-bromo-2-fluoro-6-methylbenzyl)piperidine-4-carboxylate (650 mg, 1.888 mmol) and XPhos Pd G4 (162 mg, 0.189 mmol) in 3 mL of DMF. The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The crude product was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel, washed with cold water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)piperidine-4-carboxylate (570 mg, 71% yield) as a colorless semi-solid. LCMS Method 1, LCMS (ESI, m / z): 421.2 [M+H] +

[0509] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-chloro-6-methyl-benzyl)piperidine-4-carboxylate [ka] To a suspension of activated zinc (544 mg, 8.32 mmol) in anhydrous DMF (10 mL) was added 1,2-dibromoethane (4.78 μL, 0.055 mmol), and the mixture was heated to 75 °C. After 15 min, the reaction mixture was cooled to room temperature, trimethylchlorosilane (7.09 μL, 0.055 mmol) was added, and the mixture was stirred at ambient temperature for an additional 30 min. Next, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (785 mg, 2.77 mmol) in 2 mL of anhydrous DMF was added, and the mixture was stirred at room temperature for an additional 30 min. Subsequently, methyl 1-(4-bromo-2-chloro-6-methylbenzyl)piperidine-4-carboxylate (200 mg, 0.555 mmol) and SPhos Pd G4 (44.0 mg, 0.055 mmol) in 3 mL of DMF were added. The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature and quenched with saturated ammonium chloride solution. The crude product was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel, washed with cold water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-chloro-6-methylbenzyl)piperidine-4-carboxylate (150 mg, 61% yield) as a yellow semi-solid. LCMS Method 1, LCMS (ESI, m / z): 437.4 [M+H] +

[0510] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-diethylbenzyl)piperidine-4-carboxylate [ka] To a suspension of activated zinc (2.4 g, 36.7 mmol) in anhydrous DMF (10 mL) was added 1,2-dibromoethane (0.098 mL, 1.137 mmol), and the mixture was heated to 75 °C. After 15 min, the reaction mixture was cooled to room temperature, and trimethylsilyl chloride (0.031 mL, 0.244 mmol) was added. The mixture was stirred at ambient temperature for an additional 30 min. Next, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.4 g, 8.55 mmol) in 10 mL of anhydrous DMF was added to the reaction mixture, which was stirred at room temperature for an additional 30 min. This was followed by the addition of a DMF solution of methyl 1-(4-bromo-2,6-diethylbenzyl)piperidine-4-carboxylate (900 mg, 2.444 mmol) and XPhos Pd G4 (235 mg, 0.244 mmol). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to ambient temperature and quenched with saturated ammonium chloride solution. The crude product was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel, washed with cold water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-diethylbenzyl)piperidine-4-carboxylate (447 mg, 29.3%) as a colorless oil. LCMS Method 1, LCMS (ESI, m / z): 445.4 [M+H] +

[0511] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-diisopropylbenzyl)piperidine-4-carboxylate [ka] To a suspension of activated zinc (990 mg, 15.14 mmol) in anhydrous DMF (5 mL), 1,2-dibromoethane (18.96 mg, 0.101 mmol) was added, and the mixture was heated to 60 °C. After 30 min, the reaction mixture was cooled to room temperature, and chlorotrimethylsilane (10.96 mg, 0.101 mmol) was added. The mixture was then stirred at room temperature for an additional 30 min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (857 mg, 3.03 mmol) in DMF (5 mL) was added, and the mixture was stirred at room temperature. After 2 h, a solution of methyl 1-(4-bromo-2,6-diisopropylbenzyl)piperidine-4-carboxylate (400 mg, 1.009 mmol) in anhydrous DMF (5 mL) was added, followed by X Phos Pd G4 (87 mg, 0.101 mmol) under a nitrogen atmosphere. The reaction mixture was then heated to 80°C and the progress of the reaction was monitored by TLC. After 16 hours, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered throu...

Claims

1. A compound of formula (I): 【Chemical Formula 1】 [wherein, Ring A is 【Chemical Formula 2】 ; Z １ and Z ２ are each independently CR ０ or N; L is azetidinyl optionally substituted with 1 to 5 substituents independently selected from halo and C １ -C ６ alkyl; R ０ are each independently H, -CN, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, halo, C １ -C ６ haloalkyl, or C １ -C ６ alkoxy, or alternatively, two R ０ groups together with the carbon atom to which they are attached form a fused phenylene; R １ is C ６ -C １０ aryl or 5- to 6-membered heteroaryl, each of which may be optionally substituted with 1 to 5 R' groups, and heteroaryl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R' are each independently halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ -C ６ cycloalkyl, or alternatively, two R' groups together with the carbon atom to which they are attached form a fused phenylene; R ２ is H or C １ -C ６ is alkyl; R ３ is -(CH ２ ) ｘ -CO ２ H, or alternatively, the dashed line between R ２ and R ３ represents a ring structure in which R ２ and R ３ , together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl substituted with 1 to 5 R ４ groups, where at least one R ４ group is -CO ２ H; x is from 1 to 5; R ４ each independently is -CO ２ H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, or C １ -C ６ alkoxy; R ５ and R ６ each independently is H or C １ -C ６ alkyl; n is 0 or 1] or a pharmaceutically acceptable salt thereof.

2. Formula (II) or formula (III): 【Chemical Formula 3】 [wherein, 【Chemical Formula 4】 is a 4- to 6-membered heterocyclyl; at least one R ４ group is -CO ２ H] represented by the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Z １ and Z ２ are each independently CR ０ is The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

4. Z １ and Z ２ One of them is N, and Z １ and Z ２ The other one of them is CR ０ is The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

5. R ０ are each independently H, -CN, C １ -C ３ alkyl, C ３ -C ５ cycloalkyl, halo, C １ -C ３ haloalkyl, or C １ -C ３ alkoxy, or alternatively, two R ０ groups together with the carbon atom to which they are attached form a condensed phenylene, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. 【Chemical Formula 5】 is 【Chemical Formula 6】 is The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. L is 【Chemical Formula 7】 and each of these is optionally substituted with one or two substituents independently selected from halo and C １ -C ３ alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. L is 【Chemical Formula 8】 and is the compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ is phenyl which may be optionally substituted with 1 to 3 R' groups the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. Each R' independently is halo, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, or C ３ -C ６ cycloalkyl, or alternatively, two R' groups together with the carbon atom to which they are attached form a condensed phenylene. the compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. R １ is 【Chemical Formula 9】 and is the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ２ is H or C １ -C ３ alkyl; R ３ is -(CH ２ ) ｘ -CO ２ H; x is 1 to 3, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. R ２ and R ３ together with the nitrogen atom to which they are attached form a 1 to 3 membered R ４ forms a 4- to 6-membered heterocyclyl substituted with a base; R ４ is, independently of one another, -CO ２ H, halo, C １ -C ３ alkyl, C １ -C ３ haloalkyl, or C １ -C ３ alkoxy, where at least one R ４ group is -CO ２ H, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. 【Chemical Formula 10】 is 【Chemical Formula 11】 as such, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ５ and R ６ are, independently of one another, H or C １ -C ３ alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. A compound selected from the following, or a pharmaceutically acceptable salt thereof: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [wherein, "or1" indicates that the absolute stereochemistry of the indicated atom has not been determined].

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

18. An agent for regulating sphingosine 1-phosphate receptor 5 (S1P5) comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

19. An agent for treating a neurological disorder comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

20. The agent according to claim 19, wherein the neurological disorder is Alzheimer's disease or multiple sclerosis.

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