Indanyl-containing carboxylic acid compounds for the treatment of neurodegenerative diseases - Patent Application 20070223633

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.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 130,023, filed December 23, 2020, which is hereby incorporated by reference 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] Representative embodiments include the following:

[0009] Embodiment 1. In some embodiments, a compound of formula (I): [ka] [In the formula, L is [ka] or is a bond; X and Y are independently H, O, H2, or absent; [ka] is a single, double, or triple bond; R1 is C6-C 10 aryl, fused bicyclic 8-10 membered heteroaryl, or fused bicyclic 8-10 membered heterocyclyl, each of which is optionally substituted with 1-5 R' groups, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; each R' is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H or [ka] Is it; 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 or contains a -CO2H moiety; x is 1 to 5; each R4 is independently -CO2H, halo, or C1-C6 alkyl; or two R groups together with the carbon atoms to which they are attached form a fused, bridged, or spiro C3-C5 cycloalkyl, optionally substituted with -CO2H. or a pharmaceutically acceptable salt thereof.

[0010] Embodiment 2. L, [ka] That is, 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0011] Embodiment 3. L is -C≡C-, -HC=CH-, or -CH2CH2-; The compound of embodiment 2, or a pharmaceutically acceptable salt thereof.

[0012] Embodiment 4. L is -C(O)-CH2- or -CH2-C(O)-; The compound of embodiment 2, or a pharmaceutically acceptable salt thereof.

[0013] Embodiment 5. L is a bond; 2. A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0014] Embodiment 6. R1 is phenyl, phenyl fused to a cycloalkyl, a fused bicyclic 9-membered heteroaryl, or a fused bicyclic 9-membered heterocyclyl, each of which is optionally substituted with 1-3 R' groups, wherein the heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen; A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0015] Embodiment 7. 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 1 to 6, or a pharmaceutically acceptable salt thereof.

[0016] Embodiment 8. each R' is independently Cl, F, methyl, ethyl, isopropyl, -CF3, -OCH3, or cyclopropyl; The compound of embodiment 7, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 9. R1, [ka] That is, A compound according to any one of embodiments 6 to 8, or a pharmaceutically acceptable salt thereof.

[0018] Embodiment 10. R2 is H or C1-C3 alkyl; R3 is -(CH2) x -CO2H or [ka] and; x is 1 to 3; A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment 11. R2 is H or methyl; R3 is -CH2CO2H, -(CH2)2CO2H, -(CH2)3CO2H, or [ka] That is, 11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof.

[0020] Embodiment 12. [ka] but, [ka] That is, 12. The compound of embodiment 11, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment 13. R2 and R3, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl substituted with 1-3 R4 groups, wherein at least one R4 group is -CO2H or contains a -CO2H moiety; A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment 14. R2 and R3 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1 to 3 R4 groups, wherein at least one R4 group is -CO2H or contains a -CO2H moiety; 14. A compound according to embodiment 13, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 15. each R4 is independently -CO2H, halo, or C1-C3 alkyl; or two R groups together with the carbon atoms to which they are attached form a fused, bridged, or spiro C3-C5 cycloalkyl, optionally substituted with -CO2H; wherein at least one R group is —CO2H or contains a —CO2H moiety; The compound of any one of embodiments 1 to 9, 13, and 14.

[0024] Embodiment 16. each R4 is independently -CO2H, F, or methyl; or two R groups together with the carbon atoms to which they are attached form a fused cyclopropyl, spirocyclopropyl, spirocyclobutyl, or bridged cyclopentyl, each of which is optionally substituted with —COH; wherein at least one R group is —CO2H or contains a —CO2H moiety; The compound of embodiment 15.

[0025] Embodiment 17. [ka] but, [ka] That is, A compound according to any one of embodiments 1 to 9 and 13 to 16, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 18. The compound has the formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 19. The compound has formula (IIIa) or (IIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 20. A compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0029] Embodiment 21. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0030] Embodiment 22. 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 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 21.

[0031] Embodiment 23. 21. 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 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 21.

[0032] Embodiment 24. 24. The method of embodiment 23, wherein the neurological disease is Alzheimer's disease or multiple sclerosis. DETAILED DESCRIPTION OF THE INVENTION

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 recited herein for any physical characteristic (e.g., polymer subunits, size, or thickness, etc.) should be understood to include every integer within the recited 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.

[0037] 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(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.

[0038] 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 of the formula (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 ranges from 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.

[0039] 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).

[0040] "Halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0041] "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.

[0042] 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.

[0043] A "heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are replaced with a heteroatom independently selected from O, S, and N. In some embodiments, a heterocyclyl group contains 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).

[0044] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

[0045] A "carboxy" group is a radical of the formula: --C(O)OH.

[0046] 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.

[0047] 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)).

[0048] 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).

[0049] 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.

[0050] 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).

[0051] It should also be noted that the compounds disclosed herein may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In some embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are mixtures of E and Z isomers.

[0052] "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]

[0053] 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.

[0054] 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.

[0055] 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 from 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 can otherwise vary independently from the selection of a pharmaceutically acceptable salt of each compound.

[0056] 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.

[0057] 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 the 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.

[0058] 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.

[0059] The term "effective amount" in reference to a compound disclosed herein means an amount that is capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0060] 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.

[0061] 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 combination. 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.

[0062] compound In one embodiment, a compound of formula (I): [ka] [In the formula, L is [ka] or is a bond; X and Y are independently H, O, H2, or absent; [ka] is a single, double, or triple bond; R1 is C6-C 10 aryl, fused bicyclic 8-10 membered heteroaryl, or fused bicyclic 8-10 membered heterocyclyl, each of which is optionally substituted with 1-5 R' groups, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; each R' is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H or [ka] Is it; 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 or contains a -CO2H moiety; x is 1 to 5; each R4 is independently -CO2H, halo, or C1-C6 alkyl; or two R groups together with the carbon atoms to which they are attached form a fused, bridged, or spiro C3-C5 cycloalkyl, optionally substituted with -CO2H. or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, L is a bond.

[0064] In some embodiments, L is [ka] In some embodiments, Y is H, O, H2, or absent. In some embodiments, X is H, O, H2, or absent. In some embodiments, [ka] is a single bond. In some embodiments, [ka] is a double bond. In some embodiments, [ka] is a triple bond. In some embodiments, Y and X are both absent, [ka] is a triple bond and L is -C≡C-. In some embodiments, Y and X are both H, [ka] is a double bond and L is -HC=CH-. In some embodiments, Y and X are both H2; [ka] is a single bond and L is -CH2CH2-. In some embodiments, L is -C≡C-, -HC=CH-, or -CH2CH2-. In some embodiments, Y is O, X is H2, [ka] is a single bond and L is -C(O)-CH-. In some embodiments, X is H and Y is O; [ka] is a single bond and L is -CH2-C(O)-. In some embodiments, L is -C(O)-CH2- or -CH2-C(O)-. In some embodiments, L is -C≡C-, -HC=CH-, -CH2CH2-, -C(O)-CH2-, or -CH2-C(O)-. In some embodiments, L is -C≡C-. In some embodiments, L is -HC=CH-. In some embodiments, L is -CH2CH2-. In some embodiments, L is -C(O)-CH2-. In some embodiments, L is -CH2-C(O)-.

[0065] In some embodiments, R is C-C 10 aryl, fused bicyclic 8-10 membered heteroaryl, or fused bicyclic 8-10 membered heterocyclyl, each of which is optionally substituted with 1-5 R' groups, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is a C6-C6 optionally substituted with 1-3 R' groups. 10In some embodiments, R1 is an aryl. In some embodiments, R1 is a fused bicyclic 8-10 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen and oxygen and optionally substituted with 1-5 R' groups. In some embodiments, R1 is a fused bicyclic 8-10 membered heterocyclyl containing 1-3 heteroatoms selected from nitrogen and oxygen and optionally substituted with 1-5 R' groups. In some embodiments, R1 is unsubstituted. In other embodiments, R1 is substituted with 1-5 R' groups. In some variations, R1 is substituted with 1-3 R' groups. In some variations, R1 is substituted with an R' group. In some variations, R1 is substituted with two R' groups. In some embodiments, R1 is attached to the substituent L via the aryl moiety, such as a phenyl group.

[0066] In some embodiments, R1 is phenyl, phenyl fused to a cycloalkyl, a fused bicyclic 9-membered heteroaryl, or a fused bicyclic 9-membered heterocyclyl, each of which is optionally substituted with 1-3 R' groups, wherein the heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen.

[0067] In some embodiments, R1 is phenyl optionally substituted with 1-3 R' groups. In some embodiments, R1 is phenyl fused to a cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted with 1-3 R' groups. In some embodiments, R1 is phenyl fused to a cyclohexyl.

[0068] In some embodiments, R1 is a fused bicyclic 9-membered heteroaryl containing 1-2 heteroatoms selected from nitrogen and oxygen and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heteroaryl containing 1 nitrogen atom and 1 oxygen atom and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heteroaryl containing 2 nitrogen atoms and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heteroaryl containing 1 nitrogen atom and optionally substituted with 1-3 R' groups.

[0069] In some embodiments, R1 is a fused bicyclic 9-membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heterocyclyl containing 1 oxygen atom and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heterocyclyl containing 1 nitrogen atom and optionally substituted with 1-3 R' groups. In some embodiments, R1 is a fused bicyclic 9-membered heterocyclyl containing 1 nitrogen atom and 1 oxygen atom and optionally substituted with 1-3 R' groups.

[0070] 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 Cl, F, methyl, ethyl, isopropyl, -CF, -OCH, or cyclopropyl.

[0071] 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.

[0072] 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 isopropyl.

[0073] 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.

[0074] In some embodiments, R' is C1-C6 alkoxy. In some embodiments, R' is C1-C3 alkoxy. In some embodiments, R' is -OCH3, -OCH2CH3, or -OCH(CH3)2. In some embodiments, R' is -OCH3.

[0075] 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.

[0076] In some embodiments, R1 is [ka] In some embodiments, R is [ka] wherein the fused ring system is a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclyl, or a 4- to 6-membered heteroaryl.

[0077] In some embodiments, R1 is [ka] is.

[0078] 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.

[0079] In some embodiments, R3 is -(CH2) x -CO2H or [ka] wherein x is 1 to 5. 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, -(CH2)2CO2H, or -(CH2)3CO2H. In some embodiments, R3 is -CH2CO2H. In some embodiments, R3 is -(CH2)2CO2H. In some embodiments, R3 is -(CH2)3CO2H. In some embodiments, R3 is [ka] wherein x is 1 to 5. In some embodiments, R3 is [ka] wherein x is 1 to 3. In some embodiments, R3 is [ka] is.

[0080] In some embodiments, R2 is H or C1-C3 alkyl; R3 is -(CH2) x -CO2H or [ka] and x is 1 to 3. In some embodiments, R2 is H or methyl; R3 is -CH2CO2H, -(CH2)2CO2H, -(CH2)3CO2H, or [ka] is.

[0081] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0082] 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.

[0083] In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 4-6-membered heterocyclyl substituted with 1-5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 4-6-membered heterocyclyl substituted with 1-5 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 1-5 R4 groups, where at least one R4 group contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 4-6-membered heterocyclyl that does not contain any additional heteroatoms, where the heterocyclyl is substituted with 1-5 R4 groups and at least one R4 group is -CO2H or contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 4-membered heterocyclyl substituted with 1 to 5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl substituted with 1 to 5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a 6-membered heterocyclyl substituted with 1 to 5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety.

[0084] In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1-3 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1-3 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 an azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1-3 R4 groups, where at least one R4 group contains a -CO2H moiety.

[0085] In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form an azetidinyl substituted with 1-3 R4 groups, where at least one R4 group is -CO2H or includes a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidinyl substituted with 1-3 R4 groups, where at least one R4 group is -CO2H or includes a -CO2H moiety. In some embodiments, R2 and R3, together with the nitrogen atom to which they are attached, form a piperidinyl substituted with 1-3 R4 groups, where at least one R4 group is -CO2H or includes a -CO2H moiety.

[0086] In any of the embodiments or variations of Formula (I) described herein, at least one R4 group is -CO2H or includes a -CO2H moiety.

[0087] In some embodiments, each R4 is independently -CO2H, halo, or C1-C6 alkyl. In some embodiments, each R4 is independently -CO2H, halo, or C1-C3 alkyl. In some embodiments, R4 is -CO2H. In some embodiments, R4 is halo. In some embodiments, R4 is fluoro, chloro, or bromo. In some embodiments, R4 is fluoro. 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, each R4 is independently -CO2H, F, or methyl.

[0088] In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C3-C5 cycloalkyl, which may be optionally substituted with -CO2H. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a fused C3-C5 cycloalkyl, which may be optionally substituted with -CO2H. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a bridged C3-C5 cycloalkyl, which may be optionally substituted with -CO2H. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a spiro C3-C5 cycloalkyl, which may be optionally substituted with -CO2H. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form an unsubstituted fused, bridged, or spiro C3-C5 cycloalkyl. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a fused, bridged, or spiro C3-C5 cycloalkyl substituted with -CO2H.

[0089] In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a fused cyclopropyl, spirocyclopropyl, spirocyclobutyl, or bridged cyclopentyl, each of which may be optionally substituted with —COH. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a fused cyclopropyl, which may be optionally substituted with —COH. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a spirocyclopropyl, which may be optionally substituted with —COH. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a spirocyclobutyl, which may be optionally substituted with —COH. In some embodiments, two R groups, together with the carbon atoms to which they are attached, form a bridged cyclopentyl, which may be optionally substituted with —COH.

[0090] In some embodiments, [ka] teeth, [ka] is.

[0091] In some embodiments, the compound of formula (I) has the formula (IA): [ka] wherein R′, R 2 , R 3 , and L are as described for formula (I). is a compound of

[0092] In some embodiments, the compound of formula (I) has formula (II): [ka] wherein L, R1, and R4 are as described for formula (I). is a compound of

[0093] In some embodiments, the compound of formula (I) has formula (III): [ka] wherein R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H or [ka] x is 1 to 5; L and R1 are as described for formula (I). is a compound of

[0094] In some embodiments, the compound of Formula (I) has the formula (IIIa) or (IIIb): [ka] wherein L, R1, and R3 are as described for formula (I). is a compound of

[0095] In some embodiments, the compound of Formula (I) has the formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf): [ka] wherein R1, R2, and R3 are as described for formula (I); [ka] indicates either cis or trans orientation] is a compound of

[0096] In some embodiments, the compound of Formula (I) has the formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf): [ka] wherein R1 and R4 are as described for formula (I); [ka] indicates either cis or trans orientation] is a compound of

[0097] In some embodiments, the compound of Formula (I) has the formula (VIa), (VIb), (VIc), (VId), (VIe), or (VIf): [ka] wherein R1 is as described for formula (I); R2 is H or C1-C6 alkyl; and R3 is -(CH2) x -CO2H or [ka] and x is 1 to 5; [ka] indicates either cis or trans orientation] is a compound of In the description herein, any description, variation, embodiment, or aspect of a moiety may be combined with any description, variation, embodiment, or aspect of any other moiety, and it is understood that any and all combinations of descriptions are the same as if specifically and individually set forth. For example, any description, variation, embodiment, or aspect provided herein with respect to L in formula (I) may be combined with X, Y, [ka] , R, R', R, R, R, and x, and any and all combinations are the same as if specifically and individually set forth. It is also understood that any and all descriptions, variations, embodiments, or aspects of formula (I) apply equally to and are similarly set forth, where applicable, for other formulas detailed herein, and that any and all descriptions, variations, embodiments, or aspects are the same as if they were separately and individually set forth for all formulas. For example, any description, variation, embodiment, or aspect of formula (I), where applicable, equally applies to and is equally described for any of the formulas as detailed herein (e.g., formulas (IA), (II), (III), (IIIa), (IIIb), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (VIa), (VIb), (VIc), (VId), (VIe), and (VIf), etc.), the same as if each and every description, variation, embodiment, or aspect were separately and individually described for all formulas.

[0098] 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 in 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 in 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] or a pharmaceutically acceptable salt thereof.

[0099] 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.

[0100] 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.

[0101] 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]

[0102] As outlined in Scheme 1, compounds of general formula A can be synthesized from 5-bromo-2,3-dihydro-1H-inden-1-one (intermediate I compound) via Sonogashira coupling with alkyne II, followed by reductive amination with amino acid ester III and subsequent hydrolysis. Alternatively, the ketone intermediate can be reduced to the alcohol, converted to the chloride, and then reacted with amino acid ester III and hydrolyzed to provide compounds of general formula A.

[0103] Compounds of general formula B can be obtained by Pd-catalyzed reduction of compounds of general formula A as shown in Scheme 1.

[0104] Biaryl compounds of general formula C can be synthesized from intermediate I compounds by reductive amination followed by Suzuki coupling with boronate IV and subsequent hydrolysis as outlined in Scheme 1. Alternatively, after reductive amination, the bromide intermediate can be converted to a boronate, coupled with aryl bromide V, and hydrolyzed to give compounds of general formula C.

[0105] 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).

[0106] 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.

[0107] In some embodiments, compounds of Formula (I) modulate the activity of S1P5 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the 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%.

[0108] In another aspect, provided herein is a method 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 is a method 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.

[0109] In some embodiments, administering a compound of Formula (I) to a subject susceptible to a neurological disorder prevents the subject from developing any symptoms of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a subject not yet 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.

[0110] 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).

[0111] 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.

[0112] 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).

[0113] 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.

[0114] 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).

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject in conventional formulations (e.g., capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, emulsions, and the like). 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., methyl stearate, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and the like. The pharmaceutical composition can be prepared by a commonly used method using the following additives: ammonium nitrate, magnesium, light anhydrous silicic acid, talc or sodium lauryl sulfate), 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 for both oral and parenteral administration, it is about 0.005mg / kg (subject's body weight) to about 10mg / kg (subject's body weight).

[0120] 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.

[0121] 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.

[0122] 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).

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

[0124] In 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).

[0125] The compound of formula (I) may be administered once, twice, three times, four or more times daily, hi 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 of the total daily dose.

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

[0127] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, 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 medical condition.

[0128] In one embodiment, provided herein is a capsule comprising a compound of formula (I) without any additional carriers, excipients, or vehicles.

[0129] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a 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.

[0130] 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.

[0131] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually incorporate diluents, binders, lubricants, and disintegrants and 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.

[0132] 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 other things, 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.

[0133] When it is desired to administer the compound of formula (I) as a suppository, typical bases can be used.Cocoa butter is a traditional suppository base, and 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.

[0134] 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. [Example]

[0135] 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.

[0136] 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).

[0137] As used in some of the chemical structures provided in the Examples below, the designation of a particular atom by "or1" indicates that the absolute stereochemistry of the indicated atom has not been determined.

[0138] The following abbreviations may be relevant to this application: Abbreviation ACN or MeCN: acetonitrile AcOK: Potassium acetate aq.: aqueous d:day DCM: dichloromethane DEA: Diethanolamine DIPA: Diisopropylamine DME: Dimethoxyethane DMF: dimethylformamide DMSO: dimethyl sulfoxide EA or EtOAc: Ethyl acetate EDTA: Ethylenediaminetetraacetic acid ee: enantiomeric excess equiv.: equivalent ESI: electrospray ionization h: time HEPES: (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) Hex: Hexane IPA: Isopropyl alcohol LCMS: Liquid Chromatography Mass Spectrometry MeOH: Methanol 2-Me-THF: 2-methyltetrahydrofuran Pd(Amphos)Cl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PdCl2(dppf)CH2Cl2 or Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex Pd(DTBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) PE: Petroleum ether Prep-HPLC: Preparative high-performance liquid chromatography Prep-TLC: Preparative thin-layer chromatography rpm: revolutions per minute RT: retention time sat.: saturation SFC: Supercritical Fluid Chromatography TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate TEA: Triethylamine TFA: Trifluoroacetic acid TfOH: Triflic acid THF: tetrahydrofuran Synthesis Example Example S1. 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (1) [ka]

[0139] Synthesis of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one [ka] A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol), 1,3-dichloro-2-ethynylbenzene (0.81 g, 4.74 mmol), Pd(Amphos)Cl (0 g, 0 mmol), and CuI (0 g, 0 mmol) in DIPA (10 mL, 70.86 mmol) was placed in a 100 mL round-bottom flask. The resulting solution was stirred at 60 °C for 15 h under a N atmosphere. LCMS indicated the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with sodium carbonate and brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=50%) to give the desired product, 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (900 mg, 63%), as a solid. LCMS (ESI, m / z): 302 [M+H] +

[0140] Synthesis of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a solution of NaBH3CN (83 mg, 1.330 mmol, 4.00 equiv.) in methanol (2.0 mL) was added ZnCl2 (2 M in 2-Me-THF, 0.33 mL, 0.660 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 5–10 minutes. 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (100 mg, 0.330 mmol, 1.00 equiv.) and methyl piperidine-4-carboxylate (95 mg, 0.660 mmol, 2.00 equiv.) were then added. The resulting mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC using ethyl acetate / petroleum ether (1:3) to give methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (90 mg, 63%) as a solid. LCMS (ESI, m / z): 428 [M+H] +

[0141] Synthesis of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A solution of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (90 mg, 0.210 mmol, 1.00 equiv.) and LiOH·HO (26 mg, 0.630 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 35% B in 7 min, hold at 35% B for 3 min; 210 / 254 nm; RT: 9.68 min) to give 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (1, 48.7 mg, 56%) as the HCl salt.

[0142] 1 H NMR (300 MHz, methanol-d4) δ 7.69 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.60-7.56 (m, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.47 (s, 1H), 7.38-7.32 (m, 1H), 5.03-4.99 (m, 1H), 3.60-3.53 (m, 1H), 3.39-3.35 (m, 1H), 3.27-3.18 (m, 2H), 3.12-3.04 (m, 2H), 2.63-2.54 (m, 3H), 2.29-2.21 (m, 2H), 2.00-1.85 (m, 2H)

[0143] LCMS (ESI, m / z): 414 [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 1.1 min, hold at 100% B for 0.55 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.219 min Example S2. 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (2) [ka]

[0144] Synthesis of 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene [ka] To a stirred solution of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (100 mg, 0.330 mmol, 1.00 equiv.) in 1,4-dioxane (5.0 mL) was added SOCl2 (392 mg, 3.298 mmol, 10.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 6 h. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene (120 mg, 94%) as an oil. LCMS (ESI, m / z): 285 [M+H] + (de-Cl fragment)

[0145] Synthesis of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate [ka] To a stirred solution of 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene (120 mg, 0.373 mmol, 1.00 equiv.) in acetone (5.0 mL) was added methyl 1,2,3,6-tetrahydropyridine-4-carboxylate (105 mg, 0.746 mmol, 2.00 equiv.) and KCO (396 mg, 1.866 mmol, 5.00 equiv.). The resulting mixture was stirred at 80 °C for 12 h. LCMS indicated the reaction was complete. The reaction mixture was purified by flash column chromatography (eluted with PE / EtOAc, 4 / 1) to give methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (60 mg, 38%) as a semi-solid. LCMS (ESI, m / z): 426 [M+H] +

[0146] Synthesis of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid [ka] To a stirred solution of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (55 mg, 0.129 mmol, 1.00 equiv.) in water (1.5 mL) / THF (1.5 mL) was added LiOH·HO (16 mg, 0.387 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 12 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Xselect CSH OBD Column 30*150 mm 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 48% B in 7 min; 254 / 210 nm; RT: 6.55 min) to give 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (2, 16.4 mg, 31%) as a solid.

[0147] 1 H NMR (400 MHz, methanol-d4) δ 7.70-7.67 (m, 2H), 7.61 (dd, J = 7.6, 1.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.37 (dd, J = 8.8, 7.6 Hz, 1H), 6.90-6.88 (m, 1H), 5.15 (dd, J = 8.4, 2.8 Hz, 1H), 3.99 (dd, J = 18.0, 3.2 Hz, 1H), 3.79 (dd, J = 18.0, 3.2 Hz, 1H), 3.51-3.40 (m, 2H), 3.29-3.23 (m, 1H), 3.13-3.08 (m, 1H), 2.79-2.69 (m, 2H), 2.67-2.53 (m, 2H)

[0148] LCMS (ESI, m / z): 412 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS Column 3*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B in 0.05 min; 254 nm; RT: 1.683 min Example S3. 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylic acid (3a and 3b) [ka]

[0149] Synthesis of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol [ka] To a stirred solution of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (1.2 g, 3.980 mmol, 1.00 equiv) in methanol (25.0 mL) was added NaBH4 (151 mg, 3.980 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for 45 minutes. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography using PE:EA (6:1) to give 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (870 mg, 72%) as a solid. LCMS (ESI, m / z): 303 [M+H] +

[0150] Synthesis of 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene [ka] To a stirred solution of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (300 mg, 0.990 mmol, 1.00 equiv) in 1,4-dioxane (5.0 mL) was added SOCl2 (1.4 mL, 19.980 mmol, 20.00 equiv). The resulting mixture was stirred at room temperature overnight. The crude was concentrated to dryness under reduced pressure to give 1-chloro-5-((2,6-dichlorophenyl)-ethynyl)-2,3-dihydro-1H-indene (250 mg, 79%) as an oil. LCMS (ESI, m / z): 321 [M+H] +

[0151] Synthesis of ethyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoro-piperidine-4-carboxylate [ka] To a stirred solution of 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene (250 mg, 0.780 mmol, 1.00 equiv) in MeCN (5.0 mL) was added ethyl 4-fluoropiperidine-4-carboxylate (273 mg, 1.560 mmol, 2.00 equiv) and K2CO3 (249 mg, 2.340 mmol, 3.00 equiv). The resulting mixture was stirred at 60 °C for 48 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-TLC (PE / EA=1 / 1) to give ethyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylate (220 mg, 61%). LCMS (ESI, m / z): 460 [M+H] +

[0152] Chiral Separation [ka] The mixture of isomers (220 mg, 0.478 mmol) was purified by chiral HPLC (Chiralpak IE, 2*25 cm, 5 μm column; mobile phase A: Hex (8 mmol / L NH3:MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 9 min; 220 / 254 nm; RT1: 5.88 min (Chiral Separation 1), RT2: 6.811 min (Chiral Separation 2); injection volume: 0.5 mL; number of runs: 15) to give the desired isomer, ethyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylate (100 mg, 45%, 99.5% ee, respectively), as a solid. LCMS (ESI, m / z): 460 [M+H] +

[0153] Synthesis of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylic acid from chiral separations 1 and 2 [ka] To a stirred solution of ethyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylate (100 mg, 0.220 mmol, 1.00 equiv) in THF (1.0 mL) and water (1.0 mL) was added LiOH (16 mg, 0.660 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 3-4 with 1 N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 50% B in 7 min; 254 / 210 nm; RT: 5.98 min) to give 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-4-fluoropiperidine-4-carboxylic acid (3a, 31.0 mg, 33%, 99.6% ee) and (3b, 17.6 mg, 19%, 99.2% ee) as solids in the HCl salt form.

[0154] 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.36 (dd, J = 8.8, 7.6 Hz, 1H), 5.08 (dd, J = 7.6, 3.2 Hz, 1H), 3.62-3.53 (m, 1H), 3.42-3.35 (m, 2H), 3.33-3.22 (m, 2H), 3.16-3.05 (m, 1H), 2.69-2.27 (m, 6H)

[0155] 19 F NMR (376 MHz, methanol-d4) δ -168.85

[0156] LCMS (ESI, m / z): 432 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B in 0.05 min; 254 nm; RT: 1.745 min Example S4. 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (4a and 4b) [ka]

[0157] Synthesis of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one [ka] A mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (4.50 g, 0.0213 mol, 1.00 equiv), 1-ethynyl-3-fluorobenzene (2.56 g, 0.0213 mol, 1.00 equiv), Pd(PPh3)2Cl2 (1.50 g, 2.13 mmol, 0.10 equiv), K2CO3 (8.85 g, 0.064 mol, 3.00 equiv), and CuI (0.40 g, 2.13 mmol, 0.10 equiv) in DMF (40 mL) was stirred at 80 °C for 12 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (PE:EA=3:1) to give 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (3.0 g, 54%) as a solid. LCMS (ESI, m / z): 251 [M+H] +

[0158] Synthesis of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (3.0 g, 0.012 mol, 1.00 equiv), methyl piperidine-4-carboxylate (3.45 g, 0.024 mol, 2.00 equiv), ZnCl (2-Me, 1.9 M in THF, 12.0 mL, 0.024 mol, 2.00 equiv), and NaBHCN (2.26 g, 0.036 mol, 3.00 equiv) in methanol (50 mL) was stirred at 60 °C for 12 h. LCMS showed the reaction was complete. The mixture was quenched with saturated aqueous NH Cl (50 mL) and extracted with DCM (3*80 mL). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (DCM:MeOH=10:1) to give methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (3.0 g, 67%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0159] Chiral Separation of Methyl 1-(5-((3-Fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylate [ka] The racemate (3.0 g) was separated by SFC (Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; Mobile phase A: CO₂, Mobile phase B: EtOH:ACN = 1:1 (2 mM NH₃-MeOH); Flow rate: 60 mL / min; Gradient: 60% B; 220 nm; RT1: 3.37 min; RT2: 6.56 min; Injection volume: 4 mL) to give chiral separation 1 isomer (800 mg, 27%, 100% ee) and separation 2 (700 mg, 23.6%, 99.9% ee) as solids. LCMS (ESI, m / z): 378 [M+H] +

[0160] Synthesis of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid from chiral separation 1 [ka] A mixture of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (700 mg, 1.855 mmol, 1.00 equiv) and LiOH (220 mg, 9.273 mmol, 5.00 equiv) in THF (5 mL) and water (5 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 3-4 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluted with water (0.05% HCl):ACN = 2:1) to give 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (4a, 511 mg, 76%) as a solid.

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 11.40 (s, 1H), 8.10-7.83 (m, 1H), 7.57 (s, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.35-7.27 (m, 1H), 4.98 (d, J = 3.2 Hz, 1H), 3.42-3.98 (m, 2H), 3.27-2.77 (m, 5H), 2.60-2.52 (m, 1H), 2.48-2.32 (m, 1H), 2.27-2.09 (m, 1H), 2.05-1.82 (m, 3H)

[0162] 19 F NMR (400MHz, DMSO-d6) δ -112.401

[0163] LCMS (ESI, m / z): 364 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS 50*3.0 mm 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% B for 0.7 min; 254 nm; RT: 1.597 min

[0164] Synthesis of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid from chiral separation 2 [ka] A mixture of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylate (800 mg, 2.116 mmol, 1.00 equiv) and LiOH (250 mg, 10.582 mmol, 5.00 equiv) in THF (5 mL) and water (5 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 3-4 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (eluted with water (0.05% HCl):ACN = 2:1) to give 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (4b, 689.5 mg, 89%) as a solid.

[0165] 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 11.30 (s, 1H), 8.00-7.89 (m, 1H), 7.60-7.37 (m, 5H), 7.30 (t, J = 8.4 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 3.48-3.28 (m, 2H), 3.25-2.78 (m, 5H), 2.59-2.46 (m, 1H), 2.41-2.35 (m, 1H), 2.21-1.75 (m, 4H)

[0166] 19F NMR (400MHz, DMSO-d6) δ -112.391

[0167] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS 50*3.0 mm 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% B for 0.7 min; 254 nm; RT: 1.598 min Example S5. 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethylpiperidine-4-carboxylic acid (5) [ka]

[0168] Synthesis of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol [ka] To a solution of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (3.1 g, 12.4 mmol, 1.00 equiv.) and methanol (30.0 mL) was added NaBH4 (470 mg, 12.4 mmol, 1.00 equiv) in several portions at 0 °C. The reaction mixture was stirred at room temperature for 15 minutes. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate / petroleum ether (1:7) to give 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (2.2 g, 69.6%) as a solid. LCMS (ESI, m / z): 253 [M+H] +

[0169] Synthesis of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene [ka] To a solution of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (600 mg, 2.38 mmol, 1.00 equiv) in 1,4-dioxane (5.0 mL) was added SOCl2 (2.0 mL) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. TLC showed that the reaction was complete. The resulting solution was concentrated under reduced pressure to give the crude product, 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene, as an oil, which was used directly in the next step without further purification. LCMS (ESI, m / z): 271 [M+H] +

[0170] Synthesis of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethyl-piperidine-4-carboxylate [ka] To a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (400 mg, 1.48 mmol, 2.00 equiv.), methyl 3,3-dimethylpiperidine-4-carboxylate (126 mg, 0.740 mmol, 1.00 equiv.) in MeCN (8.0 mL) was added K2CO3 (306 mg, 2.22 mmol, 3.00 equiv.) at room temperature. The resulting solution was stirred at 80 °C for 14 h. LCMS indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA=10 / 1) to give methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethylpiperidine-4-carboxylate (100 mg, 31.0%) as a semi-solid. LCMS (ESI, m / z): 406 [M+H] +

[0171] Synthesis of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethylpiperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethylpiperidine-4-carboxylate (100 mg, 0.250 mmol, 1.00 equiv) and LiOH·HO (62 mg, 1.48 mmol, 5.00 equiv) in THF (1.0 mL) and water (1.0 mL) was stirred at 80 °C for 3 days. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2 N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 49% B in 7 min; 254 / 220 nm; RT: 6.67 min) to give 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3,3-dimethylpiperidine-4-carboxylic acid (5, 36.1 mg, 37.0%) as a solid.

[0172] 1 H NMR (300 MHz, methanol-d4) δ 7.45-7.33 (m, 5H), 7.26 (d, J = 9.3 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 4.57-4.52 (m, 1H), 3.05-2.85 (m, 4H), 2.65-2.48 (m, 1H), 2.40-1.87 (m, 5H), 1.85-1.73 (m, 1H), 1.14-1.01 (m, 6H)

[0173] 19 F NMR (282 MHz, methanol-d4) δ -114.99

[0174] LCMS (ESI, m / z): 392 [M+H] +Analysis conditions: Shim-pack XR-ODS C18, 3.0*50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: ACN acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, 95% B to 2% B in 0.2 min; 254 nm; RT: 1.646 min Example S6. 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (6a and 6b) [ka]

[0175] Synthesis of methyl 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of NaCNBH3 (301 mg, 1.60 mmol, 4.0 equiv.) in methanol (5 mL) was added 5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (300 mg, 0.400 mmol, 1.0 equiv.), methyl piperidine-4-carboxylate (342 mg, 0.800 mmol, 2.0 equiv.), and ZnCl2 (2 M in THF, 0.8 mL, 1.60 mmol, 4.0 equiv.). The resulting solution was stirred at 60 °C for 72 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 column chromatography on silica gel (eluted with MeOH / DCM, 1 / 15) to give methyl 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (277 mg, 55.7%) as a solid. LCMS (ESI, m / z): 378[M+H] +

[0176] Chiral Separation of Methyl 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] The racemate was separated by SFC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH3·MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 24 min; 220 / 254 nm; RT1: 11.666 min; RT2: 18.917 min), affording the enantiomers as solids.

[0177] Synthesis of 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a solution of methyl 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 1; 92.0 mg, 0.240 mmol, 1.0 equiv.) in THF (3 mL) and water (3 mL) was added LiOH (17 mg, 0.730 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 30 min. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 3-4 with 1N HCl and then concentrated under reduced pressure. The residue was purified by Prep_HPLC (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 45% B in 7 min; 210 / 254 nm; RT: 6.27 min) to give 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (6a, 26.7 mg, 30.1%) as a solid.

[0178] 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.21 (s, 1H), 7.85-7.73 (m, 1H), 7.68-7.45 (m, 4H), 7.41-7.25 (m, 2H), 5.01-4.98 (m, 1H), 3.50-3.39 (m, 1H), 3.23-2.74 (m, 5H), 2.61-2.54(m, 1H), 2.47-2.30 (m, 2H), 2.15-1.88 (m, 3H), 1.85-1.71 (m, 1H)

[0179] LCMS (ESI, m / z): 364 [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: 1.50 mL / min; Gradient: 5% B to 95% B in 3.0 min, hold at 95% B for 0.7 min, 95% B to 5% B in 0.2 min; 254 nm; RT: 1.536 min

[0180] Synthesis of 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid from chiral separation 2 [ka] To a solution of 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 2; 86.0 mg, 0.240 mmol, 1.00 equiv.) in THF (3 mL) and water (3 mL) was added LiOH (16.0 mg, 0.730 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 30 minutes. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 3-4 with 1N HCl and then concentrated under reduced pressure. The residue was purified by Prep_HPLC (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 45% B in 7 min; 210 / 254 nm; RT: 6.27 min) to give 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (6b, 33.0 mg, 30.1%) as a solid.

[0181] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.66 (s, 1H), 7.89 (dd, J = 8.0 Hz, 1H), 7.67-7.48 (m, 4H), 7.40-7.28 (m, 2H), 5.00-4.97 (m, 1H), 3.44-3.41 (m, 1H), 3.15-3.09 (m, 2H), 3.03-2.86 (m, 3H), 2.62-2.55(m, 1H), 2.49-2.29 (m, 2H), 2.14-1.94 (m, 3H), 1.92-1.84 (m, 1H)

[0182] LCMS (ESI, m / z): 364[M+H] +Analysis conditions: Shim-pack XR-ODS C18, 3.0*50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, 95% B to 5% B in 0.2 min; 254 nm; RT: 1.529 min Example S7. (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid (7a and 7b) [ka]

[0183] Synthesis of methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate [ka] A solution of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (500 mg, 2.00 mmol, 1.00 equiv.), methyl (R)-piperidine-3-carboxylate (286 mg, 2.00 mmol, 1.00 equiv.), ZnCl (2 M in THF, 2.0 mL, 4.00 mmol, 2.00 equiv.), and NaBHCN (502 mg, 8.00 mmol, 4.00 equiv.) in methanol (5.0 mL) was stirred at 60 °C for 15 h under a N atmosphere. LCMS showed the reaction was complete. The resulting solution was diluted with 10 ml of water and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA = 10%) to give methyl (3R)-1-(5-((3-fluoro-phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate (200 mg, 26%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0184] Chiral separation of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate [ka] The racemate (200 mg) was separated by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH3·MeOH), mobile phase B: IPA; flow rate: 20 mL / min; gradient: 20% B to 20% B in 8.5 min; 220 / 254 nm; RT1: 5.278 min; RT2: 6.92 min) to give chiral separated 1 isomer (80 mg, 99% ee) as an oil.

[0185] Synthesis of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid from chiral separation 1 [ka] A solution of methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate isomer 1 (80 mg, 0.210 mmol, 1.00 equiv.) and LiOH (15 mg, 0.640 mmol, 3.00 equiv.) in THF (3.0 mL) and water (3.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: XB ridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 46% B in 7 min; 254 / 210 nm; RT: 6.38 min) to give (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid isomer 1 (7a, 46.8 mg, 60%) as a solid.

[0186] LCMS (ESI, m / z): 364 [M+H] +Analysis conditions: Poroshell EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.146 min

[0187] 1 H NMR (400 MHz, methanol-d4) δ 7.69 (d, J = 8.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.37-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.18-7.13 (m, 1H), 4.89-4.87 (m, 1H), 3.19-2.97 (m, 6H), 2.67-2.61 (m, 1H), 2.47-2.43 (m, 2H), 2.05-1.82 (m, 4H)

[0188] 19 F NMR (376 MHz, methanol-d4) δ -114.903

[0189] Chiral separation of methyl (3R)-1-(5-((3-fluoro-phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylate [ka] Racemic methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate (200 mg) was separated by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH₃·MeOH), mobile phase B: IPA; flow rate: 20 mL / min; gradient: 20% B to 20% B in 8.5 min; 220 / 254 nm; RT1: 5.278 min; RT2: 6.92 min) to give two chiral separated isomers (70 mg, 99% ee) as an oil.

[0190] Synthesis of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid from chiral separation 2 [ka] A solution of methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate isomer 2 (70 mg, 0.185 mmol, 1.00 equiv.) and LiOH (15 mg, 0.555 mmol, 3.00 equiv.) in THF (3.0 mL) and water (3.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: XB ridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 46% B in 7 min; 254 / 210 nm; RT: 6.38 min) to give (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid isomer 2 (7b, 43.4 mg, 64%) as a solid.

[0191] LCMS (ESI, m / z): 364 [M+H] +Analysis conditions: Poroshell EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.145 min

[0192] 1 H NMR (400 MHz, methanol-d4) δ 7.60-7.51 (m, 3H), 7.45-7.40 (m, 1H), 7.37-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.18-7.13 (m, 1H), 4.87-4.85 (m, 1H), 3.24-2.97 (m, 6H), 2.67-2.61 (m, 1H), 2.56-2.49 (m, 2H), 1.96-1.84 (m, 4H) Example S8. (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (8a and 8b) [ka]

[0193] Synthesis of methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate [ka] To a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (750 mg, 2.770 mmol, 1.00 equiv.), methyl (S)-piperidine-2-carboxylate (793 mg, 5.540 mmol, 2.00 equiv.) in MeCN (8.0 mL) was added K2CO3 (1.1 g, 8.310 mmol, 3.00 equiv.). The resulting mixture was stirred at 80 °C for 2 days. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:EA = 9:1) to give methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (190 mg, 18%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0194] Chiral separation of methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate [ka] Racemic methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-2-carboxylate (190 mg) was separated by Chiral SFC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH3.MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 7% B to 7% B in 8.5 min; 220 / 254 nm; Rt1: 4.995 min; Rt2: 6.813 min) to give chiral methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (enantiomer 1, 60). mg) and (enantiomer 2, 53 mg) were obtained as oils.

[0195] Synthesis of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid [ka] A mixture of (2S)-1-(5-((3-fluoro-phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (Enantiomer 1, 60 mg, 0.160 mmol, 1.00 equiv.), LiOH·HO (20 mg, 0.480 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at 60 °C for 3 days. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 6.55 min) to give the corresponding enantiomer of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (8a, 14.9 mg, 25%) as a solid.

[0196] 1 H NMR (400 MHz, methanol-d4) δ 7.68 (d, J = 8.4 Hz, 1H), 7.50-7.48 (m, 2H), 7.42-7.37 (m, 1H), 7.34-7.32 (m, 1H), 7.26-7.23 (m, 1H), 7.15-7.10 (m, 1H), 5.30 (s, 1H), 3.57-3.50 (m, 1H), 3.12-2.95 (m, 2H), 2.85-2.73 (m, 2H), 2.52-2.47 (m, 1H), 2.35-2.21 (m, 2H), 1.93-1.82 (m, 2H), 1.73-1.65 (m, 2H), 1.57-1.52 (m, 1H)

[0197] 19 F NMR (376 MHz, methanol-d4) δ -114.88

[0198] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Column: EVO C18 Column 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 0.25 min; 254 nm; RT: 1.180 min

[0199] Synthesis of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid [ka] A mixture of methyl (2S)-1-(5-((3-fluoro-phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (enantiomer 2, 53 mg, 0.14 mmol, 1.00 equiv.), LiOH·HO (18 mg, 0.480 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at 60 °C for 3 days. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2 N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 6.55 min) to give the corresponding enantiomer of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (8b, 12.8 mg, 25%) as a solid.

[0200] 1H NMR (400 MHz, methanol-d4) δ 7.66 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.19-7.13 (m, 1H), 5.30 (d, J = 8.8Hz, 1H), 3.68-3.59 (m, 1H), 3.30-3.19 (m, 2H), 3.08-3.00 (m, 1H), 2.71-2.60 (m, 1H), 2.52-2.46 (m, 1H), 2.28-2.24 (m, 2H), 1.94-1.80 (m, 4H), 1.40-1.32 (m, 1H)

[0201] 19 F NMR (376 MHz, methanol-d4) δ -114.88

[0202] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Column: EVO C18 Column 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 0.25 min; 254 nm; RT: 1.171 min Example S9. (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (9a and 9b) [ka]

[0203] Synthesis of methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate [ka] To a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (980 mg, 3.620 mmol, 1.00 equiv.), methyl (R)-piperidine-2-carboxylate (1.04 g, 7.240 mmol, 2.00 equiv.) in MeCN (8.0 mL) was added K2CO3 (2.0 g, 10.860 mmol, 3.00 equiv.). The resulting mixture was stirred at 80 °C for 2 days. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:EA = 9:1) to give methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (379 mg, 28%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0204] Chiral separation of methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-2-carboxylate [ka] Racemic methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-2-carboxylate (190 mg) was separated by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH₃·MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 9 min; 220 / 254 nm; RT1: 5.802 min; RT2: 7.402 min; injection volume: 0.8 ml; run number: 4) to give 126 mg of chiral separation 1 isomer and 133 mg of chiral separation 2 isomer as oils. LCMS (ESI, m / z): 378 [M+H] +

[0205] Synthesis of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid [ka] A mixture of methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-2-carboxylate (isomer 1, 126 mg, 0.330 mmol, 1.00 equiv.), LiOH·HO (40 mg, 0.990 mmol, 3.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was stirred at 60 °C for 3 days. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2 N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD Column, 19 × 150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 28% B to 42% B in 7 min; 254 / 210 nm; RT: 6.53 min) to give the corresponding enantiomer of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (9a, 36.5 mg, 30%) as a solid.

[0206] 1 H NMR (400 MHz, methanol-d4) δ 7.53 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.18-7.14 (m, 1H), 7.06-7.01 (m, 1H), 5.14-5.10 (m, 1H), 3.52-3.49 (m, 1H), 3.19-3.05 (m, 2H), 2.93-2.86 (m, 1H), 2.54-2.48 (m, 1H), 2.37-2.35 (m, 1H), 2.12-2.08 (m, 2H), 1.81-1.66 (m, 4H), 1.30-1.18 (m, 1H)

[0207] 19 F NMR (376 MHz, methanol-d4) δ -114.83

[0208] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Column: EVO C18 Column 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 0.25 min; 254 nm; RT: 1.176 min

[0209] Synthesis of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid [ka] A mixture of methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-2-carboxylate (isomer 2, 133 mg, 0.350 mmol, 1.00 equiv.), LiOH·HO (40 mg, 1.050 mmol, 3.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was stirred at 60 °C for 3 days. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 28% B to 42% B in 7 min; 254 / 210 nm; RT: 6.70 min) to give the corresponding enantiomer of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid (9b, 5 mg, 3.8%) as a solid.

[0210] 1H NMR (400 MHz, methanol-d4) δ 7.68 (d, J = 8.0 Hz, 1H), 7.50-7.47 (m, 2H), 7.45-7.39 (m, 1H), 7.36-7.34 (m, 1H), 7.29-7.25 (m, 1H), 7.17-7.12 (m, 1H), 5.27-5.19 (m, 1H), 3.59-3.49 (m, 1H), 3.10-2.92 (m, 2H), 2.75-2.67 (m, 2H), 2.55-2.45 (m, 1H), 2.35-2.12 (m, 2H), 1.93-1.84 (m, 2H), 1.75-1.67 (m, 2H), 1.57-1.48 (m, 1H)

[0211] 19 F NMR (376 MHz, methanol-d4) δ -114.92

[0212] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Column: EVO C18 Column 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 0.25 min; 254 nm; RT: 1.174 min Example S10. (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.2.1]-octane-8-carboxylic acid (10) [ka]

[0213] Synthesis of methyl (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate [ka] A solution of NaBHCN (113 mg, 1.800 mmol, 3.00 equiv.) and ZnCl (2.0 M in THF, 0.6 mL, 1.200 mmol, 2.00 equiv.) in methanol (5 mL) was stirred at room temperature for 15 minutes. 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (150 mg, 0.600 mmol, 1.00 equiv.) and methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-8-carboxylate (122 mg, 0.720 mmol, 1.20 equiv.) were then added. The resulting mixture was stirred at 60 °C for 72 hours. LCMS indicated the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (eluting with water (5 mM NH4HCO3) / ACN, 20 / 80) to give methyl (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 25%) as a solid. LCMS (ESI, m / z): 404 [M+H] +

[0214] Synthesis of (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-aza-bicyclo[3.2.1]-octane-8-carboxylic acid [ka] To a solution of methyl (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.150 mmol, 1.00 equiv.) in THF (1 mL) and water (0.3 mL) was added LiOH·HO (19 mg, 0.450 mmol, 3.00 equiv.). The reaction was stirred at 80 °C for 48 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1 N HCl and then concentrated under reduced pressure. The residue was purified by C18 flash column chromatography (eluted with water (5 mM NH4HCO3) / ACN, 35 / 65) to give (1R,5S,8s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo-[3.2.1]-octane-8-carboxylic acid (10, 22.5 mg, 38%) as a solid.

[0215] 1 H NMR (300 MHz, DMSO-d6) δ 7.52-7.39 (m, 4H), 7.34-7.26 (m, 3H), 4.36-4.27 (m, 1H), 2.88-2.74 (m, 3H), 2.49-2.42 (m, 2H), 2.2.35-2.24 (m, 4H), 2.05-2.00 (m, 2H), 1.69-1.58 (m, 4H)

[0216] 19 F NMR (282 MHz, DMSO-d6) δ -115.0

[0217] LCMS (ESI, m / z): 390 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 30% B to 60% B in 2.5 min, 60% B to 95% B in 0.5 min, hold at 95% for 0.6 min, 95% B to 5% B in 0.1 min; 254 / 220 nm; RT: 1.939 min Example S11. 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid (11) [ka]

[0218] Synthesis of tert-butyl 8-cyano-5-azaspiro[2.5]octane-5-carboxylate [ka] To a solution of tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.0 g, 4.440 mmol, 1.00 equiv.), 1-(1-iodoethylsulfonyl)-4-methylbenzene (1.8 g, 5.770 mmol, 1.20 equiv.) in DME (5.0 mL) was added t-BuOK (1.2 g, 10.65 mmol, 2.40 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 8 h, then quenched with water (20 mL) and diluted with ethyl acetate (20 mL). The separated aqueous layer was extracted with ethyl acetate (20 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3) / ACN, 20 / 80) to give tert-butyl 8-cyano-5-azaspiro[2.5]octane-5-carboxylate (657 mg, 62%) as an oil. LCMS (ESI, m / z): 181 [M+H] +

[0219] Synthesis of 5-azaspiro[2.5]octane-8-carbonitrile [ka] To a solution of tert-butyl 8-cyano-5-azaspiro[2.5]octane-5-carboxylate (432 mg, 1.828 mmol, 1.00 equiv.) in DCM (3.0 mL) was added TFA (0.3 mL). The reaction was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The pH value of the solution was adjusted to 9-10 by adding saturated aqueous Na2CO3. The resulting solution was diluted with water (10 mL) and DCM (20 mL). The separated organic layer was concentrated in vacuo to give 5-azaspiro[2.5]octane-8-carbonitrile (crude) (350 mg, 140%) as a solid. LCMS (ESI, m / z): 137 [M+H] +

[0220] Synthesis of 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile [ka] To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (348 mg, 1.630 mmol, 1.00 equiv) in DCM (3.0 mL) was added SOCl (5.0 mL). The reaction was stirred for 4 h at room temperature. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude material was used in the next step. KCO (519 mg, 4.900 mmol, 3.00 equiv) and 5-azaspiro[2.5]octane-8-carbonitrile (444 mg, 3.267 mmol, 2.00 equiv) were added to the crude material in MeCN (3.0 mL). The reaction was stirred for 12 h at room temperature. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure and the remaining oil was purified by flash C18 silica column chromatography (eluting with water (5 mM NH4HCO3) / ACN, 25 / 75) to give 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile (400 mg, 73%) as a solid. LCMS (ESI, m / z): 331 [M+H] +

[0221] Synthesis of methyl 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate [ka] To a solution of the compound 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile (360 mg, 1.087 mmol, 1.00 equiv) in methanol (5.0 mL) was added HO (5.0 mL) and HSO (5.0 mL). The reaction was stirred for 12 hours at 90 °C, and LCMS indicated completion. The solvent was evaporated, and the remaining oil was purified by flash C18 silica column chromatography (eluting with water (5 mM NHHCO) / ACN, 30 / 70) to give methyl 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (200 mg, 50%) as an oil. LCMS (ESI, m / z): 364 [M+H] +

[0222] Synthesis of methyl 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro-[2.5]octane-8-carboxylate [ka] A solution of methyl 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (160 mg, 0.440 mmol, 1.00 equiv), 1-ethynyl-2-fluorobenzene (158 mg, 1.320 mmol, 3.00 equiv), Pd(PPh)Cl (30 mg, 0.040 mmol, 0.10 equiv), KCO (181 mg, 1.320 mmol, 3.00 equiv), and CuI (4 mg, 0.020 mmol, 0.05 equiv) in DMF (10.0 mL) was stirred for 12 h at 80 °C under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (eluted with water (5 mM NH4HCO3) / ACN, 40 / 60) to give methyl 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (146 mg, 82%) as an oil. LCMS (ESI, m / z): 404 [M+H] +

[0223] Synthesis of 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid [ka] To a solution of the compound methyl 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (146 mg, 0.360 mmol, 1.00 equiv) in THF (4.0 mL) and water (0.8 mL) was added LiOH·HO (91 mg, 2.170 mmol, 3.00 equiv). The reaction was stirred at 80 °C for 4 days. LCMS showed the reaction was complete. THF was evaporated, and the remaining oil was treated with water. The pH of the solution was adjusted to 4-5 with HCl (0.5 mol / L). The mixture was extracted with EA (2 × 30 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 44% B in 7 min; 254 / 210 nm) to give 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid (11, 26.8 mg, 0.068 mmol, 18%) as a solid.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.65-7.57 (m, 1H), 7.53-7.23 (m, 6H), 4.31-4.27 (m, 1H), 2.93-2.60 (m, 3H), 2.63-2.53 (m, 1H), 2.44-2.31 (m, 1H), 2.21-2.10 (m, 1H), 2.07-1.70 (m, 5H), 0.60-0.20 (m, 4H)

[0225] 19 F NMR (376 MHz, DMSO-d6) δ -110.59

[0226] LCMS (ESI, m / z): 390 [M+H] + Analysis conditions: Column: Titank C18 Column 3.0*50 mm, 3.0 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 1.4 min, hold at 95% for 0.8 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 1.192 min Example S12. 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid (12) [ka]

[0227] Synthesis of 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile [ka] To a solution of 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile (110 mg, 0.330 mmol, 1.00 equiv.) in THF (5 mL) was added 1-ethynyl-3-fluorobenzene (100 mg, 0.830 mmol, 2.5 equiv.), Pd(PPh3)2Cl2 (23 mg, 0.030 mmol, 0.10 equiv.), and TEA (0.2 mL, 0.990 mmol, 3.00 equiv.). The resulting mixture was stirred at 60 °C for 12 h. LCMS indicated the reaction was complete. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc 7 / 1) to give 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile (30 mg, 26%) as a solid. LCMS (ESI, m / z): 371 [M+H] +

[0228] Synthesis of 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid [ka] To a solution of 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile (30 mg, 0.080 mmol, 1.00 equiv.) in methanol (1 mL) and water (1 mL) was added KOH (45 mg, 0.810 mmol, 10.0 equiv.). The reaction was stirred at 90 °C for 80 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1 N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: Xselect CSH OBD Column 30*150 mm, 5 μm; Mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 63% B to 93% B in 7 min; 254 / 210 nm; RT: 6.40 min) to give 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid (12, 7.6 mg, 23%) as a solid.

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 7.50-7.45 (m, 1H), 7.41-7.38 (m, 4H), 7.31-7.25 (m, 2H), 4.31-4.26 (m, 1H), 2.90-2.83 (m, 1H), 2.79-2.66 (m, 2H), 2.61-2.54 (m, 1H), 2.41-2.32 (m, 1H), 2.20-2.13 (m, 1H), 2.06-1.95 (m, 2H), 1.91-1.75 (m, 3H), 0.53-0.48 (m, 1H), 0.43-0.38 (m, 1H), 0.34-0.22 (m, 2H)

[0230] 19 F NMR (376 MHz, DMSO-d6) δ -114.9

[0231] LCMS (ESI, m / z): 390 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B in 0.5 min; 254 nm; RT: 1.608 min Example S13. (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (13a and 13b) [ka]

[0232] Synthesis of methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] A solution of NaBHCN (753 mg, 11.99 mmol, 3.00 equiv.) and ZnCl (2.0 M in THF, 4.0 mL, 7.99 mmol, 2.00 equiv.) in methanol (8 mL) was stirred at room temperature for 15 minutes. 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (1.0 g, 4.00 mmol, 1.00 equiv.) and methyl (S)-pyrrolidine-3-carboxylate (1.5 g, 11.99 mmol, 3.00 equiv.) were then added. The resulting mixture was stirred at 60 °C for 12 hours. LCMS indicated the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 1 / 1) to give methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (400 mg, 28%) as a solid. LCMS (ESI, m / z): 364 [M+H] +

[0233] Synthesis of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a solution of compound methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (200 mg, 0.550 mmol, 1.00 equiv.) in THF (3 mL) and water (0.5 mL) was added LiOH·HO (46 mg, 1.100 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 24 hours. LCMS showed that the reaction was complete. The reaction mixture was acidified to pH 4-5 by adding 1N HCl and then concentrated under reduced pressure. (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylic acid (180 mg, 99%) was obtained as a solid. LCMS (ESI, m / z): 350 [M+H] +

[0234] Chiral separation of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] Racemic (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (100 mg) was separated by Prep-SFC (column: Chiralpak IG, 20*250 mm, 5 μm; mobile phase A: CO, mobile phase B: EtOH / ACN (1 / 1, 2 mM NH-MeOH); flow rate: 45 mL / min; gradient: 50% B; 220 nm; RT: 5.98 min) to give chiral separation of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 1 (13a, 32.5 mg, 33%) as a solid.

[0235] 1H NMR (300 MHz, methanol-d4) δ 7.65-7.50 (m, 3H), 7.42-7.33 (m, 2H), 7.29-7.24 (m, 1H), 7.17-7.12 (m, 1H), 4.97-4.94 (m, 1H), 3.69-3.63 (m, 1H), 3.53-3.42 (m, 3H), 3.26-3.18 (m, 2H), 3.07-2.99 (m, 1H), 2.61-2.34 (m, 3H), 2.27-2.21 (m, 1H)

[0236] 19 F NMR (282 MHz, methanol-d4) δ -114.8

[0237] LCMS (ESI, m / z): 350 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B in 0.5 min; 254 / 220 nm; RT: 1.597 min

[0238] Chiral separation of methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] Racemic methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (150 mg) was separated by preparative chiral HPLC (column: Chiralpak IA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% TFA)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 23 min; 220 / 254 nm; RT1: 10.778 min; RT2: 15.769 min; injection volume: 1 mL; number of runs: 7) to obtain chiral separation of two isomers of methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (60 mg). mg) as an oil. LCMS (ESI, m / z): 364 [M+H] +

[0239] Synthesis of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl rel-(3S)-1-[5-[2-(3-fluorophenyl)ethynyl]indan-1-yl]pyrrolidine-3-carboxylate (60 mg, 0.160 mmol, 1.00 equiv.) in THF (3 mL) and water (0.5 mL) was added LiOH·HO (24 mg, 0.600 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 24 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (MeCN in water (0.05% NH4HCO3), 30% to 46% in 7 min; 70 mL / min, 254 / 210 nm) to give the corresponding enantiomer of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (13b, 46.9 mg, 78%) as a solid. LCMS (ESI, m / z): 350 [M+H] +

[0240] 1 H NMR (300 MHz, methanol-d4) δ 7.62-7.48 (m, 3H), 7.44-7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.17-7.11 (m, 1H), 4.84-4.82 (m, 1H), 3.60-3.54 (m, 1H), 3.49-3.34 (m, 3H), 3.26-3.17 (m, 2H), 3.09-2.96 (m, 1H), 2.58-2.43 (m, 2H), 2.30-2.20 (m, 2H)

[0241] 19 F NMR (282 MHz, methanol-d4) δ 114.85

[0242] LCMS (ESI, m / z): 350 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B in 0.5 min; 254 / 220 nm; RT: 1.602 min Example S14. (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (14a and 14b) [ka]

[0243] Synthesis of methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (1.0 g, 3.995 mmol, 1.00 equiv.) and methyl rac-(3R)-pyrrolidine-3-carboxylate (1.5 g, 11.990 mmol, 3.00 equiv.) in methanol (12.0 mL) was added NaBHCN (753 mg, 11.990 mmol, 3.00 equiv.) and ZnCl (2 M in THF, 4.0 mL, 7.990 mmol, 2.00 equiv.). The mixture was stirred at 60 °C for 16 h. The target product could be detected by LCMS. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3*40 mL). The organic layers were combined, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 75% B to 85% B in 4 min; 254 / 210 nm.) to give (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (400 mg, 27%) as a solid. LCMS (ESI, m / z): 364 [M+H] +

[0244] Chiral separation of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate [ka] The racemate (400 mg) was separated by prep-chiral HPLC (column: Chiralpak IA, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH₃·MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 10 min; 220 / 254 nm; RT1: 5.741 min; RT2: 7.442 min; injection volume: 0.5 mL; run number: 15) to give 150 mg of isomer 1 and 150 mg of isomer 2. LCMS (ESI, m / z): 364 [M+H]+

[0245] Synthesis of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a stirred solution of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (Enantiomer 1, 50 mg, 0.140 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH·HO (17 mg, 0.410 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 2 h under air. The target product could be detected by LCMS. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica (mobile phase A: water (0.1% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14% B to 44% B in 7 min; 254 / 210 nm) to give the corresponding enantiomer of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (14a, 19.5 mg, 40%) as a semisolid.

[0246] 1 H NMR (300 MHz, methanol-d4) δ 7.69 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.54-7.51 (m, 1H), 7.46-7.40 (m, 1H), 7.39-7.34 (m, 1H), 7.29-7.25 (m, 1H), 7.19-7.12 (m, 1H), 5.01 (dd, J = 7.8, 2.7 Hz, 1H), 3.70-3.36 (m, 4H), 3.30-3.23 (m, 2H), 3.09-2.99 (m, 1H), 2.67-2.33 (m, 4H)

[0247] 19F NMR (282 MHz, CDCl3-d) δ -112.644

[0248] LCMS (ESI, m / z): 350 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 1.99 min, hold at 95% for 0.7 min, 95% B to 5% B in 0.05 min; 254 nm; RT: 1.677 min

[0249] Synthesis of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a stirred solution of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (enantiomer 2, 50 mg, 0.140 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH·HO (17 mg, 0.410 mmol, 3.00 equiv.). The mixture was stirred at room temperature for 2 h under air. The product was detected by LCMS. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica (mobile phase A: water (0.1% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14% B to 44% B in 7 min; 254 / 210 nm) to give the corresponding enantiomer of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (14b, 16.0 mg, 33%) as a semisolid.

[0250] 1H NMR (300 MHz, methanol-d4) δ 7.68 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.54-7.51 (m, 1H), 7.46-7.30 (m, 2H), 7.30-7.25 (m, 1H), 7.19-7.12 (m, 1H), 5.02 (dd, J = 7.8, 2.7 Hz, 1H), 3.72-3.37 (m, 5H), 3.28-3.23 (m, 1H), 3.09-2.99 (m, 1H), 2.67-2.57 (m, 1H), 2.54-2.43 (m, 2H), 2.34-2.25 (m, 1H)

[0251] 19 F NMR (282 MHz, CDCl3-d) δ -112.636

[0252] LCMS (ESI, m / z): 390 [M+H] + Analysis conditions: Column: Xbridge Shield RP18, 4.6*50 mm, 3.5 μm; Mobile phase A: 0.04% NH₃·H₂O, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 1.99 min, hold at 95% for 0.79 min, 95% B to 10% B in 0.06 min; 254 nm; RT: 1.160 min Example S15. (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (15) [ka]

[0253] Synthesis of ethyl (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylate [ka] To a stirred solution of 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (100 mg, 0.332 mmol, 1.00 equiv.) in methanol (5.0 mL) was added ethyl (1R,5R)-3-azabicyclo[3.1.0]hexane-1-carboxylate (77 mg, 0.498 mmol, 1.50 equiv.), NaCNBH (84 mg, 1.328 mmol, 4.00 equiv.), and ZnCl (2.0 M in THF, 0.33 mL, 0.664 mmol, 2.00 equiv.). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 48 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc, 3 / 1) to give ethyl (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (124 mg, 85%) as a semi-solid. LCMS (ESI, m / z): 440 [M+H] +

[0254] Synthesis of (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid [ka] To a stirred solution of ethyl (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (124 mg, 0.282 mmol, 1.00 equiv.) in water (2.0 mL) / THF (2.0 mL) was added LiOH·HO (47 mg, 1.126 mmol, 4.00 equiv.). The resulting mixture was stirred at room temperature for 72 h. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 40% B in 7 min; 254 / 210 nm; RT: 6.12 min) to give (1R,5R)-3-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (15, 48.3 mg, 41%) as a solid.

[0255] 1 H NMR (400 MHz, methanol-d4) δ 7.76-7.71 (m, 1H), 7.64 (s, 1H), 7.59-7.57 (m, 1H), 7.51-7.49 (m, 2H), 7.39-7.34 (m, 1H), 5.07-5.01 (m, 1H), 4.04-3.74 (m, 4H), 3.30-3.28 (m, 1H), 3.08-3.02 (m, 1H), 2.64-2.58 (m, 1H), 2.49-2.40 (m, 2H), 1.76-1.66 (m, 1H), 1.52-1.39 (m, 1H)

[0256] LCMS (ESI, m / z): 412 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS Column 3*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B in 0.05 min; 254 nm; RT: 1.651 min Example S16. (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (16) [ka]

[0257] Synthesis of ethyl (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate [ka] To a solution of NaBHCN (110 mg, 1.760 mmol, 4.00 equiv.) in methanol (2.0 mL) was added ZnCl (2M in 2-Me-THF, 0.44 mL, 0.880 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 5–10 minutes. Then, 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (110 mg, 0.440 mmol, 1.00 equiv.) and ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate (102 mg, 0.660 mmol, 1.50 equiv.) were added. The resulting mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate / petroleum ether (1 / 7) to give ethyl (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (83 mg, 48%) as a semi-solid. LCMS (ESI, m / z): 390 [M+H] +

[0258] Synthesis of (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid [ka] A solution of ethyl (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (83 mg, 0.212 mmol, 1.00 equiv.) and LiOH HO (51 mg, 1.272 mmol, 6.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at 80 °C for 14 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1 N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (column: XBridge Prep C18 OBD Column, 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 45% B in 7 min; 210 / 254 nm; RT: 6.42 min) to give (1R,5S,6r)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (16, 4.0 mg, 5.2%) as a solid.

[0259] 1 H NMR (400 MHz, methanol-d4) δ 7.58-7.54 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 9.6 Hz, 1H), 7.18-7.14 (m, 1H), 4.75-4.60 (m, 1H), 3.51-3.39 (m, 4H), 3.21-3.15 (m, 1H), 3.05-2.95 (m, 1H), 2.47-2.38 (m, 2H), 2.16-2.10 (m, 2H), 1.84-1.76 (m, 1H)

[0260] 19F NMR (376 MHz, methanol-d4) δ -114.89

[0261] LCMS (ESI, m / z): 362 [M+H] + Analysis conditions: 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 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.250 min Example S17. (1R,5S,6s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (17) [ka]

[0262] Synthesis of ethyl (1R,5S,6s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate [ka] To a solution of NaBHCN (110 mg, 1.760 mmol, 4.00 equiv.) in methanol (2.0 mL) was added ZnCl (2M in 2-Me-THF, 0.44 mL, 0.880 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 5–10 minutes. Then, 5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (110 mg, 0.440 mmol, 1.00 equiv.) and ethyl (1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-carboxylate (102 mg, 0.660 mmol, 1.50 equiv.) were added. The resulting mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate / petroleum ether (1 / 7) to give ethyl (1R,5S,6s)-3-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate (17, 130 mg, 75%) as a semi-solid. LCMS (ESI, m / z): 390 [M+H] + Example S18. 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (18) [ka]

[0263] Synthesis of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate [ka] A mixture of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (12.0 g, 38.690 mmol, 1.00 equiv), 1,3-dichloro-2-ethynylbenzene (16.5 g, 96.710 mmol, 2.50 equiv), Pd(Amphos)Cl (1.4 g, 1.930 mmol, 0.05 equiv), and CuI (737 mg, 3.870 mmol, 0.10 equiv) in DIPA (240 mL, 0.161 mol / L) was stirred at 45 °C for 16 h under a nitrogen atmosphere. TLC showed the reaction was complete, and the mixture was quenched with NaHCO (sat. aq., 500 mL) and extracted with DCM (500 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE:EA=3:1) to give the desired product, methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (12.0 g, 77%) as a solid. LCMS (ESI, m / z): 400 [M+H] +

[0264] Synthesis of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A mixture of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate (12.0 g, 29.980 mmol, 1.00 equiv), LiOH (2.2 g, 89.930 mmol, 3.00 equiv) in THF (100 mL) and water (100 mL) was stirred at 25 °C for 0.5 h. TLC showed the reaction was complete. The mixture was quenched with HCl (2 N, 500 mL) and extracted with DCM (500 mL x 3). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (MeCN:HO = 2:3) to give the desired product, 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (18, 7.15 g, 62%, >99% ee) as a solid. 1 H NMR (400 MHz, methanol-d4) δ 7.50 - 7.25 (m, 5H), 7.22 - 7.08 (m, 1H), 4.65 - 4.75 (m, 1H), 4.23 - 4.10 (m, 2H), 4.10 - 3.94 (m, 2H), 3.27 - 3.15 (m, 1H), 3.07 - 2.92 (m, 1H), 2.90 - 2.73 (m, 1H), 2.44 - 2.21 (m, 1H), 2.09 - 1.92 (m, 1H). LCMS (ESI, m / z): 386 [M+H] + Example S19. 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (19) [ka]

[0265] Synthesis of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A mixture of the single enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (6.0 g, 19.320 mmol, 1.00 equiv), 1-ethynyl-3-fluorobenzene (9.3 g, 77.280 mmol, 4.00 equiv), Pd(PPh3)2Cl2 (1.3 g, 1.932 mmol, 0.10 equiv), and TEA (8.1 mL, 57.960 mmol, 3.00 equiv) in THF (100.0 mL) was stirred at 60 °C for 12 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with DCM (3 x 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 (PE / EA, 2 / 1) to give the corresponding enantiomer of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (5.5 g, 77%) as an oil. LCMS (ESI, m / z): 350 [M+H] +

[0266] Synthesis of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A mixture of the single enantiomer of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate (5.0 g, 14.310 mmol, 1.00 equiv) and LiOH (2.7 g, 114.48 mmol, 8.00 equiv) in THF (25.0 mL) and water (25.0 mL) was stirred at 60 °C for 0.5 h. LCMS showed the reaction was complete. The reaction mixture was acidified to 3-4 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 60% B to 75% B in 5 min; 254 / 210 nm) to give the respective enantiomers of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (19, 3.31 g, 68%) as solids.

[0267] 1 H NMR (400 MHz, methanol-d4) δ 7.61-7.54 (m, 2H), 7.53-7.47 (m, 1H), 7.47-7.39 (m, 1H), 7.39-7.33 (m, 1H), 7.32-7.24 (m, 1H), 7.20-7.12 (m, 1H), 4.92-4.88 (m, 1H), 4.37 (t, J = 8.8 Hz, 2H), 4.28-4.18 (m, 2H), 3.47-3.34 (m, 1H), 3.24-3.12 (m, 1H), 3.08-2.96 (m, 1H), 2.60-2.45 (m, 1H), 2.25-2.16 (m, 1H)

[0268] 19 F NMR (376 MHz, methanol-d4) δ -114.856

[0269] LCMS (ESI, m / z): 336 [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: water / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, 254 nm; RT: 1.583 min Example S20. 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (20) [ka]

[0270] Synthesis of methyl 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] To a solution of the single enantiomer of methyl 1-(5-ethynyl-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (150 mg, 0.590 mmol, 1.00 equiv), 2-bromo-1,4-difluorobenzene (125 mg, 0.650 mmol, 1.10 equiv), and K2CO3 (243 mg, 1.76 mmol, 3.00 equiv) in DMF (3.0 mL) was added XPhos Pd G3 (50 mg, 0.060 mmol, 0.10 equiv). The flask was evacuated and flushed with nitrogen five times. The mixture was stirred at 70 °C under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with ethyl acetate / petroleum ether, 1 / 2) to give one enantiomer of methyl 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (130 mg, 60%) as an oil. LCMS (ESI, m / z): 368 [M+H] +

[0271] Synthesis of 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] To a solution of the single enantiomer of methyl 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (130 mg, 0.350 mmol, 1.00 equiv.) in THF (3.0 mL) and water (0.3 mL) was added LiOH·HO (30 mg, 0.710 mmol, 2.00 equiv.). The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 22% B to 47% B in 7 min, hold at 47% B for 1 min; 254 / 210 nm; RT: 7.33 min) to give the corresponding enantiomer of 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (20, 80.9 mg, 64%) as a solid.

[0272] 1 H NMR (400 MHz, methanol-d4) δ 7.62-7.58 (m, 2H), 7.51 (dd, J = 7.6, 1.2 Hz, 1H), 7.33-7.29 (m, 1H), 7.24-7.14 (m, 2H), 5.00 (dd, J = 7.6, 2.8 Hz, 1H), 4.54-4.50 (m, 2H), 4.43-4.37 (m, 2H), 3.74-3.65 (m, 1H), 3.24-3.16 (m, 1H), 3.07-3.00 (m, 1H), 2.60-2.50 (m, 1H), 2.26-2.18 (m, 1H)

[0273] 19 F NMR (376 MHz, methanol-d4) δ -117.8, -120.5

[0274] LCMS (ESI, m / z): 354 [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: 1.542 min Example S21. 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (21) [ka] A solution of methyl 2-[5-[2-(2,6-dichlorophenyl)ethynyl]indan-1-yl]-2-azaspiro[3.3]heptane-6-carboxylate (50 mg, 0.110 mmol, 1.00 equiv.) and LiOH (8 mg, 0.330 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 15 h. LCMS indicated the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: X Bridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 45% B in 7 min; 254 / 210 nm; RT: 6.63 min) to give 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (21, 14.3 mg, 29.5%) as a solid.

[0275] LCMS (ESI, m / z): 426 [M+H] +Analysis conditions: HALO C18, 3.0*30 mm, 2.0 μm; Mobile phase A: water + 0.05% TFA. Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 1.2 min, hold at 100% B for 0.6 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.038 min

[0276] 1 H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J = 11.2 Hz, 2H), 7.46-7.43 (m, 2H), 7.40-7.31 (m, 2H), 3.73-3.71 (m, 1H), 3.32-3.28 (m, 2H), 3.19-3.14 (m, 3H), 2.96-2.84 (m, 2H), 2.782.72 (m, 1H), 2.20-2.19 (m, 3H), 2.04-1.97 (m, 1H), 1.81-1.78 (m, 1H) Example S22. 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (22a and 22b) [ka]

[0277] Synthesis of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-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 (500 mg, 1.480 mmol, 1.00 equiv), 1,3-dichloro-2-ethynylbenzene (505 mg, 2.960 mmol, 2.00 equiv), Pd(PPh3)2Cl2 (103 mg, 0.148 mmol, 0.10 equiv), and TEA (0.3 mL, 4.440 mmol, 3.00 equiv) in THF (10.0 mL) was stirred at 60 °C for 12 h under a nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (PE:EA=1:1) to give methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (350 mg, 55%) as an oil. LCMS (ESI, m / z): 428 [M+H] +

[0278] Synthesis of methyl 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (350 mg, 0.817 mmol, 1.00 equiv) and PtO2 (70 mg, 0.20 w / w) in methanol (8.0 mL) was stirred at 25 °C for 1 h under a hydrogen atmosphere. LCMS showed the reaction was complete. The solid was filtered off. The filtrate was concentrated under reduced pressure to give methyl 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, crude) as an oil. LCMS (ESI, m / z): 432 [M+H] +

[0279] Synthesis of 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.460 mmol, 1.00 equiv) and LiOH·HO (97 mg, 2.300 mmol, 5.00 equiv) in water / THF (2 / 2 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3–4 with 1 N HCl. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (22a, 88.9 mg, 46%) as a solid.

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.34-7.25 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.14-7.05 (m, 2H), 4.27 (s, 1H), 3.15-3.06 (m, 2H), 2.93-2.64 (m, 5H), 2.50 (s, 1H), 2.35-2.05 (m, 3H), 1.99 (d, J = 7.2 Hz, 2H), 1.89-1.69 (m, 2H), 1.62-1.43 (m, 2H)

[0281] LCMS (ESI, m / z): 418 [M+H] +Analysis conditions: Column: EVO C18 Column 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 1.99 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 220 nm; RT: 1.225 min

[0282] Synthesis of 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.460 mmol, 1.00 equiv) and LiOH·HO (97 mg, 2.300 mmol, 5.00 equiv) in water / THF (2 / 2 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3–4 with 1 N HCl. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (22b, 105.2 mg, 54%) as a solid.

[0283] 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.34-7.25 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.13-7.05 (m, 2H), 4.26 (t, J = 7.2 Hz, 1H), 3.15-3.06 (m, 2H), 2.91-2.68 (m, 5H), 2.46 (s, 1H), 2.29-2.12 (m, 3H), 2.09-1.95 (m, 2H), 1.88-1.70 (m, 2H), 1.67-1.38 (m, 2H)

[0284] LCMS (ESI, m / z): 418 [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 1.99 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 220 nm; RT: 1.227 min Example S23. 1-(5-(2-(2,6-dichlorophenyl)acetyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (23) [ka]

[0285] A solution of the single enantiomer of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (600 mg, 1.45 mmol, 1.00 equiv) in acetic acid (2 mL) and TfOH (1 mL, 11.3 mmol, 7.00 equiv) was stirred at 150° C. for 8 hours under microwave irradiation. LCMS showed the reaction was complete. The solvent was removed under reduced pressure, and the residue was purified by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.3% TFA): EtOH = 60:40, mobile phase B: IPA; flow rate: 20 mL / min; gradient: 30% B to 30% B in 27 min; 220 / 254 nm; RT: 16.438 min) and prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 42% B in 7 min; 254 / 210 nm; RT: 6.438 min). min) to afford (R)-1-(5-(2-(2,6-dichlorophenyl)acetyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (23, 5 mg, 0.771%) as a solid.

[0286] 1 H NMR (400 MHz, methanol-d4) δ 8.18 (s, 1H), 8.14 (dd, J = 8.0, 1.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 5.07 (dd, J = 8.4, 3.2 Hz, 1H), 4.82 (s, 2H), 3.57-3.50 (m, 2H), 3.32-3.10 (m, 5H), 2.71-2.54 (m, 2H), 2.28-2.20 (m, 2H), 2.05-1.90 (m, 2H)

[0287] LCMS (ESI, m / z): 432[M+H] +Analysis conditions: Shim-pack XR-ODS C18, 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 0.2 min; 254 nm; RT: 1.512 min Example S24. 1-(5-(2-(2,6-dichlorophenyl)-2-oxoethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (24) [ka]

[0288] A solution of the single enantiomer of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (600 mg, 1.45 mmol, 1.00 equiv) in acetic acid (2 mL) and TfOH (1 mL, 11.3 mmol, 7.00 equiv) was stirred at 150° C. for 8 hours under microwave irradiation. LCMS showed the reaction was complete. The solvent was removed under reduced pressure, and the residue was purified by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.3% TFA): EtOH = 60:40, mobile phase B: IPA; flow rate: 20 mL / min; gradient: 30% B to 30% B in 27 min; 220 / 254 nm; RT: 24.691 min) and prep-HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 42% B in 7 min; 254 / 210 nm; RT: 6.25 min). min) to afford a single enantiomer of 1-(5-(2-(2,6-dichlorophenyl)-2-oxoethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (24, 20 mg, 3.19%) as a solid.

[0289] 1H NMR (400 MHz, methanol-d4) δ 7.58 (d, J = 8.0 Hz, 1H), 7.47-7.41 (m, 3H), 7.32-7.26 (m, 2H), 4.96-4.92 (m, 1H), 4.25 (s, 2H), 3.55-3.51 (m, 1H), 3.33-3.30 (m, 1H), 3.22-3.10 (m, 2H), 3.03-2.86 (m, 2H), 2.65-2.47 (m, 3H), 2.30-2.19 (m, 2H), 1.97-1.76 (m, 2H)

[0290] LCMS (ESI, m / z): 432[M+H] + Analysis conditions: Shim-pack XR-ODS C18, 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 0.2 min; 254 nm; RT: 1.533 min Example S25. 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (25a and 25b) [ka]

[0291] Synthesis of methyl 1-(5-((2-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (500 mg, 1.480 mmol, 1.00 equiv.) in DMF (4 mL) was added 1-chloro-2-ethynylbenzene (606 mg, 4.43 mmol, 3.00 equiv.), Pd(PPh3)2Cl2 (20 mg, 0.150 mmol, 0.100 equiv.), CuI (57.3 mg, 0.300 mmol, 0.200 equiv.), and K2CO3 (0.84 mL, 4.43 mmol, 3.00 equiv.). The resulting solution was stirred at 80 °C overnight. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with ethyl acetate / petroleum ether, 1 / 2) to give methyl 1-(5-((2-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (512 mg, 87.9%) as an oil. LCMS (ESI, m / z): 394 [M+H] +

[0292] Synthesis of methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-((2-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (512 mg, 1.30 mmol, 1.00 equiv.) in methanol (5 mL) was added Pd / C (51 mg, 10% w / w). The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered through Celite, and the filter cake was washed with methanol (3*50 mL). The mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluted with ethyl acetate / petroleum ether, 1 / 2) to give methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (457 mg, 77.1%) as an oil. LCMS (ESI, m / z): 398 [M+H] +

[0293] Chiral Separation of Methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] 457 mg of the racemate was separated by chiral HPLC (column: Chiralpak IG, 2.0*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH₃·MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 16 mL / min; gradient: 50% B to 50% B in 14 min; 220 / 254 nm; RT1: 7.002 min; RT2: 9.054 min; injection volume: 1.1 mL; number of runs: 8) to give chiral separation 1 isomer (192 mg, 100% ee) and chiral separation 2 isomer (190 mg, 100% ee).

[0294] Synthesis of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 1, 180 mg, 0.450 mmol, 1.00 equiv.) and LiOH (32.5 mg, 1.36 mmol, 3.00 equiv.) in THF (2 mL) and water (2 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3-4 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: XBridge Prep C18 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: 2% B to 8% B in 10 min; 210 / 254 nm; RT: 7.68 min) to give the respective enantiomers of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (25a, 85.5 mg, 0.222 mmol, 49.1% yield) as solids.

[0295] 1 H NMR (300 MHz, DMSO-d6) δ 12.00 (br, 1H), 7.43-7.33 (m, 2H), 7.28-7.20 (m, 2H), 7.16 (d, J = 10.4 Hz, 1H), 7.09-7.04 (m, 2H), 4.23 (t, J = 9.2 Hz, 1H), 2.97-2.92 (m, 2H), 2.83-2.71 (m, 5H), 2.48-2.43 (m, 1H), 2.28-2.09 (m, 3H), 2.00-1.93 (m, 2H), 1.82-1.72 (m, 2H), 1.63-1.40 (m, 2H)

[0296] LCMS (ESI, m / z): 384 [M+H] +Analysis conditions: Shim-pack XR-ODS C18, 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 0.2 min; 220 nm; RT: 1.655 min

[0297] Synthesis of the individual enantiomers of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 2, 192 mg, 0.450 mmol, 1.00 equiv) and LiOH (61 mg, 1.36 mmol, 3.00 equiv) in THF (2 mL) and water (2 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3-4 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XBridge Prep C18 OBD, 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: 22% B to 52% B in 7 min; 210 / 254 nm; RT: 5.95 min) to give the respective enantiomers of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (25b, 108.1 mg, 61.8%) as solids.

[0298] 1H NMR (300 MHz, DMSO-d6) δ 12.00 (br, 1H), 7.43-7.33 (m, 2H), 7.26-7.22 (m, 2H), 7.16 (d, J = 10.4 Hz, 1H), 7.09-7.04 (m, 2H), 4.26-4.21 (m, 1H), 2.97-2.92 (m, 2H), 2.83-2.71 (m, 5H), 2.48-2.43 (m, 1H), 2.28-2.08 (m, 3H), 2.00-1.93 (m, 2H), 1.82-1.72 (m, 2H), 1.63-1.40 (m, 2H)

[0299] LCMS (ESI, m / z): 384 [M+H] + Analysis conditions: Shim-pack XR-ODS C18, 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, 0.2 minutes, 100% B, 5% B; 220 nm; RT: 1.653 min Example S26. 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26a and 26b)

[0300] Synthesis of 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid

change

[0301] 1 H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.36-7.24 (m, 1H), 7.21-6.97 (m, 6H), 4.23 (t, J = 6.9 Hz, 1H), 2.84-2.66 (m, 7H), 2.44 (s, 1H), 2.32-2.04 (m, 3H), 2.04-1.90 (m, 2H), 1.84-1.68 (m, 2H), 1.66-1.36 (m, 2H)

[0302] 19 F NMR (376 MHz, methanol-d4) δ -116.135

[0303] LCMS (ESI, m / z): 368 [M+H] +Analysis conditions: Column: Titank C18 Column 3.0*50 mm, 3.0 μm; Mobile phase A: Water + 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 1.39 min, hold at 95% for 0.7 min, 95% B to 10% B in 0.03 min; 210 nm; RT: 1.137 min

[0304] Synthesis of 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka]

[0305] Synthesis of methyl 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of the other enantiomer of methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 0.790 mmol, 1.00 equiv) and Pd / C (60 mg, w / w=0.2) in methanol (5.0 mL) was stirred at room temperature for 12 hours under a hydrogen atmosphere. LCMS showed the reaction was complete. The solid was filtered off. The filtrate was concentrated under reduced pressure to give methyl 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 50%) as an oil. LCMS (ESI, m / z): 382 [M+H] +

[0306] Synthesis of 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of methyl 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 0.390 mmol, 1.00 equiv) and LiOH HO (83 mg, 1.950 mmol, 5.00 equiv) in THF / water (1 / 1, 4 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3–4 with 1 N HCl. The resulting mixture was concentrated under reduced pressure, and the crude product 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: 18% B to 48% B in 7 min; 210 / 254 nm; RT: 6.17 min) to give 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (26b, 47.7 mg, 32%) as a solid.

[0307] 1 H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.37-7.14 (m, 1H), 7.14-6.97 (m, 6H), 4.23 (t, J = 6.7 Hz, 1H), 2.88-2.62 (m, 7H), 2.44 (s, 1H), 2.33-2.09 (m, 3H), 2.08-1.92 (m, 2H), 1.80-1.69 (m, 2H), 1.61-1.33 (m, 2H)

[0308] 19 F NMR (376 MHz, DMSO-d6) δ -116.147

[0309] LCMS (ESI, m / z): 368 [M+H] +Analysis conditions: Column: Titank C18 Column 3.0*50 mm, 3.0 μm; Mobile phase A: Water + 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 1.39 min, hold at 95% for 0.7 min, 95% B to 10% B in 0.03 min; 210 nm; RT: 1.131 min Example S27. 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (27a and 27b) [ka]

[0310] Synthesis of methyl 1-(5-((3-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A solution of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (1.0 g, 2.96 mmol, 3.00 equiv.), 1-chloro-2-ethynylbenzene (1.2 g, 8.88 mmol, 3.00 equiv.), Pd(PPh3)2Cl2 (207 mg, 0.296 mmol, 0.10 equiv.), CuI (56 mg, 0.296 mmol, 0.10 equiv.), and K2CO3 (897 mg, 8.88 mmol, 3.00 equiv.) in DMF (10 mL) was stirred at 80 °C for 15 h under a N2 atmosphere. LCMS indicated the reaction was complete. The resulting solution was diluted with 20 mL of water and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA=30%) to give methyl 1-(5-((3-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (580 mg, 50%) as an oil. LCMS (ESI, m / z): 394 [M+H] +

[0311] Synthesis of methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A solution of methyl 1-(5-((3-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (580 mg, 1.47 mmol, 1.00 equiv.) and PtO2 (110 mg, 0.2 w / w) in THF (3 mL) was stirred at room temperature for 1 h under an H2 atmosphere. TLC showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=50%) to give methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 51%) as an oil. LCMS (ESI, m / z): 398 [M+H] +

[0312] Chiral Separation [ka] Racemic methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg) was separated by chiral HPLC (column: Chiralpak IG, 2*25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH₃·MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 20% B to 20% B in 13 min; 220 / 254 nm; RT1: 7.219 min; RT2: 8.912 min) to give chiral separated 1 isomer (110 mg, 100% ee) as an oil. LCMS (ESI, m / z): 398 [M+H] +

[0313] Synthesis of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A solution of methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 1, 110 mg, 0.280 mmol, 1.00 equiv.) and LiOH (20 mg, 0.830 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The resulting solution was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmoL / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.28 min) to give one enantiomer of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (27a, 47.5 mg, 45%) as a solid.

[0314] LCMS (ESI, m / z): 384[M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 210 nm; RT: 1.167 min

[0315] 1 H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 4H), 7.16-7.14 (m, 1H), 7.08-7.02 (m, 2H), 4.25-4.20 (m, 1H), 2.85-2.65 (m, 7H), 2.50-2.44 (m, 1H), 2.27-2.08 (m, 3H), 2.01-1.93 (m, 2H), 1.82-1.72 (m, 2H), 1.63-1.43 (m, 2H)

[0316] Synthesis of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka]

[0317] A solution of the other enantiomer of methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (chiral separation 2, 150 mg, 0.377 mmol, 1.00 equiv.) and LiOH (26 mg, 1.13 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The resulting solution was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmoL / L NH4HCO3 + 0.1% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.28 min) to give the corresponding enantiomer of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (27b, 48.0 mg, 33%) as a solid.

[0318] LCMS (ESI, m / z): 384 [M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 210 nm; RT: 1.151 min

[0319] 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.14 (m, 5H), 7.08-7.02 (m, 2H), 4.26-4.21 (m, 1H), 2.87-2.65 (m, 7H), 2.50-2.45 (m, 1H), 2.27-2.08 (m, 3H), 2.01-1.93 (m, 2H), 1.82-1.72 (m, 2H), 1.63-1.43 (m, 2H) Example S28. 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (28a and 28b) [ka]

[0320] Synthesis of methyl 1-(5-((2,6-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a solution of one enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 0.890 mmol, 1.00 equiv.) in DMF (4.0 mL) was added K2CO3 (367 mg, 2.660 mmol, 3.00 equiv.), Pd(PPh3)2Cl2 (124 mg, 0.180 mmol, 0.200 equiv.), and CuI (84 mg, 0.440 mmol, 0.050 equiv.) at room temperature. The resulting solution was stirred at 60 °C for 12 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate / petroleum ether (1 / 2) to give methyl 1-(5-((2,6-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 85%) as a semi-solid. LCMS (ESI, m / z): 396 [M+H] +

[0321] Synthesis of methyl 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a solution of methyl 1-(5-((2,6-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 0.760 mmol, 1.00 equiv) in methanol (10 mL) was added Pd / C (300 mg, 1.00 w / w). The reaction mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. LCMS showed that the reaction was complete. The resulting mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude product, methyl 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg) as a solid, which was used in the next step without further purification. LCMS (ESI, m / z): 400 [M+H] +

[0322] Synthesis of 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A solution of methyl 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 0.380 mmol, 1.00 equiv.), LiOH.HO (47.2 mg, 1.13 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1 N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B in 7 min; 210 / 254 nm; RT: 4.77 min) to give one enantiomer of 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (28a, 60.3 mg, 41%) as a solid.

[0323] 1 H NMR (300 MHz, methanol-d4) δ 7.43 (d, J = 7.5 Hz, 1H), 7.24-7.19 (m, 1H), 7.16 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.8 Hz, 2H), 4.82-4.77 (m, 1H), 3.37-3.35 (m, 1H), 3.15-3.04 (m, 2H), 2.98-2.83 (m, 7H), 2.46-2.33 (m, 3H), 2.10-1.80 (m, 4H)

[0324] 19 F NMR (282 MHz, methanol-d4) δ-118.08

[0325] LCMS (ESI, m / z): 386 [M+H] + Analysis conditions: Column: Titank C18 Column 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 1.40 min, hold at 95% for 0.80 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 1.157 min

[0326] Following the same procedure as above, compound 28b was obtained using the other enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate. Example S29. 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (29) [ka]

[0327] Synthesis of methyl 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate [ka] A mixture of methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (400 mg, 1.14 mmol, 1.00 equiv.), 1,3-dichloro-2-ethynylbenzene (293 mg, 1.71 mmol, 1.50 equiv.), Pd(PPh3)2Cl2 (80 mg, 0.110 mmol, 0.10 equiv.), CuI (22 mg, 0.110 mmol, 0.10 equiv.), and K2CO3 (474 ​​mg, 3.430 mmol, 3.00 equiv.) in DMF (10 mL) was stirred at 80 °C for 15 h under a N2 atmosphere. LCMS indicated the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=50%) to give methyl 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (200 mg, 39.8%) as an oil. LCMS (ESI, m / z): 440 [M+H] +

[0328] Synthesis of methyl 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate [ka] A mixture of methyl 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (150 mg, 0.350 mmol, 1.00 equiv.) and PtO2 (15 mg, 0.070 mmol, 0.2 w / w) in THF (5.0 mL) was stirred at room temperature for 15 hours under an H2 atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product, methyl 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate, was used directly in the next step without further purification. LCMS (ESI, m / z): 444 [M+H] +

[0329] Synthesis of 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid [ka] A solution of methyl 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (30 mg, 0.070 mmol, 1.00 equiv.) and LiOH (5 mg, 0.210 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: XB ridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 53% B in 7 min, hold at 53% B for 1 min; 254 / 210 nm; RT: 7.92 min) to give the desired compound, 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (29, 10.2 mg, 34%), as a solid.

[0330] LCMS (ESI, m / z): 430 [M+H] + Analysis conditions: Poroshell EVO C18, 3.0*50 mm, 2.6 μm; mobile phase A: water / 5mM NH4HCO3, mobile phase B: ACN; flow rate: 1.20 mL / min; グラジエント: 2.0 minutes, 10% B, 95% B, 95% Bで0.6 minutes to maintain, 0.15 minutes to 95% Bから10% B; 210 nm; RT: 1.219 min

[0331] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 3.66-3.64 (m, 1H), 3.27-3.24 (m, 1H), 3.17-3.047 (m, 4H), 3.02 (d, J = 7.2 Hz, 1H), 2.93-2.85 (m, 2H), 2.75-2.67 (m, 3H), 2.27-2.19 (m, 4H), 1.99-1.94 (m, 1H), 1.79-1.73 (m, 1H) Example S30. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (30a and 30b)

change

[0332] Synthesis of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-azetidine-3-carboxylate

change

[0333] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A solution of the single enantiomer of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (120 mg, 0.360 mmol, 1.00 equiv.) and LiOH (26 mg, 1.08 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified with 2N HCl to pH 5-6 and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 7.00 min) to give the single enantiomer of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (30a, 23.5 mg, 20%) as a solid.

[0334] LCMS (ESI, m / z): 368 [M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.217 min

[0335] 11H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.0 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.84 (s, 1H), 3.55 - 3.48 (m, 2H), 3.24 - 3.15 (m, 3H), 3.01 - 2.93 (m, 1H), 2.83 - 2.76 (m, 1H), 2.20 - 2.14 (m, 1H), 2.10 - 2.01 (m, 1H), 1.89 - 1.82 (m, 1H), 1.06 - 0.97 (m, 2H), 0.78 - 0.72 (m, 2H)

[0336] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid

Chem.

[0337] Synthesis of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate

Chem.

[0338] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A solution of the other enantiomer of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (120 mg, 0.360 mmol, 1.00 equiv.) and LiOH (26 mg, 1.08 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 7.00 min) to give the other enantiomer of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (30b, 30.7 mg, 24.0%) as a solid.

[0339] LCMS (ESI, m / z): 368 [M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.217 min

[0340] 11H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.0 Hz, 1H), 7.52 - 7.50 (m, 2H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.81 - 3.78 (m, 1H), 3.55 - 3.48 (m, 2H), 3.24 - 3.15 (m, 3H), 2.98 - 2.92 (m, 1H), 2.82 - 2.75 (m, 1H), 2.20 - 2.13 (m, 1H), 2.08 - 1.99 (m, 1H), 1.85 - 1.81 (m, 1H), 1.05 - 1.00 (m, 2H), 0.76 - 0.72 (m, 2H) Example S31. 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (31a and 31b)

Chem.

[0341] Synthesis of methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate

Chem.

[0342] Synthesis of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A solution of one enantiomer of methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (200 mg, 0.560 mmol, 1.00 equiv.), 4-bromo-1-cyclopropyl-2-fluorobenzene (120 mg, 0.560 mmol, 1.00 equiv.), Pd(dppf)Cl (82 mg, 0.112 mmol, 0.20 equiv.), and CsCO (548 mg, 1.68 mmol, 3.00 equiv.) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was stirred at 90 °C for 2 h under a N atmosphere. LCMS indicated the reaction was complete. The resulting solution was diluted with 10 ml of water and then extracted with ethyl acetate (3*10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=30%) to give one enantiomer of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (90 mg, 44%) as an oil. LCMS (ESI, m / z): 366 [M+H] +

[0343] Synthesis of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A solution of one enantiomer of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (130 mg, 0.360 mmol, 1.00 equiv.) and LiOH (26 mg, 1.08 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmOL / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give the corresponding enantiomer of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (31a, 25.8 mg, 29%) as a solid.

[0344] LCMS (ESI, m / z): 352 [M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.141 min

[0345] 1H NMR (400 MHz, メタノール-d4) δ 7.60-7.52 (m, 3H), 7.37-7.30 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 4.75 (dd, J = 7.6, 2.8 Hz, 1H), 4.28-4.23 (m, 2H), 4.17-4.08 (m, 2H), 3.41-3.35 (m, 1H), 3.24-3.16 (m, 1H), 3.06-2.98 (m, 1H), 2.53-2.43 (m, 1H), 2.22-2.09 (m, 2H), 1.06-0.97 (m, 2H), 0.83-0.76 (m, 2H)

[0346] 19 F NMR (376 MHz, メタノール-d4) δ -122.338

[0347] Synthesis of methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate

change

[0348] Synthesis of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate [ka] A mixture of the other enantiomer of methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (200 mg, 0.560 mmol, 1.00 equiv.), 4-bromo-1-cyclopropyl-2-fluorobenzene (120 mg, 0.560 mmol, 1.00 equiv.), Pd(dppf)Cl (82 mg, 0.112 mmol, 0.200 equiv.), and CsCO (548 mg, 1.680 mmol, 3.00 equiv.) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was stirred at 90 °C for 2 h under a N atmosphere. LCMS indicated the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=30%) to give the other enantiomer of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (130 mg, 64%) as an oil. LCMS (ESI, m / z): 366 [M+H] +

[0349] Synthesis of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid [ka] A solution of the other enantiomer of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (130 mg, 0.360 mmol, 1.00 equiv.) and LiOH (26 mg, 1.08 mmol, 3.00 equiv.) in THF (2.0 mL) and water (1.0 mL) was stirred at room temperature for 15 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The crude product 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 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give the corresponding enantiomer of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid (31b, 38.2 mg, 31%) as a solid.

[0350] LCMS (ESI, m / z): 352 [M+H] + Analysis conditions: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.122 min

[0351] 1H NMR (400 MHz, メタノール-d4) δ 7.60-7.52 (m, 3H), 7.37-7.29 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 4.81 (dd, J = 7.6, 2.8 Hz, 1H), 4.34-4.29 (m, 2H), 4.22-4.14 (m, 2H), 3.41-3.35 (m, 1H), 3.25-3.17 (m, 1H), 3.06-2.98 (m, 1H), 2.54-2.45 (m, 1H), 2.25-2.09 (m, 2H), 1.08-0.97 (m, 2H), 0.83-0.75 (m, 2H)

[0352] 19 F NMR (376 MHz, メタノール-d4) δ -114.9 Example S32. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (32a and 32b)

change

[0353] Synthesis of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate

change

[0354] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a solution of one enantiomer of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (131 mg, 0.320 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH (23 mg, 0.960 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature for 30 minutes. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 3-4 with 1N HCl and then concentrated under reduced pressure. The residue was purified by HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 40% B in 10 min; 254 / 210 nm; RT: 8.80 min) to give one enantiomer of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (32a, 41 mg, 32.3%) as a solid.

[0355] 1 H NMR (300 MHz, methanol-d4) δ 7.70-7.58 (m, 4H), 7.49 (dd, J = 8.1, 1.8 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 5.01-4.97 (m, 1H), 3.57-3.52 (m, 1H), 3.41-3.34 (m, 1H), 3.28-2.98 (m, 4H), 2.65-2.54 (m, 3H), 2.67-2.20 (m, 3H), 2.04-1.84 (m, 2H), 1.09-1.02 (m, 2H), 0.76-0.71 (m, 2H)

[0356] LCMS (ESI, m / z): 396 [M+H] +Analysis conditions: Shim-pack XR-ODS C18, 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: 20% B to 60% B in 2.5 min, 60% B to 95% B in 0.5 min, hold at 95% B for 0.6 min, 95% B to 5% B in 0.1 min; 254 nm; RT: 2.345 min

[0357] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka]

[0358] Synthesis of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, 0.590 mmol, 1.00 equiv.) and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (329 mg, 1.18 mmol, 2.00 equiv.) in toluene (2 mL) and water (1 mL) was added Pd(DTBPF)Cl (46.1 mg, 0.060 mmol, 0.100 equiv.) and KPO (375 mg, 1.77 mmol, 3.00 equiv.). The resulting mixture was stirred at 90 °C for 4 hours. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with ethyl acetate / petroleum ether, 1 / 1) to give methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (268 mg, 89.5%) as an oil. LCMS (ESI, m / z): 410 [M+H] +

[0359] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a solution of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (268 mg, 0.320 mmol, 1.00 equiv.) in THF (2 mL) and water (2 mL) was added LiOH (47 mg, 0.960 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature for 30 minutes. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 3-4 with 1N HCl and then concentrated under reduced pressure. The residue was purified by HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 40% B in 10 min; 254 / 210 nm; RT: 8.80 min) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (32b, 41 mg, 31.18%) as a solid.

[0360] 1 H NMR (400 MHz, methanol-d4) δ 7.70-7.67 (m, 1H), 7.65-7.63 (m, 2H), 7.61-7.57 (m, 1H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 5.00-4.98 (m, 1H), 3.58-3.54 (m, 1H), 3.38-3.34 (m, 1H), 3.27-2.98 (m, 4H), 2.65-2.54 (m, 3H), 2.67-2.20 (m, 3H), 2.02-1.81 (m, 2H), 1.08-1.01 (m, 2H), 0.75-0.71 (m, 2H)

[0361] LCMS (ESI, m / z): 396 [M+H] +Analysis conditions: Shim-pack XR-ODS C18, 3.0*50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, 95% B to 5% B in 0.3 min; 254 nm; RT: 1.170 min Example S33. 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (33) [ka]

[0362] Synthesis of methyl 1-(5-(3-chloro-4-(prop-1-en-2-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of 4-bromo-2-chloro-1-isopropenylbenzene (300 mg, 1.300 mmol, 1.00 equiv.), Pd(dppf)Cl (189 mg, 0.260 mmol, 0.20 equiv.), and CSCO (1.27 g, 3.890 mmol, 3.00 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) was added methyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (749 mg, 1.9400 mmol, 1.50 equiv.). The resulting mixture was stirred at 90 °C for 1 day. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3*15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with PE / EtOAc 6 / 1) to give methyl 1-(5-(3-chloro-4-(prop-1-en-2-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (230 mg, 43.2%). LCMS (ESI, m / z): 410 [M+H] +

[0363] Synthesis of methyl 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of methyl 1-(5-(3-chloro-4-(prop-1-en-2-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (50 mg, 0.1200 mmol, 1.00 equiv.) in MeOH (2 mL) was added Pd / C (8 mg, 0.16 w / w). The resulting mixture was evacuated and flushed with nitrogen, followed by hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give methyl 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (37 mg) as crude, which was used directly in the next step. LCMS (ESI, m / z): 412 [M+H] +

[0364] Synthesis of 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a solution of methyl 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (37 mg, 0.090 mmol, 1.00 equiv.) in THF (1.5 mL) and water (1.5 mL) was added LiOH·HO (11 mg, 0.2700 mmol, 3.00 equiv.). The resulting mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was acidified to pH 4-5 by adding 1N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: X select CSH F-phenyl OBD Column 19*150 mm 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 41% B in 7 min, hold at 41% B for 1 min; 210 / 254 nm; RT: 7.92 min) to give 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (33, 8.8 mg, 23.9%) as a solid.

[0365] 1 H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.73-7.65 (m, 4H), 7.52 (d, J = 7.8 Hz, 1H), 4.99-4.96 (m, 1H), 3.33-2.90 (m, 8H), 2.51-2.43 (m, 2H), 2.14-1.85 (m, 5H), 1.27 (d, J = 6.6 Hz, 6H)

[0366] LCMS (ESI, m / z): 398 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS C18 100A column 3.0*50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, 95% B to 5% B in 0.05 min; 254 nm; RT: 2.013 min Example S34. (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (34a and 34b) [ka]

[0367] Synthesis of methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (R)-pyrrolidine-3-carboxylate (1.84 g, 14.2 mmol, 2.00 equiv.) and 5-bromo-2,3-dihydro-1H-inden-1-one (1.50 g, 7.11 mmol, 1.00 equiv.) in methanol (20 mL) was added NaBHCN (1.82 g, 28.4 mmol, 4.00 equiv.) and ZnCl (1.9 M in THF, 7.11 mL, 14.2 mmol, 2.00 equiv.). The resulting solution was stirred at 80 °C overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (3 * 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with PE / EtOAc 3 / 1) to give methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (1.60 g, 69.4%) as an oil. LCMS (ESI, m / z): 324 [M+H] +

[0368] Chiral separation of methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] 3.50 g of racemic methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate was separated by SFC (Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA; Flow rate: 100 mL / min; Gradient: 20% B; 220 nm) to give chiral separation 1 enantiomer (1.40 g, 96.1% ee) at a retention time of 2.53 min and chiral separation 2 enantiomer (1.30 g, 99.2% ee) at a retention time of 2.88 min.

[0369] Synthesis of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of chiral separation 1 enantiomer of methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (150 mg, 0.460 mmol, 1.00 equiv.) and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (141 mg, 0.510 mmol, 1.10 equiv.) in 1,2-dimethoxyethane (2 mL) and water (0.5 mL) was added Pd(PPh3)4 (53.5 mg, 0.050 mmol, 0.100 equiv.) and Na2CO3 (147 mg, 1.39 mmol, 3.00 equiv.). The resulting mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. 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 (eluted with PE / EtOAc, 1 / 1) to afford the corresponding enantiomer of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 54.6%) as an oil. LCMS (ESI, m / z): 396 [M+H] +

[0370] Synthesis of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a stirred solution of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (60.0 mg, 0.150 mmol, 1.00 equiv.) in THF (2.5 mL) was added a solution of LiOH·HO (20.0 mg, 0.480 mmol, 3.00 equiv.) in water (0.5 mL). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 210 / 254 nm; RT: 6.38 min) to give the respective enantiomers of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylic acid (34a, 14.8 mg, 25.4% yield) as solids.

[0371] 1 H NMR (400 MHz, methanol-d6) δ 7.64-7.62 (m, 2H), 7.59 (s, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.72-4.70 (m, 1H), 3.38-3.35 (m, 2H), 3.28-3.20 (m, 3H), 3.08-2.98 (m, 2H), 2.53-2.36 (m, 2H), 2.28-2.16 (m, 3H), 1.09-1.03 (m, 2H), 0.77-0.73 (m, 2H)

[0372] LCMS (ESI, m / z): 382 [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 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.220 min

[0373] Synthesis of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka]

[0374] Synthesis of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of the chiral separated two enantiomers of methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (150 mg, 0.460 mmol, 1.00 equiv.) and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (141 mg, 0.510 mmol, 1.10 equiv.) in 1,2-dimethoxyethane (2 mL) and water (0.5 mL), Pd(PPh3)4 (53.5 mg, 0.050 mmol, 0.100 equiv.) and Na2CO3 (147 mg, 1.39 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. 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 (eluted with PE / EtOAc, 1 / 1) to afford the corresponding enantiomer of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 54.6%) as an oil. LCMS (ESI, m / z): 396 [M+H] +

[0375] Synthesis of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.250 mmol, 1.00 equiv.) in THF (2.5 mL) was added a solution of LiOH·HO (30.0 mg, 0.710 mmol, 3.00 equiv.) in water (0.5 mL). The resulting solution was stirred at 25 °C for 2 h. The reaction mixture was acidified to pH 4-5 by the addition of 1 N HCl and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B in 10 min, hold at 45% B for 1 min; 210 / 254 nm; RT: 10.02 min) to give each enantiomer of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (34b, 49.5 mg, 51.1%) as a solid.

[0376] 1 H NMR (400 MHz, methanol-d6) δ 7.66-7.64 (m, 2H), 7.62 (s, 1H), 7.56 (dd, J = 8.0, 2.0 Hz, 1H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.88-4.83 (m, 1H), 3.57-3.53 (m, 1H), 3.45-3.38 (m, 2H), 3.31-3.23 (m, 2H), 3.10-3.01 (m, 2H), 2.60-2.43 (m, 2H), 2.29-2.20 (m, 3H), 1.10-1.05 (m, 2H), 0.77-0.73 (m, 2H)

[0377] LCMS (ESI, m / z): 382 [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 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.220 min Example S35. (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (35a and 35b) [ka]

[0378] Chiral separation of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] 3.00 g of the racemic product, methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate, was separated by SFC (Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (2 mmol / L NH3-MeOH); Flow rate: 100 mL / min; Gradient: 25% B; 220 nm) to give chiral separation 1 enantiomer (1.10 g, ee=96.9%) at a retention time of 2.61 min and chiral separation 2 enantiomer (900 mg, ee=98.0%) at a retention time of 3.35 min.

[0379] Synthesis of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of the chirally separated two enantiomers of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (400 mg, 1.23 mmol, 1.00 equiv.) in 1,4-dioxane (5.0 mL) was added bis(pinacolato)diboron (469 mg, 1.85 mmol, 1.5 equiv.), PdCl(dppf)CHCl (100 mg, 0.120 mmol, 0.100 equiv.), and AcOK (362 mg, 3.70 mmol, 3.00 equiv.). The resulting solution was stirred at 80 °C for 2 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (EA:PE=1:4) to give the corresponding enantiomer of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (300 mg, 65%) as an oil. LCMS (ESI, m / z): 372 [M+H] +

[0380] Synthesis of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (200 mg, 0.540 mmol, 1.00 equiv.) in 1,4-dioxane (2.0 mL), 4-bromo-2-chloro-1-cyclopropylbenzene (186 mg, 0.810 mmol, 1.50 equiv.), water (0.2 mL), PdCl(dppf)CHCl (88.0 mg, 0.110 mmol, 0.200 equiv.), and CsCO (527 mg, 1.620 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 80 °C for 2 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (EA:PE=2:3) to give each enantiomer of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 46%) as an oil. LCMS (ESI, m / z): 396 [M+H] +

[0381] Synthesis of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] A mixture of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.250 mmol, 1.00 equiv.) and LiOH HO (53.0 mg, 1.25 mmol, 5.00 equiv.) in THF (2 mL) and water (2 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give the respective enantiomers of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (35a, 20 mg, 21%) as solids. LCMS (ESI, m / z): 382 [M+H] +

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.45 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.17 (d, J = 6.0 Hz, 1H), 3.02-2.94 (m, 1H), 2.89-2.84 (m, 1H), 2.82-2.77 (m, 2H), 2.70-2.67 (m, 1H), 2.62-2.57 (m, 2H), 2.20-2.13 (m, 1H), 2.10-2.05 (m, 2H), 1.95-1.90 (m, 2H), 1.05-1.00 (m, 2H), 0.76-0.72 (m, 2H)

[0383] LCMS (ESI, m / z): 382 [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; 210 nm; RT: 1.204 min

[0384] Synthesis of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka]

[0385] A mixture of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.250 mmol, 1.00 equiv.) and LiOH·HO (53 mg, 1.250 mmol, 5.00 equiv.) in THF (4.0 mL) / water (4.0 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (35b, 40.6 mg, 42%) as a solid.

[0386] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 2.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.47-7.45 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.16 (t, J = 6.0 Hz, 1H), 3.03-2.87 (m, 2H), 2.85-2.76 (m, 2H), 2.74-2.70 (m, 1H), 2.64-2.57 (m, 2H), 2.21-2.14 (m, 1H), 2.12-2.07 (m, 2H), 1.96-1.86 (m, 2H), 1.06-1.01 (m, 2H), 0.77-0.73 (m, 2H)

[0387] LCMS (ESI, m / z): 382 [M+H] + Analysis conditions: カラム: EVO C18, 3.0*50 mm, 2.6 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: アセトニトリル; flow rate: 1.20 mL / min; グラジエント: 1.99 minutes to 10% Bから95% B, 95%で0.6 minutes to maintain, 0.15 minutes and 95% Bから10% B; 210 nm; RT: 1.203 min Example S36. (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (36a and 36b)

change

[0388] Synthesis of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate

change

[0389] Synthesis of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylic acid [ka] To a stirred solution of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (50.0 mg, 0.130 mmol, 1.00 equiv.) in THF (1 mL) and water (1 mL) was added LiOH·HO (27.6 mg, 0.660 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH OBD Column 30*150 mm 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 43% B in 7 min; 254 / 210 nm; RT: 6.68 min) to give each enantiomer of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (36a, 14.8 mg, 30.6%) as a solid.

[0390] 1 H NMR (400 MHz, methanol-d6) δ 7.74-7.67 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.40-7.33 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 5.05-5.01 (m, 1H), 3.90-3.78 (m, 1H), 3.71-3.59 (m, 2H), 3.54-3.47 (m, 1H), 3.42-3.33 (m, 1H), 3.12-3.06 (m, 1H), 2.66-2.48 (m, 3H), 2.41-2.38 (m, 1H), 2.24-2.11 (m, 2H), 1.07-1.02 (m, 2H), 0.81-0.77 (m, 2H)

[0391] 19 F NMR (376 MHz, methanol-d6) δ -122.2

[0392] LCMS (ESI, m / z): 366 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.577 min

[0393] Synthesis of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylic acid [ka]

[0394] Synthesis of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a solution of chiral separated two isomers of methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (150 mg, 0.460 mmol, 1.00 equiv.), KPO (294 mg, 1.39 mmol, 3.00 equiv.), and 2-(4-cyclopropyl-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121 mg, 0.460 mmol, 1.00 equiv.) in 1,4-dioxane (3 mL) and water (0.3 mL) was added Pd(dppf)Cl·DCM (37.8 mg, 0.050 mmol, 0.10 equiv.). The reaction mixture was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with EA. The solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH 15 / 1) to give the corresponding enantiomer of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (150 mg, 85.4%) as an oil. LCMS (ESI, m / z): 380 [M+H] +

[0395] Synthesis of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.260 mmol, 1.00 equiv.) in THF (4 mL) and water (4 mL) was added LiOH·HO (55.3 mg, 1.32 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH OBD Column 30*150 mm 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give each enantiomer of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (36b, 33.6 mg, 34.7%) as a solid.

[0396] 1 H NMR (400 MHz, methanol-d6) δ 7.71 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.63-7.58 (m, 1H), 7.40-7.32 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 5.04-5.01 (m, 1H), 3.95-3.82 (m, 1H), 3.75-3.62 (m, 1H), 3.59-3.46 (m, 2H), 3.41-3.29 (m, 2H), 3.13-3.05 (m, 1H), 2.66-2.22 (m, 4H), 2.174-2.10 (m, 1H), 1.07-1.01 (m, 2H), 0.81-0.77 (m, 2H)

[0397] 19 F NMR (376 MHz, methanol-d6) δ -122.2

[0398] LCMS (ESI, m / z): 366 [M+H] + Analysis conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 20% B to 50% B in 2.7 min, 50% B to 95% B in 0.3 min, hold at 95% for 0.6 min, 95% B to 5% B in 0.1 min; 254 nm; RT: 2.656 min Example S37. (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (37a and 37b) [ka]

[0399] Synthesis of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of NaBHCN (3.64 g, 56.9 mmol, 4.00 equiv.) in methanol (20 mL) was added ZnCl (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 (S)-pyrrolidine-3-carboxylate (3.67 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 NaSO and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with PE:EA=3:1 to give methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (3.00 g, 65%) as an oil. LCMS (ESI, m / z): 324 [M+H] +

[0400] Chiral separation of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] 3.00 g of the racemic product was separated by SFC (Column: CHIRAL ART Amylose-C NEO, 3*25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (2 mmol / L NH3-MeOH); Flow rate: 100 mL / min; Gradient: 25% B; 220 nm) to give chiral separation 1 enantiomer (1.10 g, ee=96.9%) with a retention time of 2.61 min and chiral separation 2 enantiomer (900 mg, ee=98.0%) with a retention time of 3.35 min. LCMS (ESI, m / z): 324 [M+H] +

[0401] Synthesis of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of chiral separation 1 enantiomer of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (400 mg, 1.23 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL), bis(pinacolato)diboron (469 mg, 1.85 mmol, 1.5 equiv.), PdCl(dppf)·DCM (100 mg, 0.120 mmol, 0.100 equiv.), and AcOK (362 mg, 3.70 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 80 °C for 2 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (EA:PE=1:4) to give the corresponding enantiomer of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (300 mg, 65%) as an oil. LCMS (ESI, m / z): 372 [M+H] +

[0402] Synthesis of methyl (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate [ka] To a stirred solution of methyl (3S)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.270 mmol, 1.00 equiv.) in 1,4-dioxane (2 mL) and water (0.2 mL), 4-bromo-1-cyclopropyl-2-fluorobenzene (87.0 mg, 0.400 mmol, 1.50 equiv.), PdCl(dppf)·DCM (44.0 mg, 0.050 mmol, 0.200 equiv.), and CsCO (263 mg, 0.810 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 80 °C for 2 h under a nitrogen atmosphere. 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 silica gel chromatography (EA:PE=2:3) to give each enantiomer of methyl (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 49%) as an oil. LCMS (ESI, m / z): 380 [M+H] +

[0403] Synthesis of (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid [ka] A mixture of methyl (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.250 mmol, 1.00 equiv.) and LiOH·HO (53.0 mg, 1.25 mmol, 5.00 equiv.) in THF (2 mL) / water (2 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give the respective enantiomers of (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (37a, 36.6 mg, 37%) as solids. LCMS (ESI, m / z): 366 [M+H] +

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.47-7.38 (m, 3H), 7.35 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 4.17 (d, J = 6.0 Hz, 1H), 3.02-2.95 (m, 1H), 2.91-2.85 (m, 1H), 2.84-2.77 (m, 2H), 2.71-2.67 (m, 1H), 2.63-2.58 (m, 2H), 2.10-2.03 (m, 3H), 1.96-1.90 (m, 2H), 1.02-0.98 (m, 2H), 0.79-0.75 (m, 2H)

[0405] 19 F NMR (376 MHz, DMSO-d6) δ -120.46

[0406] LCMS (ESI, m / z): 366 [M+H] + Analysis conditions: Column: Xbridge RP18, 4.6*50 mm, 3.5 μm; Mobile phase A: Water / 0.04% NH₃·H₂O, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 1.75 min, hold at 95% for 1.15 min, 95% B to 10% B in 0.01 min; 254 nm; RT: 1.165 min

[0407] Synthesis of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid from chiral separation 2 [ka] A mixture of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (100 mg, 0.250 mmol, 1.00 equiv.) and LiOH HO (53.0 mg, 1.25 mmol, 5.00 equiv.) in THF (2 mL) and water (2 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; 254 / 210 nm; RT: 6.42 min) to give the respective enantiomers of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid (37b, 40.6 mg, 42%) as solids. LCMS (ESI, m / z): 382 [M+H] +

[0408] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 2.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.47-7.45 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.16 (d, J = 6.0 Hz, 1H), 3.03-2.95 (m, 1H), 2.92-2.87 (m, 1H), 2.84-2.79 (m, 2H), 2.73-2.70 (m, 1H), 2.64-2.59 (m, 2H), 2.21-2.14 (m, 1H), 2.12-2.07 (m, 2H), 1.96-1.90 (m, 2H), 1.06-1.01 (m, 2H), 0.77-0.73 (m, 2H)

[0409] LCMS (ESI, m / z): 382 [M+H] + Analysis conditions: カラム: EVO C18, 3.0*50 mm, 2.6 μm; mobile phase A: water (5 mM NH4HCO3), mobile phase B: アセトニトリル; flow rate: 1.20 mL / min; グラジエント: 2.00 minutes, 10% B, 95% B, 95%, 0.60 minutes, 0.15 minutes, 95% B, 10% B; 210 nm; RT: 1.203 min Example S38. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid (38)

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[0410] Synthesis of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylate

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[0411] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid [ka] A mixture of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylate (110 mg, 0.270 mmol, 1.00 equiv.) and LiOH (19 mg, 0.800 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 pH of the solution was adjusted to 3-4 with 2N HCl. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by prep-HPLC (column: YMC-Triart Diol Hilic, 20*150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 7 min; 254 / 210 nm; RT: 6.73 min) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxylic acid (38, 26.4 mg, 24.7%) as a solid.

[0412] 1 H NMR (400 MHz, chloroform-d) δ 7.56-7.48 (m, 2H), 7.41-7.33 (m, 3H), 6.97 (d, J = 8.0 Hz, 1H), 4.54-4.50 (m, 1H), 3.13-2.95 (m, 3H), 2.76-2.53 (m, 4H), 2.26-2.19 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.75 (m, 2H), 1.26-0.98 (m, 2H), 0.74-0.68 (m, 2H)

[0413] LCMS (ESI, m / z): 396 [M+H] +Analysis conditions: 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 2.0 min, hold at 95% B for 0.6 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.311 min Example S39. 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (39) [ka]

[0414] Synthesis of methyl 2-azaspiro[3.3]heptane-6-carboxylate [ka] To a solution of 2-(tert-butyl) 6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate (1.0 g, 3.922 mmol, 1.00 equiv.) in DCM (10 mL) was added TBSOTf (2.1 g, 7.843 mmol, 2.00 equiv.) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting solution was concentrated under reduced pressure. The crude methyl 2-azaspiro[3.3]heptane-6-carboxylate (700 mg) was used directly in the next step without further purification. LCMS (ESI, m / z): 156 [MH] +

[0415] Synthesis of methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate [ka] To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (400 mg, 1.896 mmol, 1.00 equiv.), ZnCl (258 mg, 1.896 mmol, 1.00 equiv.), and methyl 2-azaspiro[3.3]heptane-6-carboxylate (353 mg, 2.275 mmol, 1.50 equiv.) in methanol (10 mL) was added NaBHCN (358 mg, 5.688 mmol, 3.00 equiv.). The resulting solution was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (eluting with water (0.05% TFA) / ACN, 3 / 1) to give methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (400 mg, 60.3%) as an oil. LCMS (ESI, m / z): 350 [M+H] +

[0416] Synthesis of methyl 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate [ka] To a solution of methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (189 mg, 0.540 mmol, 1.00 equiv.), CsCO (527 mg, 1.620 mmol, 3.00 equiv.), and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.540 mmol, 1.00 equiv.) in 1,4-dioxane (3.0 mL) and water (0.3 mL) was added Pd(dppf)Cl-DCM (44 mg, 0.054 mmol, 0.10 equiv.). The reaction mixture was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc. The solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluted with DCM / MeOH 15 / 1) to give methyl 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (110 mg, 48.3%) as a solid. LCMS (ESI, m / z): 422 [M+H] +

[0417] Synthesis of 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid [ka] To a solution of methyl 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylate (100 mg, 0.240 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL) was added LiOH·HO (50 mg, 1.180 mmol, 5.00 equiv.). The resulting solution was stirred overnight at room temperature. LCMS indicated the reaction was complete. The reaction mixture was acidified to pH 4-5 by the addition of 1N HCl and then concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH OBD Column 30*150 mm 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 47% B in 7 min; 254 / 210 nm; RT: 5.93 min) to give 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (39, 27.2 mg, 28%) as a solid.

[0418] 1 H NMR (400 MHz, methanol-d4) δ 7.65-7.64 (m, 2H), 7.62-7.56 (m, 2H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.50-4.47 (m, 1H), 4.31-4.26 (m, 2H), 4.21-4.15 (m, 1H), 3.33-3.31 (m, 1H), 3.27-3.19 (m, 1H), 3.11-3.04 (m, 2H), 2.68-2.64 (m, 1H), 2.60-2.48 (m, 4H), 2.28-2.15 (m, 2H), 1.10-1.05 (m, 2H), 0.77-0.73 (m, 2H)

[0419] LCMS (ESI, m / z): 408 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS C18 100A Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 20% B to 65% B in 2.5 min, 65% B to 95% B in 0.5 min, hold at 95% B for 0.6 min; 254 nm; RT: 2.248 min Example S40. 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (40) [ka]

[0420] Synthesis of methyl 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of the single enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (92 mg, 0.270 mmol, 1.00 equiv) in 1,4-dioxane (3.0 mL) and water (0.3 mL) was added (3,5-dimethoxyphenyl)boronic acid (100 mg, 0.550 mmol, 2.00 equiv), Pd(dppf)Cl (22 mg, 0.030 mmol, 0.10 equiv), and CsCO (268 mg, 0.820 mmol, 3.00 equiv). The reaction was stirred at 80 °C for 3 h. LCMS indicated the reaction was complete. The residue was purified by flash C18 silica column chromatography (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min; 254 / 210 nm) to give the single enantiomer of methyl 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 69% yield) as an oil. LCMS (ESI, m / z): 396 [M+H] +

[0421] Synthesis of 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] To a stirred solution of the single enantiomer of methyl 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 0.380 mmol, 1.00 equiv) in THF (3.0 mL) and water (0.6 mL) was added LiOH HO (47 mg, 1.140 mmol, 3.00 equiv). The reaction was stirred at room temperature for 5 h. LCMS indicated the reaction was complete. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B to 46% B in 7 min; 254 / 210 nm; RT: 5.95 min) to give the single enantiomer of 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (40, 35.6 mg, 23% yield) as a solid.

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.52-7.43 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 2.0 Hz, 2H), 6.48 (m, 1H), 4.31 (t, J = 7.2 Hz, 1H), 3.8 (s, 6H), 2.98-2.72 (m, 3H), 2.54-2.53 (m, 1H), 2.32-2.27 (m, 1H), 2.22-2.13 (m, 2H), 2.07-1.98 (m, 2H), 1.88-1.71 (m, 2H), 1.65-1.42 (m, 2H)

[0423] LCMS (ESI, m / z): 382 [M+H] +Analysis conditions: Column: Titank C18, 3.0*50 mm, 3.0 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 1.80 min, hold at 95% for 0.8 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.178 min Example S41. 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (41) [ka]

[0424] Synthesis of methyl 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] A mixture of 2-(2,3-dihydrobenzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.820 mmol, 1.00 equiv.), the single enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (274 mg, 0.820 mmol, 1.00 equiv.), Pd(dppf)Cl (60 mg, 0.080 mmol, 0.10 equiv.), and CsCO (794 mg, 2.440 mmol, 3.00 equiv.) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was stirred at 90 °C for 15 h under a N atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with 20 mL of water and then extracted with ethyl acetate (3*10 mL). The combined organic layers were washed with aqueous Na2CO3 and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE=16%) to afford the single enantiomer of methyl 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylate (120 mg, 53.6%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0425] Synthesis of 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A solution of one enantiomer of methyl 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (110 mg, 0.290 mmol, 1.00 equiv.) and LiOH (21 mg, 0.870 mmol, 3.00 equiv.) in THF (2 mL) and water (1 mL) was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting solution was acidified to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 22% B in 8 min; 254 / 210 nm; RT: 7.53 min) to give one enantiomer of the desired compound, 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (41, 24.6 mg, 23.4%), as a solid.

[0426] LCMS (ESI, m / z): 364 [M+H] + Analysis conditions: Poroshell HPH-C18, 3.0*50 mm, 2.7 μm; Mobile phase A: Water / 5 mM NH4HCO3. Mobile phase B: ACN; Flow rate: 1.20 mL / min; Gradient: 10% B to 45% B in 1.7 min, 45% B to 95% B in 0.3 min, hold at 95% B for 0.7 min, 95% B to 10% B in 0.1 min; 254 nm; RT: 1.513 min

[0427] 11H NMR (400 MHz, DMSO-d6) δ 7.44-7.41 (m, 2H), 7.29 (dd, J = 7.6, 6.0 Hz, 2H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 4.56 (t, J = 8.4 Hz, 2H), 4.30 (t, J = 7.6 Hz, 1H), 3.20 (t, J = 8.4 Hz, 3H), 2.95-2.75 (m, 3H), 2.32-2.25 (m, 1H), 2.20-2.14 (m, 2H), 2.03 (q, J = 3.6 Hz, 2H), 1.84-1.75 (m, 2H), 1.65-1.55 (m, 1H), 1.52-1.43 (m, 1H) Example S42. 1-(5-(benzo[d]oxazol-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (42)

Chem.

[0428] Synthesis of methyl 1-(5-(benzo[d]oxazol-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate

Chem.

[0429] Synthesis of 1-(5-(benzo[d]oxazol-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of one enantiomer of methyl 1-(5-(benzo[d]oxazol-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (89 mg, 0.240 mmol, 1.00 equiv.) and LiOH (17 mg, 0.710 mmol, 3.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 5–6 with CH3COOH. The resulting mixture was concentrated under reduced pressure, and 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 HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 8% B to 38% B in 7 min; 254 / 210 nm; RT: 5.87 min) to give one enantiomer of 1-(5-(benzo[d]oxazol-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (42, 9.1 mg, 0.024 mmol, 10.1% yield) as a solid.

[0430] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 8.4, 1.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 4.33 (t, J = 7.2 Hz, 1H), 2.98-2.91 (m, 1H), 2.87-2.79 (m, 2H), 2.56-2.53 (m, 1H), 2.33-2.27 (m, 1H), 2.22-2.15 (m, 2H), 2.07-2.02 (m, 2H), 1.85-1.76 (m, 2H), 1.66-1.54 (m, 1H), 1.53-1.40 (m, 1H)

[0431] LCMS (ESI, m / z): 363 [M+H]+ Analysis conditions: Shim-pack XR-ODS C18, 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 0.2 min; 254 nm; RT: 1.316 min Example S43. 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (43) [ka]

[0432] Synthesis of methyl 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate [ka] To a stirred solution of one enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (100 mg, 0.300 mmol, 1.00 equiv.) in DME (2 mL) / water (0.2 mL) was added 2,3-dihydrobenzofuran-5-ylboronic acid (53 mg, 0.330 mmol, 1.10 equiv.), Pd(PPh3)4 (34 mg, 0.030 mmol, 0.100 equiv.), and Na2CO3 (94 mg, 0.890 mmol, 3.00 equiv.). The resulting mixture was stirred at 90 °C overnight. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with DCM / MEOH, 10 / 1) to give one enantiomer of methyl 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (94 mg, 84.2%) as an oil. LCMS (ESI, m / z): 378 [M+H] +

[0433] Synthesis of 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] A mixture of one enantiomer of methyl 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (94 mg, 0.250 mmol, 1.00 equiv.) and LiOH (32 mg, 0.750 mmol, 3.00 equiv.) in THF (1 mL) and water (1 mL) was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete. The pH of the solution was adjusted to 3-4 with 2N HCl. The resulting mixture was concentrated under reduced pressure, and 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: 12% B to 40% B in 8 min; 254 / 210 nm; RT: 7.45 min) to give one enantiomer of 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (43, 38.5 mg, 42.3%) as a solid.

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (br, 1H), 7.50 (s, 1H), 7.41-7.34 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.56 (t, J = 8.4 Hz, 2H), 4.29 (t, J = 7.2 Hz, 1H), 3.25-3.21 (m, 2H), 2.94-2.75 (m, 3H), 2.59-2.51 (m, 1H), 2.31-2.25 (m, 1H), 2.21-2.14 (m, 2H), 2.02 (q, J = 7.6 Hz, 2H), 1.84-1.75 (m, 2H), 1.65-1.55 (m, 1H), 1.52-1.43 (m, 1H)

[0435] LCMS (ESI, m / z): 364 [M+H] +Analysis conditions: Shim-pack XR-ODS C18, 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 0.2 min; 254 nm; RT: 1.391 min Example S44. 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylic acid (44) [ka]

[0436] Synthesis of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylate [ka] To a solution of one enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 0.440 mmol, 1.00 equiv.), indan-5-ylboronic acid (86 mg, 0.530 mmol, 1.20 equiv.) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added CsCO (433 mg, 1.330 mmol, 3.00 equiv.) and Pd(dppf)Cl (72 mg, 0.090 mmol, 0.20 equiv.). The resulting solution was stirred at 80 °C for 3 h under a nitrogen atmosphere. 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 silica gel chromatography (PE / EA=9 / 1) to give one enantiomer of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylate (140 mg, 84%) as an oil. LCMS (ESI, m / z): 376 [M+H] +

[0437] Synthesis of 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylic acid [ka] A mixture of one enantiomer of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylate (100 mg, 0.270 mmol, 1.00 equiv.) and LiOH·HO (33 mg, 0.800 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 8 min; 254 / 210 nm; RT: 6.32 min) to give one enantiomer of 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylic acid (44, 29.7 mg, 30%) as a solid.

[0438] 1 H NMR (400 MHz, methanol-d4) δ 7.58-7.52 (m, 3H), 7.46 (s, 1H), 7.37-7.35 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.38-3.34 (m, 3H), 3.20-3.14 (m, 2H), 3.06-2.89 (m, 6H), 2.85-2.81 (m, 1H), 2.48-2.38 (m, 2H), 2.35-2.27 (m, 1H), 2.15-2.03 (m, 4H), 1.97-1.83 (m, 1H)

[0439] LCMS (ESI, m / z): 362 [M+H] +Analysis conditions: Column: Poroshell HPH-C18 Column 3.0*50 mm, 2.7 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 50% B in 2.0 min, 50% B to 95% B in 0.25 min, hold at 95% for 0.45 min, 95% B to 10% B in 0.1 min; 254 nm; RT: 1.916 min Example S45. 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylic acid (45) [ka]

[0440] Synthesis of 2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 4-bromoindane (300 mg, 1.520 mmol, 1.00 equiv.), bis(pinacolato)diboron (580 mg, 2.280 mmol, 1.50 equiv.) in 1,4-dioxane (4.0 mL), AcOK (447 mg, 4.570 mmol, 3.00 equiv.) and Pd(dppf)Cl (124 mg, 0.150 mmol, 0.10 equiv.) were added at room temperature. The resulting solution was stirred at 80 °C for 3 h under a nitrogen atmosphere. 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 silica gel chromatography (PE / EA=10 / 1) to give 2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260 mg, 69%) as an oil. LCMS (ESI, m / z): 245 [M+H] +

[0441] Synthesis of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylate [ka] To a solution of one enantiomer of methyl 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (270 mg, 0.800 mmol, 1.00 equiv.), 2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (234 mg, 0.960 mmol, 1.20 equiv.) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added CsCO (781 mg, 2.390 mmol, 3.00 equiv.) and Pd(dppf)Cl. 2· DCM (130 mg, 0.160 mmol, 0.20 equiv.) was added at room temperature. The resulting mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA=2 / 1) to give one enantiomer of methyl 1-(2,2′,3,3′-tetrahydro-1H,1′H-[4,5′-biinden]-1′-yl)piperidine-4-carboxylate (200 mg, 66%) as an oil. LCMS (ESI, m / z): 376 [M+H] +

[0442] Synthesis of 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylic acid [ka] A mixture of one enantiomer of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylate (100 mg, 0.270 mmol, 1.00 equiv.) and LiOH·HO (34 mg, 0.810 mmol, 3.00 equiv.) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for 12 h. LCMS indicated the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and then concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B in 8 min; 254 / 210 nm; RT: 6.32 min) to give one enantiomer of 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylic acid (45, 47.8 mg, 49%) as a solid.

[0443] 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.32-7.23 (m, 3H), 7.22-7.19 (m, 2H), 7.16-7.11 (m, 1H), 4.30 (t, J = 7.2 Hz, 1H), 2.93-2.75 (m, 7H), 2.56-2.52 (m, 1H), 2.33-2.26 (m, 1H), 2.21-2.13 (m, 2H), 2.05-1.91 (m, 4H), 1.84-1.74 (m, 2H), 1.67-1.58 (m, 1H), 1.54-1.42 (m, 1H)

[0444] LCMS (ESI, m / z): 362 [M+H] +Analysis conditions: Column: Titank C18 Column 3.0*50 mm, 3.0 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 1.8 min, hold at 95% for 0.8 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.316 min Biological Examples Example B1. Cell membrane preparation

[0445] CHO cells expressing recombinant S1P5 receptor were cultured at 500 cm 2 Once confluent, cells were cultured in culture dishes and rinsed with cell lifting buffer (10 mM HEPES, 154 mM NaCl, 6.85 mM EDTA, pH 7.4) for detachment. Cells were then pelleted by centrifugation, resuspended, and homogenized in membrane preparation buffer (10 mM HEPES and 10 mM EDTA, pH 7.4) using a Polytron PT 1200E homogenizer (Kinematica, Lucerne, Switzerland). Cellular proteins were pelleted by centrifugation (48,000 x g, 4°C, 30 min). The resulting supernatant was discarded, and the pellet was resuspended in membrane preparation buffer and homogenized a second time, followed by centrifugation as described above. The final cell protein pellet was suspended in ice-cold resuspension buffer (10 mM HEPES and 0.1 mM EDTA, pH 7.4), aliquoted, and stored at -80°C until use. Example B2. GTPγS Binding Assay

[0446] [ 35Functional binding assays for [S]-GTPγS were performed in a 96-well non-binding surface plate in a final volume of 200 μL. Test compounds were serially diluted in DMSO and added to the assay plate in a total volume of 0.4 μL using a Tecan D300E digital dispenser. A 400 μM stock solution of sphingosine-1-phosphate (S1P) control was prepared separately by creating a 400 μM stock solution from a 100 nmol S1P pellet in 10 mM Na2CO3 containing 2% β-cyclodextrin. Serial dilutions of S1P were made using complete assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.1% fatty acid-free bovine serum albumin (BSA), and 30 μg / mL saponin, pH 7.4) and transferred to wells already containing 0.4 μL DMSO. Next, complete assay buffer was added to all wells, except for the nonspecific binding (NSB) wells, to a total volume of 40 μL. For NSB wells, 40 μL / well of 50 μM GTPγS (Sigma-Aldrich, St. Louis, MO, Cat. No. G8634) was added to wells containing 0.4 μL of DMSO. The assay was initiated by adding 120 μL / well of CHO-S1P receptor membrane solution containing 40 μg / mL membrane protein, 16.67 μM guanosine diphosphate (GDP; Sigma-Aldrich, St. Louis, MO, Cat. No. G7127), and 2.5 mg / mL WGA PVT SPA beads in complete buffer. The assay plate was then sealed and incubated for 30 minutes at room temperature with gentle agitation. Next, 1 nM [[S1P-1, S1P-2, S1P-3, S1P-4, S1P-5, S1P-6, S1P-7, S1P-8, S1P-9, S1P-10, S1P-11, S1P-12, S1P-13, S1P-14, S1P-15, S1P-16, S1P-17, S1P-18, S1P-19, S1P-20, S1P-21, S1P-22, S1P-23, S1P-24, S1P-25, S1P-26, S1P-27, S1P-28, S1P-29, S1P-30, S1P-31, S1P-32, S1P-33, S1P-34, S1P-35, S1P-36, S1P-37, S1P-38, S1P-39, S1P-40, S1P-41, S1P-42, S1 35[S]-GTPγS (PerkinElmer, Waltham, MA, catalog no. NEG030X250UC) was added to the assay plate at 40 μL / well to a final concentration of 200 pM, and the plate was further incubated at room temperature for 40 minutes with gentle agitation. The assay was terminated by centrifugation of the plate (1000 rpm, 3 minutes) using an Eppendorf 5810R centrifuge (Eppendorf, Hamburg, Germany), and G protein-bound radioactivity was quantified using a MicroBeta2 microplate scintillation counter (PerkinElmer, Waltham, MA). This assay is an indicator of S1P5 agonism, as G protein-bound radioactivity directly correlates with receptor activation and binding to G proteins. The results are shown in Table 2. [Table 14] [Table 15]

[0447] The present invention has been described in some detail by way of illustration and example for ease of understanding, but the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, L is, 【Chemistry 2】 or a bond; X and Y are independently H, O, H ２ , or absent; 【Chemistry 3】 is a single, double, or triple bond; R １ is C ６ -C １０ aryl, a fused bicyclic 8-10 membered heteroaryl, or a fused bicyclic 8-10 membered heterocyclyl, each of which is optionally substituted with 1-5 R' groups, where the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; Each R' is independently halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C ６ is cycloalkyl; R ２ is H or C １ -C ６ is alkyl; R ３ is -(CH ２ ) ｘ -CO ２ H or 【Chemistry 4】 Is it; Or, R ２ and R ３ The dashed line between ２ and R ３ together with the nitrogen atom to which they are attached, 1 to 5 R ４ represents a ring structure forming a 4- to 6-membered heterocyclyl substituted with a group, wherein at least one R ４ The group is —CO ２ H or -CO ２ comprising an H moiety; x is 1 to 5; Each R ４ are independently -CO ２ H, halo, or C １ -C ６ Is it an alkyl group? Or two R's ４ The groups, together with the carbon atoms to which they are attached, are represented by -CO ２ fused, bridged, or spiro C optionally substituted with H; ３ -C ５ forming a cycloalkyl group. or a pharma- ceutically acceptable salt thereof.

2. L, 【Chemistry 5】 2. The compound of claim 1, wherein:

3. L is -C≡C-, -HC=CH-, or -CH ２ CH ２ 3. The compound of claim 2, wherein: -, or a pharma- ceutically acceptable salt thereof.

4. L is -C(O)-CH ２ - or -CH ２ The compound of claim 2, which is -C(O)-, or a pharma- ceutically acceptable salt thereof.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

6. R １ is phenyl, phenyl fused to a cycloalkyl, a fused bicyclic 9-membered heteroaryl, or a fused bicyclic 9-membered heterocyclyl, each of which is optionally substituted with 1-3 R′ groups, wherein the heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen; 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. Each R' is independently halo, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, or C ３ -C ６ is cycloalkyl, 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. Each R' is independently Cl, F, methyl, ethyl, isopropyl, -CF ３ , -OCH ３ or cyclopropyl; 8. The compound of claim 7, or a pharma- ceutically acceptable salt thereof.

9. R １ but, 【Chemistry 6】 That is, The compound according to any one of claims 6 to 8, or a pharma- ceutically acceptable salt thereof.

10. R ２ is H or C １ -C ３ is alkyl; R ３ But -(CH ２ ) ｘ -CO ２ H or 【Chemistry 7】 and x is 1 to 3; 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

11. R ２ is H or methyl; R ３ But -CH ２ CO ２ H, -(CH ２ ) ２ CO ２ H, -(CH ２ ) ３ CO ２ H, or 【Chemistry 8】 That is, 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof.

12. 【Chemical 9】 but, 【Chemistry 10】 That is, 12. The compound of claim 11, or a pharma- ceutically acceptable salt thereof.

13. R ２ and R ３ together with the nitrogen atom to which they are attached, 1 to 3 R ４ 4 to 6 membered heterocyclyl substituted with a group, wherein at least one R ４ The group is —CO ２ H or -CO ２ Contains the H moiety, 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

14. R ２ and R ３ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl, each of which is represented by one to three R ４ group, where at least one R ４ The group is —CO ２ H or -CO ２ Contains the H moiety, 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof.

15. Each R ４ are independently -CO ２ H, halo, or C １ -C ３ Is it an alkyl group? Or two R's ４ When the groups, together with the carbon atoms to which they are attached, are —CO ２ fused, bridged, or spiro C optionally substituted with H; ３ -C ５ Forming a cycloalkyl, Here, at least one R ４ The group is —CO ２ H or -CO ２ Contains the H moiety, 15. The compound according to any one of claims 1 to 9, 13 and 14, or a pharma- ceutically acceptable salt thereof.

16. Each R ４ are independently -CO ２ H, F, or methyl; Or two R's ４ When the radicals, together with the carbon atoms to which they are attached, form a fused cyclopropyl, spirocyclopropyl, spirocyclobutyl, or bridged cyclopentyl, each of which is represented by -CO ２ optionally substituted with H; Here, at least one R ４ The group is —CO ２ H or -CO ２ Contains the H moiety, 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof.

17. 【Chemical 11】 but, 【Chemistry 12】 That is, 17. The compound according to any one of claims 1 to 9 and 13 to 16, or a pharma- ceutically acceptable salt thereof.

18. The compound has the formula (II): 【Chemistry 13】 18. The compound according to any one of claims 1 to 9 and 13 to 17, which is a compound of the formula: or a pharma- ceutically acceptable salt thereof.

19. The compound has the formula (IIIa) or (IIIb): 【Chemistry 14】 13. The compound according to any one of claims 1 to 12, which is a compound of the formula: or a pharma- ceutically acceptable salt thereof.

20. A compound selected from compounds 1 to 45 set forth in Table 1 below, or a pharma- ceutically 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】

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

22. 21. An agent for modulating sphingosine 1-phosphate receptor 5 (S1P5), comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

23. A drug for treating a neurological disease, comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

24. The method of claim 23, wherein the neurological disease is Alzheimer's disease or multiple sclerosis.

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