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

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 with related applications This application claims priority to U.S. Provisional Application No. 63 / 130,023, filed on 23 December 2020, which is incorporated herein by reference in its entirety as appropriate.

[0002] field This disclosure relates, in general, to compounds, compositions, and methods for preparing them, as well as to the use of compounds and compositions for treating neurodegenerative diseases. [Background technology]

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadeca-4-enyl-1-phosphate) is a bioactive sphingolipid synthesized by the turnover of sphingolipids in cells and by the extracellular action of secreted sphingosine kinases. S1P binds to and stimulates members of the endothelial cell differentiation gene family (EDG receptors), which are cell 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 a variety of cellular responses, including proliferation, cytoskeleton formation and migration, adhesion and tight junction assembly, and morphogenesis.

[0004] S1P5 is primarily expressed in the central nervous system. Specifically, S1P5 is highly expressed in oligodendrocytes (oligodendrocytes) and oligodendrocyte progenitor 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 nerve cells. Compounds that bind to S1P5 may modulate S1P5 function and may be useful in the treatment of neurodegenerative diseases.

[0005] Accordingly, in one embodiment, compounds that modulate S1P5 for use in the treatment of neurodegenerative diseases are provided herein. [Overview of the project]

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

[0007] This embodiment can be better understood by referring to embodiments and examples for carrying out the invention, which are intended to be typical examples of non-limiting embodiments.

[0008] Typical embodiments include the following:

[0009] Embodiment 1. In some embodiments, formula (I): [ka] [In the formula, L is [ka] or combination; X and Y are independently H, O, H2, or absent; [ka] It is a single, double, or triple bond; R1 is C6-C 10 An aryl, a fused bicyclic 8-10 membered heteroaryl, or a fused bicyclic 8-10 membered heterocyclil, each of which may be appropriately substituted with 1-5 R' groups, where the heterocyclil and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; Each R' is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R2 is either H or a C1-C6 alkyl group; 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, along with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline substituted with 1-5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety; x is between 1 and 5; Each R4 is independently -CO2H, halo, or C1-C6 alkyl. Alternatively, the two R4 groups, together with the carbon atom to which they are bonded, may form a condensation, crosslink, or spiro-C3-C5 cycloalkyl group, which may be appropriately substituted with -CO2H. Compounds thereof or pharmaceutically acceptable salts thereof are provided herein.

[0010] Embodiment 2. L, [ka] That is, The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

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

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

[0013] Embodiment 5. L is a bond. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0014] Embodiment 6. R1 is a phenyl, a phenyl condensed with a cycloalkyl group, a condensed bicyclic 9-membered heteroaryl, or a condensed bicyclic 9-membered heterocyclil, each of which may be appropriately substituted with 1 to 3 R' groups, where the heterocyclil and heteroaryl contain 1 to 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 a 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 described in Embodiment 7, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 9. R1 is [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 either H or a C1-C3 alkyl group; R3 is -(CH2) x -CO2H or [ka] and; x is between 1 and 3. A compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof.

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

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

[0021] Embodiment 13. R2 and R3, together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline substituted with 1-3 R4 groups, where 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 bonded, form azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with 1 to 3 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety. The compound described in Embodiment 13, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 15. Each R4 is independently -CO2H, halo, or C1-C3 alkyl. Alternatively, two R4 groups, together with the carbon atom to which they are bonded, may form a condensation, crosslink, or spiro-C3-C5 cycloalkyl group, which may be appropriately substituted with -CO2H. Here, at least one R4 group is -CO2H or contains a -CO2H moiety. A compound according to any one of embodiments 1 to 9, 13, and 14.

[0024] Embodiment 16. Each R4 is independently -CO2H, F, or methyl. Alternatively, two R4 groups, together with the carbon atoms to which they are bonded, form condensed cyclopropyl, spirocyclopropyl, spirocyclobutyl, or crosslinked cyclopentyl, which may each be appropriately substituted with -CO2H. Here, at least one R4 group is -CO2H or contains a -CO2H moiety. The compound described in 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 aforementioned compound is of formula (II): [ka] A compound of any one of embodiments 1-9 and 13-17, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 19. The compound is of formula (IIIa) or (IIIb): [ka] A compound of which is one of the compounds described in any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof.

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

[0029] Embodiment 21. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0030] Embodiment 22. A method for modifying sphingosine 1-phosphate receptor 5 (S1P5), characterized by contacting S1P5 with an effective amount of a compound described in any one of Embodiments 1 to 20, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 21.

[0031] Embodiment 23. A method for treating a neurological disorder in a subject requiring treatment, characterized by administering to the subject an effective amount of a compound described in any one of Embodiments 1 to 20, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 21.

[0032] Embodiment 24. The method according to Embodiment 23, wherein the neurological disease is Alzheimer's disease or multiple sclerosis. [Modes for carrying out 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 a described feature or component as mentioned, but not as excluding the presence or addition of one or more features or 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 instead 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 comprises at least 90%, 95%, 97%, 98%, or 99% of the described features or components that make it so. In another embodiment, the term "consisting of" excludes from any subsequent enumeration any other features or components that are not essential to the technical effect to be achieved.

[0035] As used herein, the term “or” should be interpreted as a compatible “or” meaning either one or any combination thereof. 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 arise only when the combination of elements, functions, steps, or actions is in any way inherently mutually exclusive.

[0036] In this specification, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the range described, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise specified. Similarly, any numerical ranges listed herein relating to any physical characteristics (e.g., polymer subunits, size, or thickness) should be understood to include any integer within the range listed, 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] The "alkyl" group consists of 1 to 10 carbon atoms (C1-C 10Alkyls are saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbons having typically 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 2 to 6 carbon atoms (C2-C6 alkyl). In some embodiments, alkyls are saturated alkyl groups. Typical saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, -tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, alkyl groups are unsaturated alkyl groups, also called alkenyl or alkynyl groups. 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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). Alkyl groups can be substituted or unsubstituted.Where an alkyl group described herein is referred to as “substituted,” it means any substituent as found in the representative compounds and embodiments disclosed herein, as well as halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylal Killamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imide; 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; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or may be substituted with -B(OH)2.In certain embodiments, where an alkyl group described herein is said to be “substituted,” it may be substituted with any substituent as found in the representative compounds and embodiments disclosed herein, as well as halogens (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] The "cycloalkyl" group is a monocyclic ring or a group of fused or crosslinked rings, which may be substituted as appropriate, and consists of 3 to 10 carbon atoms (C3-C 10is a saturated or partially saturated cyclic alkyl group of (cycloalkyl). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, by way of example, monocyclic structures (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like), or bicyclic 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, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl group can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0039] The "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms (C6-C 14 aryl) having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group has 6 to 14 carbons (C6-C 14 aryl), in other embodiments, 6 to 12 (C6-C 12 aryl) or 6 to 10 carbon atoms (C6-C 10The group contains an aryl group in its ring portion. Specific aryl groups include phenyl, biphenyl, naphthyl, and similar groups. The aryl group can be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and similar groups).

[0040] "Halogen" or "halo" refers to 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, such as 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 (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo radicals (C1-C3 haloalkyl). The halo radicals may be exactly the same or they may be different. Unless expressly otherwise specified, the haloalkyl group may be substituted as appropriate.

[0042] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in a heteroaromatic ring system, where the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms in the ring portion of the group, and in other embodiments, 6 to 9 or 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-restrictive examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridadinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl (e.g., indolyl-2-onyl or isoindoline-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., a Examples of heteroaryl groups include, but are not limited to, the groups (zabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]xazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinoline-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be substituted or unsubstituted.

[0043] A "heterocyclyl" is a non-aromatic cycloalkyl group in which 1 to 4 of the ring carbon atoms are independently substituted with heteroatoms 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. Heterocyclyls may also be bonded to other groups at any ring atom (i.e., at any carbon or heteroatom of the heterocyclic ring). Heterocycloalkyl groups may be substituted or unsubstituted. Heterocyclyl groups encompass 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 condensed into an aryl or heteroaryl ring, regardless of its bond to the rest of the molecule. The phrase also includes bridging polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]phenoxathiinyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or multiple substituted (for example, pyridyl or morpholinyl groups that are two, three, four, five, or six-substituted, or two-substituted, by various substituents such as those described below, but are not limited to these).

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

[0045] The "carboxyl" group is a radical with the formula: -C(O)OH.

[0046] Where a group described herein (except alkyl groups) is said to be “substituted,” it may be substituted with any suitable substituent. Examples of substituents include those found in the representative compounds and embodiments disclosed herein, as well as halogens (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)2, O(alkyl)aminocarbonyl; monocyclic or condensed or These include cycloalkyls (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be non-condensed polycyclic; heterocyclyls (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiadinyl), which may be monocyclic or condensed or non-condensed polycyclic; monocyclic or condensed or non-condensed polycyclic aryl or heteroaryls (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanil, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridadinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranil) aryloxys; aralkyloxys; heterocyclyloxys; and heterocyclylalkoxys.

[0047] Embodiments of this disclosure are intended to encompass pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers of compounds provided herein (e.g., compounds of formula (I)).

[0048] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, such as inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of a compound of formula (I) include, but are not limited to, metal 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, ethensulfonic acid, formic acid, fumaric acid, furic 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, mucinic 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 salts, formate salts, and mesylate salts. Other examples are well known in the art, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th See eds., Mack Publishing, Easton PA (1995).

[0049] Unless otherwise specified, the terms “stereoisomer” or “stereoisomerically pure” as used herein mean one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains about 80% by weight of one stereoisomer of that compound and less than about 20% by weight of other stereoisomers of that compound, or about 90% by weight of one stereoisomer of that compound and less than about 10% by weight of other stereoisomers of that compound, or about 95% by weight of one stereoisomer of that compound and less than about 5% by weight of other stereoisomers of that compound, or about 97% by weight of one stereoisomer of that 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 stereoisomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equimolar or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques (e.g., chiral columns or chiral resolution 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); and 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 compound is isolated as either the E or Z isomer. In other embodiments, the compound is a mixture of the 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 differ depending on whether the compound is a solid or in an organic solution 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 apparent to those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compound of formula (I) are within the scope of this disclosure.

[0054] It should also be noted that the compounds disclosed herein may contain atomic isotopes in unnatural proportions of one or more atoms. For example, a compound may contain radioactive isotopes (e.g., tritium). 3 H), Iodine-125 ( 125 I), Sulfur 35 ( 35 S), or carbon-14 ( 14 C) may be radioactively labeled, or deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen 15( 15Isotope enrichment may occur with N, etc. As used herein, “isotopologs” are isotope-enriched compounds. The term “isotopologs” refers to atoms that have an isotope composition other than the natural isotope composition of that atom. “Isotope-enriched” may also refer to compounds that contain at least one atom that has an isotope composition other than the natural isotope composition of that atom. The term “isotopologs” refers to the amount of each isotope present for a given atom. Radiolabeled and isotope-enriched compounds are useful as therapeutic agents, e.g., cancer treatments, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo contrast agents. All isotope variations of the compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologs of the compounds disclosed herein are provided, for example, isotopologs are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, “deuterated” refers to at least one hydrogen (H) that has deuterium (D or 2 A compound substituted with (represented by H) means that the compound is concentrated with deuterium at at least one position.

[0055] It is understood that, regardless of stereoisomer or isotopic composition, each compound disclosed herein may be provided in any form of the pharmaceutically acceptable salts described herein. Similarly, it is understood that the isotopic composition may vary independently of the stereoisomer composition of each compound referred to herein. Furthermore, although the isotopic composition is limited to the elements present in each compound or its salt disclosed herein, it may otherwise vary independently of the selection of a pharmaceutically acceptable salt of each compound.

[0056] Please note that if there is a discrepancy between the depicted structure and its name, the depicted structure should be given more weight.

[0057] As used herein, “to treat” means to alleviate, in whole or in part, one or more of the symptoms of a disorder, disease or condition, or a disorder, disease or condition, or symptoms associated with such a disorder, disease or condition, or to slow or halt the further progression or worsening of those symptoms, or to reduce or eliminate the cause of the disorder, disease or condition itself. In one embodiment, the disorder is a neurodegenerative disease or its symptoms as described herein.

[0058] As used herein, “prevent” means a method of delaying, and / or preventing, in whole or in part, the onset, recurrence, or progression of a disorder, disease, or condition; a method of preventing a subject from contracting a disorder, disease, or condition; or a method of reducing the risk to a subject from contracting a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or its symptoms as described herein.

[0059] The term “effective amount” in relation to the compounds disclosed herein means an amount that can treat or prevent the disorder, disease or condition, or symptoms thereof, disclosed herein.

[0060] As used herein, the terms “subject” or “patient” include, but are not limited to, animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs; in one embodiment, mammals; and in another embodiment, humans. In one embodiment, the subject is a human being who has or is at risk of having an S1P5-mediated disease or its symptoms.

[0061] Various features of the present invention may be described in the context of a single embodiment, but features may also be provided separately or in any suitable combination. Conversely, the present invention may be described herein in the context of separate embodiments for clarity, but the present invention may also be implemented in a single embodiment.

[0062] compound In one embodiment, equation (I): [ka] [In the formula, L is [ka] or combination; X and Y are independently H, O, H2, or absent; [ka] It is a single, double, or triple bond; R1 is C6-C 10 An aryl, a fused bicyclic 8-10 membered heteroaryl, or a fused bicyclic 8-10 membered heterocyclil, each of which may be appropriately substituted with 1-5 R' groups, where the heterocyclil and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; Each R' is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R2 is either H or a C1-C6 alkyl group; 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, along with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline substituted with 1-5 R4 groups, where at least one R4 group is -CO2H or contains a -CO2H moiety; x is between 1 and 5; Each R4 is independently -CO2H, halo, or C1-C6 alkyl. Alternatively, the two R4 groups, together with the carbon atom to which they are bonded, may form a condensation, crosslink, or spiro-C3-C5 cycloalkyl group, which may be appropriately substituted with -CO2H. Compounds thereof or pharmaceutically acceptable salts thereof are provided herein.

[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] It is a single bond. In some embodiments, [ka] It is a double bond. In some embodiments, [ka] It is a triple bond. In some embodiments, both Y and X are absent. [ka] It is a triple bond, and L is -C≡C-. In some embodiments, Y and X are both H. [ka] It is a double bond, and L is -HC=CH-. In some embodiments, Y and X are both H2. [ka] The bond 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, and X is H2. [ka] It is a single bond, and L is -C(O)-CH2-. In some embodiments, X is H2 and Y is O. [ka] L 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, R1 is C6-C 10 An aryl, a fused bicyclic 8-10 membered heteroaryl, or a fused bicyclic 8-10 membered heterocyclil, each of which may be appropriately substituted with 1-5 R' groups, where the heterocyclil and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R1 is a C6-C which may be appropriately substituted with 1-3 R' groups. 10It is an aryl compound. In some embodiments, R1 is a fused bicyclic 8-10 member heteroaryl compound comprising 1-3 heteroatoms selected from nitrogen and oxygen, which may be appropriately substituted with 1-5 R' groups. In some embodiments, R1 is a fused bicyclic 8-10 member heterocyclil compound comprising 1-3 heteroatoms selected from nitrogen and oxygen, which may be appropriately 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 R' groups. In some variations, R1 is substituted with 2 R' groups. In some embodiments, R1 is bonded to substituent L via the aryl moiety, for example, via a phenyl group.

[0066] In some embodiments, R1 is a phenyl, a cycloalkyl-condensed phenyl, a condensed bicyclic 9-membered heteroaryl, or a condensed bicyclic 9-membered heterocyclil, each of which may be appropriately substituted with 1 to 3 R' groups, where the heterocyclil and heteroaryl contain 1 to 2 heteroatoms selected from nitrogen and oxygen.

[0067] In some embodiments, R1 is a phenyl which may be appropriately substituted with 1 to 3 R' groups. In some embodiments, R1 is a phenyl condensed with a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) which may be appropriately substituted with 1 to 3 R' groups. In some embodiments, R1 is a phenyl condensed with cyclohexyl.

[0068] In some embodiments, R1 is a condensed bicyclic nine-membered heteroaryl compound comprising one to two heteroatoms selected from nitrogen and oxygen, which may be appropriately substituted with one to three R' groups. In some embodiments, R1 is a condensed bicyclic nine-membered heteroaryl compound comprising one nitrogen atom and one oxygen atom, which may be appropriately substituted with one to three R' groups. In some embodiments, R1 is a condensed bicyclic nine-membered heteroaryl compound comprising two nitrogen atoms, which may be appropriately substituted with one to three R' groups. In some embodiments, R1 is a condensed bicyclic nine-membered heteroaryl compound comprising one nitrogen atom, which may be appropriately substituted with one to three R' groups.

[0069] In some embodiments, R1 is a condensed bicyclic 9-membered heterocycline comprising 1 to 2 heteroatoms selected from nitrogen and oxygen, which may be appropriately substituted with 1 to 3 R' groups. In some embodiments, R1 is a condensed bicyclic 9-membered heterocycline comprising 1 oxygen atom, which may be appropriately substituted with 1 to 3 R' groups. In some embodiments, R1 is a condensed bicyclic 9-membered heterocycline comprising 1 nitrogen atom, which may be appropriately substituted with 1 to 3 R' groups. In some embodiments, R1 is a condensed bicyclic 9-membered heterocycline comprising 1 nitrogen atom and 1 oxygen atom, which may be appropriately substituted with 1 to 3 R' groups.

[0070] In some embodiments, each R' is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. In some embodiments, each R' is independently a halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl. In some embodiments, each R' is independently Cl, F, methyl, ethyl, isopropyl, -CF3, -OCH3, or cyclopropyl.

[0071] In some embodiments, R' is a 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 a C1-C6 alkyl group. In some embodiments, R' is a C1-C3 alkyl group. 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 a C1-C6 haloalkyl. In some embodiments, R' is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R' is a C1-C3 haloalkyl. In some embodiments, R' is a 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 a C1-C6 alkoxy. In some embodiments, R' is a 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 a C3-C6 cycloalkyl group. In some embodiments, R' is a C3-C5 cycloalkyl group. 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, R1 is [ka] In the formula, the fused ring structure is a C3-C6 cycloalkyl, a 4-6 membered heterocyclyl, or a 4-6 membered heteroaryl.

[0077] In some embodiments, R1 is [ka] That is the case.

[0078] In some embodiments, R2 is H or a C1-C6 alkyl group. In some embodiments, R2 is H. In some embodiments, R2 is a C1-C6 alkyl group. In some embodiments, R2 is a C1-C3 alkyl group. 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] In the formula, 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 It 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] In the formula, x is 1 to 5. In some embodiments, R3 is [ka] In the formula, x is 1 to 3. In some embodiments, R3 is [ka] That is the case.

[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] That is the case.

[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] That is the case.

[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 bound, form a 4-6 membered heterocycline 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 bound, form a 4-6 membered heterocycline 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 bound, form a 4-6 membered heterocycline 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 bound, form a 4-6 membered heterocycline that does not contain any further heteroatoms, where the heterocycline is 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 bound, form a four-membered heterocycline substituted with 1 to 5 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 bound, form a five-membered heterocycline substituted with 1 to 5 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 bound, form a six-membered heterocycline substituted with 1 to 5 R4 groups, where at least one R4 group is -CO2H or includes a -CO2H moiety.

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

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

[0086] In any embodiment or variation of formula (I) described herein, at least one R4 group is either -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 R4 groups, together with the carbon atom to which they are bonded, form a condensed, crosslinked, or spiro-C3-C5 cycloalkyl group, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form a condensed C3-C5 cycloalkyl group, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form a crosslinked C3-C5 cycloalkyl group, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form a spiro-C3-C5 cycloalkyl group, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form an unsubstituted condensed, crosslinked, or spiro-C3-C5 cycloalkyl group. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form a condensed, crosslinked, or spiro-C3-C5 cycloalkyl group, which may be optionally substituted with -CO2H.

[0089] In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form condensed cyclopropyl, spirocyclopropyl, spirocyclobutyl, or crosslinked cyclopentyl, each of which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form condensed cyclopropyl, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form spirocyclopropyl, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form spirocyclobutyl, which may be optionally substituted with -CO2H. In some embodiments, two R4 groups, together with the carbon atom to which they are bonded, form crosslinked cyclopentyl, which may be optionally substituted with -CO2H.

[0090] In some embodiments, [ka] teeth, [ka] That is the case.

[0091] In some embodiments, the compound of formula (I) is formula (IA): [ka] [In the formula, R', R2, R3, and L are as described for formula (I)] It is a compound of [the compound].

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

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

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

[0096] In some embodiments, the compound of formula (I) is of formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf): [Chemical formula] [In the formula, R1 and R4 are as described for formula (I), [ka] [This indicates either the cis or trans direction.] It is a compound of [the compound].

[0097] In some embodiments, the compound of formula (I) is (VIa), (VIb), (VIc), (VId), (VIe), or (VIf): [ka] [In the formula, R1 is as described for formula (I); R2 is H or C1-C6 alkyl; R3 is -(CH2) x -CO2H or [ka] x is 1 to 5; [ka] [This indicates either the cis or trans direction.] It is a compound of [the compound]. In this specification, any description, variation, embodiment, or aspect of a part may be combined with any description, variation, embodiment, or aspect of any other part, and it is understood that any combination of descriptions is the same as if it were described specifically and individually. For example, any description, variation, embodiment, or aspect provided herein with respect to L of formula (I) is X, Y, [ka] Any description, variation, embodiment, or aspect of R1, R’, R2, R3, R4, and x may be combined, and every combination is the same as if specifically and individually recited. All descriptions, variations, embodiments, or aspects of formula (I) are, where applicable, equally applicable to, and described in the same manner as, other formulas detailed herein, and it is also understood that every description, variation, embodiment, or aspect is the same as if separately and individually recited for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) are, where applicable, equally applicable to, and described in the same manner as, any of the formulas (such as formula (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.) detailed herein, and every description, variation, embodiment, or aspect is the same as if separately and individually recited for all formulas.

[0098] In some embodiments, compounds selected from the compounds described in Table 1 or pharmaceutically acceptable salts thereof are provided. The specific compounds described in this disclosure including Table 1 are presented as specific stereoisomers and / or in non-stereochemical forms, but it is understood that any and all stereochemical forms (such as any enantiomers or diastereomers) of any of the compounds of this disclosure including Table 1, and any tautomers or other forms are described herein. [[ID=​​​​​​​​​​​​​​​​​​ [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] In this specification, it is understood that combinations of substituents and / or variables in the formulas depicted are permissible only if such contributions result in a stable compound.

[0100] Furthermore, all compounds of formula (I) existing in the form of free bases or acids can be converted to their pharmaceutically acceptable salts by treatment with suitable inorganic or organic bases or acids using methods known to those skilled in the art. Salts of compounds of formula (I) can be converted to their free base or acid forms by standard techniques.

[0101] Synthesis method The compounds described herein may be prepared using conventional organic synthesis and commercially available starting materials, or by methods provided herein. For example, but not limited to, the compound of formula (I) may 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 exemplary schemes and examples to obtain the desired compounds. [ka]

[0102] As outlined in Scheme 1, the compound of general formula A can be synthesized from 5-bromo-2,3-dihydro-1H-inden-1-one (intermediate compound I) via Sonogashira coupling with alkyne II, followed by reductive amination with amino acid ester III and subsequent hydrolysis. Alternatively, the compound of general formula A can be obtained by reducing the ketone intermediate to an alcohol, converting it to a chloride, reacting it with amino acid ester III, and hydrolyzing it.

[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] The biaryl compounds of general formula C can be synthesized from intermediate compound I 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 boronate, coupled with aryl bromide V, and hydrolyzed to obtain the compound of general formula C.

[0105] How to use Embodiments of this disclosure provide a method for modulating sphingosine 1-phosphate receptor 5 (S1P5) in a subject requiring treatment, characterized by administering an effective amount of a compound of formula (I) to the subject. 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 embodiment, a method for modulating S1P5 is provided herein, characterized by contacting S1P5 with an effective amount of the 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, the compound of formula (I) modulates 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) reduces the activity of S1P5 to approximately 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 to 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 embodiment, a method for treating a neurological disorder in a subject requiring treatment is provided herein, characterized by administering an effective amount of a compound of formula (I) to the subject. In some embodiments, a method for preventing a neurological disorder in a subject requiring prevention is provided herein, characterized by administering an effective amount of a compound of formula (I) to the subject. 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, administration of a compound of formula (I) to subjects susceptible to neurological disorders prevents the subjects from developing any symptoms of neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects that do not yet show symptoms of neurological disorders prevents the subjects from developing any symptoms of neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment reduces the severity of neurological disorders in the subjects. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment stabilizes neurological disorders (prevents or delays their worsening). In some embodiments, administration of a compound of formula (I) to subjects in need of treatment delays the onset or recurrence of neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment slows the progression of neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment provides partial remission of neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment provides complete remission of neurological disorders. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the dose of one or more other drugs required to treat the neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment enhances the effect of another drug used to treat the neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment slows the progression of the neurological disorder. In some embodiments, administration of 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, administration of a compound of formula (I) to a subject in need of treatment extends the survival time of a subject with a neurological disorder.

[0110] In one embodiment, a method is provided herein for preventing a subject susceptible to neurological disorders from developing any symptoms of any neurological disorder, characterized by administering a compound of formula (I) to the subject. In several embodiments, a method is provided herein for preventing a subject that does not yet show symptoms of any neurological disorder from developing any symptoms of any neurological disorder, characterized by administering a compound of formula (I) to the subject.

[0111] In some embodiments, a method for reducing the severity of a neurological disorder in a subject is provided herein, characterized by administering a compound of formula (I) to the subject. In some embodiments, a method for stabilizing a neurological disorder in a subject is provided herein, characterized by administering a compound of formula (I) to the subject. In some embodiments, the method prevents the worsening of the neurological disorder. In some embodiments, the method delays the worsening of the neurological disorder.

[0112] In another embodiment, the present invention provides a method for delaying the onset or recurrence of a neurological disorder in a subject, characterized by administering a compound of formula (I) to the subject.

[0113] In some embodiments, a method for slowing the progression of a neurological disease in a subject is provided herein, characterized by administering a compound of formula (I) to the subject. In some embodiments, the method provides partial remission of the neurological disease. In some embodiments, the method provides complete remission of the neurological disease.

[0114] In a further embodiment, a method for reducing the dose of one or more other drugs necessary to treat a neurological disorder in a subject is provided herein, characterized by administering a compound of formula (I) to the subject. In some embodiments, a method for enhancing the effect of another drug used to treat a neurological disorder in a subject is provided herein, characterized by administering a compound of formula (I) to the subject.

[0115] A method for delaying the progression of a neurological disease in a subject, characterized by administering a compound of formula (I) to the subject, is also provided herein. In some embodiments, the method improves the quality of life of a subject with a neurological disease. In some embodiments, the method extends the survival period of a subject with a neurological disease.

[0116] In another embodiment, the present invention provides a method for treating neurological symptoms caused by a disease in a subject requiring treatment, characterized by administering an effective amount of the compound of formula (I) to the subject. In some embodiments, the present invention provides a method for preventing neurological symptoms caused by a disease in a subject requiring prevention, characterized by administering an effective amount of the compound of formula (I) to the subject. In some embodiments, administration of the compound of formula (I) to a subject susceptible to a disease causing neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administration of the compound of formula (I) to a subject that has not yet shown neurological symptoms of a disease causing neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administration of the compound of formula (I) to a subject requiring treatment reduces the degree of neurological symptoms caused by the disease in the subject. In some embodiments, administration of the compound of formula (I) to a subject requiring treatment stabilizes the neurological symptoms of the disease (prevents or delays the worsening of neurological symptoms). In some embodiments, administration of the compound of formula (I) to a subject requiring treatment delays the onset or recurrence of neurological symptoms caused by the disease. In some embodiments, administration of 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, administration of a compound of formula (I) to a subject in need of treatment provides partial remission of a neurologically symptomatic disease. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment provides complete remission of a neurologically symptomatic disease. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the dose of one or more other drugs required to treat a neurologically symptomatic disease. In some embodiments, administration of 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, administration of a compound of formula (I) to a subject in need of treatment delays the progression of a neurologically symptomatic disease.In some embodiments, administration of a compound of formula (I) to subjects in need of treatment improves the quality of life of subjects with neurological disorders. In some embodiments, administration of a compound of formula (I) to subjects in need of treatment extends the survival time of subjects with neurological disorders. In some embodiments, the disorder is Niemann-Pick disease.

[0117] In some embodiments, compounds of formula (I) are used to treat Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis, scleroderma, graft-versus-host disease, transplanted organ rejection (but not limited to bone marrow and parenchymal organ rejection), acute or chronic immune diseases 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, sepsis syndrome, and other conditions. Hexy, infections, parasitic diseases, acute transverse myelitis, Huntington's disease, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, sporadic polyglandular dysfunction type I and polyglandular dysfunction type II, Schmidt syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitis, enteritis synovitis, chlamydia, Yersinia and monkey Monera-associated arthropathy, atherosclerosis / arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, bullous 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 disorders, hepatitis B, hepatitis C, unclassified immunodeficiency Diseases (unclassifiable hypogammaglobulinemia), dilated cardiomyopathy, infertility, female infertility, ovarian dysfunction, premature ovarian failure, fibrous 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 Sjögren's disease,Lung disease associated with ankylosing spondylitis, diffuse vasculitic lung disease, lung disease associated with hemosiderin deposition, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyte infiltrative lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease due to organ transplantation, chronic immune disease due to organ transplantation, osteoarthritis, primary sclerosing bile ductus Vasculitis, type 1 psoriasis, type 2 psoriasis, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility due to idiopathic or NOS, sperm autoimmune, multiple sclerosis (all subtypes), sympathetic ophthalmitis, secondary pulmonary hypertension due to connective tissue disease, Goodpasture syndrome, pulmonary symptoms of polyarteritis nodosa, acute rheumatic fever, rheumatic spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis / arteritis, autoimmune Thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goiterous 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 injury, cholestasis, idiopathic liver disease, drug-induced hepatitis, non-alcoholic fatty liver disease, allergies and asthma, Group B Streptococcus (GBS) infection, mental 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), 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 antibody syndrome, antireceptor hypersensitivity reaction, aortic aneurysm and peripheral artery aneurysm, 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 lymphoma, burns, cardiac arrhythmias, cardiac stun Syndrome), cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammatory response, cartilage transplant rejection, cerebellar cortical degeneration, cerebellar diseases, disorganized 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 poisoning, 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, Boxer dementia, demyelinating diseases, dengue hemorrhagic fever, dermatitis, skin diseases, diabetes, diabetes (Mellitus), diabetic arteriosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglia disorders, middle-aged Down syndrome, drug-induced movement disorders induced by CNS dopamine receptor blockers, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrine disorders, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal disorders and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymic graft rejection, Friedreich's ataxia, functional peripheral artery disease, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, graft rejection of any organ or tissue, gram-negative bacterial sepsis, gram-positive bacterial sepsis, granuloma due to intracellular organisms, hairy cell leukemia, Haller-Vorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (type A), His bundle arrhythmias, HIV infection / HIV neuropathy, Hodgkin's disease,Hyperactivity, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypoactivity, hypothalamic-pituitary-adrenal axis assessment, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, aortitis, influenza A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's positivity Sarcoma, kidney graft rejection, Legionella, leishmaniasis, leprosy, corticospinal system lesions, fatty edema, liver graft rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcal bacteremia, metabolic / idiopathic, migraine, mitochondrial multiple system disease, mixed connective tissue disease, monoclonal immunoglobulinemia, multiple myeloma, multiple system degeneration (Mencel Dejerine-Thomas disease) 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, nephrotic syndrome, neurodegenerative diseases, neurogenic muscular atrophy, neutropenic fever, non-Hodgkin lymphoma, occlusion of the abdominal aorta and its branches, obstructive arterial disease, okt3 therapy, orchitis / epididymitis, orchitis / pi Puccat reconstruction, organ enlargement, osteoporosis, pancreatic graft rejection, pancreatic cancer, paraneoplastic syndrome / hypercalcemia associated with malignant tumors, parathyroid graft rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerosis, peripheral vascular disease, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuritis, organ enlargement, endocrine abnormalities, monoclonal immunoglobulinemia, and skin symptom syndrome), post-perfusion syndrome, post-pump syndrome (post Pump syndrome, post-MI cardiotomy syndrome, pre-eclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiotherapy, Raynaud's phenomenon and Raynaud's disease, Raynaud's disease, Refsum disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, senile chorea, Lewy body dementia, seronegative arthropathy, shock, sickle cell anemia,Allograft rejection, skin lesion syndrome, small intestine 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, transplantation, trauma / bleeding, type III hypersensitivity reaction, type IV hypersensitivity, unstable angina, uremia, urinary tract sepsis, 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, xenograft rejection of any organ or tissue, acute pain, age-related memory impairment (AAMI), anxiety and attention deficit disorder (disorder), global attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, central nervous system-related pain syndrome, central stroke pain, chemotherapy-induced neuropathy, agnosia and dysfunction in mental 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, Lewy body dementia, depression in Cushing's syndrome, CNS dysfunction associated with traumatic brain injury, disorders with memory impairment, dizziness, substance abuse, epilepsy, HIV sensory neuropathy, Huntington's disease, hyperalgesia such as 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 changes, motion sickness, multiple sclerosis pain, narcolepsy, the need for neovascularization due to skin graft angiogenesis and poor circulation, the need for neovascularization due to wound healing, neuropathic pain, neuropathy, neuropathy secondary to tumor infiltration, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, Parkinson's disease pain, pathological sleepiness, phantom limb pain, Pick's disease, polycystic ovary syndrome, post-traumatic stress disorder, postherpetic neuralgia, post-mastectomy pain, postoperative pain,It is useful in treating disorders selected from psychotic depression, schizoaffective disorder, seizures, senile dementia, septic 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 syndrome, treatment-resistant depression, trigeminal neuralgia, type II diabetes, vertigo, and vestibular disorders.

[0118] Pharmaceutical composition and route of administration The compounds provided herein may be administered orally, topically, or parenterally to a target in conventional formulations (e.g., capsules, microcapsules, tablets, granules, powders, lozenges, 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 target in conventional formulation forms (e.g., capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions). Suitable formulations may include 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 hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and lubricants (e.g., stearate). It can be prepared by commonly used methods using compounds such as magnesium, light anhydrous silicic acid, talc, or sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition may be at a level that produces the desired effect, for example, in unit doses for both oral and parenteral administration, from about 0.005 mg / kg (body weight of the subject) to about 10 mg / kg (body weight of the subject).

[0120] The dose of the compound of formula (I) to be administered to a subject can vary considerably and may depend on the judgment of the healthcare provider. Generally, the compounds disclosed herein can be administered one to four times a day at doses ranging from about 0.001 mg / kg (body weight of the subject) to about 10 mg / kg (body weight of the subject), although the above doses may be appropriately adjusted depending on the subject's age, weight, and medical condition, as well as the type of administration. In one embodiment, the dose is about 0.001 mg / kg (body weight of the subject) to about 5 mg / kg (body weight of the subject), about 0.01 mg / kg (body weight of the subject) to about 5 mg / kg (body weight of the subject), about 0.05 mg / kg (body weight of the subject) to about 1 mg / kg (body weight of the subject), about 0.1 mg / kg (body weight of the subject) to about 0.75 mg / kg (body weight of the subject), or about 0.25 mg / kg (body weight of the subject) to about 0.5 mg / kg (body weight of the subject). In one embodiment, one dose is given per day. In any given case, the amount of compound of formula (I) administered depends 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 subjects in doses ranging from about 0.01 mg / day to about 750 mg / day, from about 0.1 mg / day to about 375 mg / day, from about 0.1 mg / day to about 150 mg / day, from about 0.1 mg / day to about 75 mg / day, from about 0.1 mg / day to about 50 mg / day, from about 0.1 mg / day to about 25 mg / day, or from about 0.1 mg / day to about 10 mg / day.

[0122] In another embodiment, unit dose formulations comprising a compound of formula (I) in amounts of 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 are provided herein.

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

[0124] In another embodiment, unit dose formulations comprising a compound of formula (I) in amounts of 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 are provided herein.

[0125] The compound of formula (I) may be administered once, twice, three times, four times, or more times per day. In certain embodiments, doses of 100 mg or less are administered as a once-daily dose, and doses greater than 100 mg are administered twice daily in amounts equal to half of the total daily dose.

[0126] The compound of formula (I) may 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, transdermally, rectally, mucous membranes, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is at the discretion of the healthcare provider and may depend in part on the site of the medical condition.

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

[0129] In another embodiment, a composition comprising an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or vehicle is provided herein, wherein the pharmaceutically acceptable carrier or vehicle may include additives, diluents, 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, lozenges, suppositories, and suspensions, and the like. The compositions may be formulated to contain a daily dose, or a convenient portion of a daily dose, in dose units, 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. Generally, all compositions are prepared according to methods known in pharmacochemistry. Capsules may be prepared by mixing the compound of formula (I) with a suitable carrier or diluent and filling a capsule with an appropriate amount of the mixture. Common carriers and diluents include, but are not limited to, inert powders (e.g., various types of starch), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), wheat flour, and similar edible powders.

[0131] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations typically incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic rubbers 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 stearate 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 rubber. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, and sodium lauryl sulfate may be used. Tablets may be coated with sugars as flavoring and fillers, or with film-forming protective agents, to modify the tablet's solubility. Compositions may also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0133] When it is desirable 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 increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0134] The effects of the compound of formula (I) can be delayed or prolonged by appropriate formulations. 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 multiple different dissolution rates, and filling capsules with mixtures of pellets. Tablets or capsules can be coated with a membrane 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 emulsified vehicle, which allows for slow dispersion of the compound in serum. [Examples]

[0135] The following examples are presented as illustrations, not as limitations. The compounds were named using an automated name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of the chemical structures while supporting the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art may modify the procedures described in the examples to arrive at the desired compounds.

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

[0137] As used in some of the chemical structures provided in the following examples, the designation of a particular atom by "or1" indicates that the absolute stereochemistry of the indicated atom could not be determined.

[0138] The following abbreviations may be relevant to this application. Abbreviation ACN or MeCN: Acetonitrile AcOK: Potassium acetate aq.: water-based d:day DCM: Dichloromethane DEA: Diethanolamine DIPA: Diisopropylamine DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethyl sulfoxide EA or methoxy: ethyl acetate EDTA: Ethylenediaminetetraacetic acid ee: Enantiomer 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(diphenylphosphin)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: Trifuric 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)Cl2 (0 g, 0 mmol), and CuI (0 g, 0 mmol) was placed in DIPA (10 mL, 70.86 mmol) in a 100 mL round-bottom flask. The resulting solution was stirred at 60°C for 15 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with sodium carbonate and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE = 50%) to obtain the target 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), ZnCl2 (2M in 2-Me-THF, 0.33 mL, 0.660 mmol, 2.00 equiv.) was added. The resulting solution was stirred at room temperature for 5-10 minutes. Next, 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 added. The resulting mixture was stirred at 60°C for 16 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain 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·H2O (26 mg, 0.630 mmol, 3.00 equiv.) was stirred in THF (1.0 mL) and water (1.0 mL) at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and then concentrated under vacuum. 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 over 7 minutes, holding at 35% B for 3 minutes; 210 / 254 nm; RT: 9.68 min) to obtain 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] +Analytical 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), SOCl2 (392 mg, 3.298 mmol, 10.0 equiv.) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 6 hours. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden (120 mg, 94%) as 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), methyl 1,2,3,6-tetrahydropyridine-4-carboxylate (105 mg, 0.746 mmol, 2.00 equiv.) and K2CO3 (396 mg, 1.866 mmol, 5.00 equiv.) were added. The resulting mixture was stirred at 80°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was purified by flash column chromatography (PE / Âti, eluted at 4 / 1) to obtain 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-tetrahydropyridine-4-carboxylic acid [ka] In 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), LiOH·H2O (16 mg, 0.387 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at room temperature for 12 hours. LC-MS indicated that 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 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 over 7 minutes; 254 / 210 nm; RT: 6.55 min) to obtain 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] +Analytical 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 at 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B at 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), NaBH4 (151 mg, 3.980 mmol, 1.00 equiv) was added. The resulting mixture was stirred at room temperature for 45 minutes. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using PE:EA (6:1) to obtain 5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-ol (870 mg, 72%) as a solid. LC-MS (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), SOCl2 (1.4 mL, 19.980 mmol, 20.00 equiv) was added. The resulting mixture was stirred overnight at room temperature. The crude product was concentrated under reduced pressure to dryness to obtain 1-chloro-5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden (250 mg, 79%) as 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-fluoropiperidine-4-carboxylate [ka] In 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), ethyl 4-fluoropiperidine-4-carboxylate (273 mg, 1.560 mmol, 2.00 equiv) and K2CO3 (249 mg, 2.340 mmol, 3.00 equiv) were added. The resulting mixture was stirred at 60°C for 48 hours. LC-MS indicated that 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 obtain ethyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-indene-1-yl)-4-fluoropiperidine-4-carboxylate (220 mg, 61%). LCMS (ESI, m / z): 460 [M+H] +

[0152] Chiral separation [ka] A mixture of isomers (220 mg, 0.478 mmol) was purified by chiral HPLC (column: Chiralpak IE, 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 9 mins; 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 obtain 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] LiOH (16 mg, 0.660 mmol, 3.00 equiv) was added 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). The resulting mixture was stirred at room temperature for 1 hour. LC-MS indicated that 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, 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 mins; 254 / 210 nm; RT1: 5.98 min) to obtain 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 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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B at 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B at 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) was stirred at 80°C for 12 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain 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), ZnCl2 (1.9 M in 2-Me THF, 12.0 mL, 0.024 mol, 2.00 equiv), and NaBH3CN (2.26 g, 0.036 mol, 3.00 equiv) was stirred at 60°C for 12 hours in methanol (50 mL). LC-MS indicated that the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with DCM (3 x 80 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (DCM:MeOH=10:1) to obtain methyl 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (3.0 g, 67%) as 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] A racemic mixture (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 obtain chiral isomer 1 (800 mg, 27%, 100% ee) and isomer 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 hour. LC-MS indicated that 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 (eluting with water (0.05% HCl):ACN=2:1) ​​to obtain 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] +Analytical 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 over 2.0 min, retention 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 hour. LC-MS indicated that 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 (eluting with water (0.05% HCl):ACN=2:1) ​​to obtain 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] + Analytical 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 over 2.0 min, retention 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), NaBH4 (470 mg, 12.4 mmol, 1.00 equiv.) was added in several portions at 0°C. The reaction mixture was stirred at room temperature for 15 minutes. TLC indicated 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 obtain 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), SOCl2 (2.0 mL) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours. TLC indicated that the reaction was complete. The resulting solution was concentrated under reduced pressure to obtain the crude product 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden as 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] In 8.0 mL of MeCN, a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (400 mg, 1.48 mmol, 2.00 equiv.) and methyl 3,3-dimethylpiperidine-4-carboxylate (126 mg, 0.740 mmol, 1.00 equiv.) was added, to which K2CO3 (306 mg, 2.22 mmol, 3.00 equiv.) was added at room temperature. The resulting solution was stirred at 80°C for 14 hours. LC-MS indicated that 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 obtain 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·H2O (62 mg, 1.48 mmol, 5.00 equiv) was stirred at 80°C for 3 days in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that 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 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 over 7 minutes; 254 / 220 nm; RT: 6.67 min) to obtain 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] +Analytical 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 over 2.0 min, hold at 95% B for 0.7 min, 95% B to 2% B over 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), 5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-one (300 mg, 0.400 mmol, 1.0 equiv.), methylpiperidine-4-carboxylate (342 mg, 0.800 mmol, 2.0 equiv.), and ZnCl2 (2M in THF, 0.8 mL, 1.60 mmol, 4.0 equiv.) were added. The resulting solution was stirred at 60°C for 72 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (MeOH / DCM, elution at 1 / 15) to obtain 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 racemic mixture 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 over 24 minutes; 220 / 254 nm; RT1: 11.666 min; RT2: 18.917 min) to obtain the enantiomers as solids.

[0177] Synthesis of 1-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid [ka] LiOH (17 mg, 0.730 mmol, 3.0 equiv.) was added 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). The resulting solution was stirred at room temperature for 30 minutes. LC-MS indicated that 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 over 7 minutes; 210 / 254 nm; RT: 6.27 min) to obtain 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] + Analytical 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 over 3.0 min, hold at 95% B for 0.7 min, 95% B to 5% B over 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] LiOH (16.0 mg, 0.730 mmol, 2.00 equiv.) was added 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). The resulting solution was stirred at room temperature for 30 minutes. LC-MS indicated that 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 over 7 minutes; 210 / 254 nm; RT: 6.27 min) to obtain 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] +Analytical 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.), ZnCl2 (2M in THF, 2.0 mL, 4.00 mmol, 2.00 equiv.), and NaBH3CN (502 mg, 8.00 mmol, 4.00 equiv.) was stirred in methanol (5.0 mL) for 15 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The resulting solution was diluted with 10 mL of water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA = 10%) to obtain methyl (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-piperidine-3-carboxylate (200 mg, 26%) as 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 racemic mixture (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 minutes; 220 / 254 nm; RT1: 5.278 min; RT2: 6.92 min), and one chiral isomer (80 mg, 99% ee) was obtained as 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, 0.64 mmol, 3.00 equiv.) in THF (3.0 mL) and water (3.0 mL) was stirred at room temperature for 15 hours. LC-MS indicated that 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.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 46% B over 7 minutes; 254 / 210 nm; RT: 6.38 min) to obtain (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-fluorophenyl)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 mins; 220 / 254 nm; RT1: 5.278 min; RT2: 6.92 min) to obtain two chiral isomers (70 mg, 99% ee) as 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 hours. LC-MS indicated that 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.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 46% B over 7 minutes; 254 / 210 nm; RT: 6.38 min) to obtain (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] +Analytical 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] In 8.0 mL of MeCN, a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (750 mg, 2.770 mmol, 1.00 equiv.) and methyl (S)-piperidine-2-carboxylate (793 mg, 5.540 mmol, 2.00 equiv.) was added, to which K2CO3 (1.1 g, 8.310 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 80°C for 2 days. LC-MS indicated 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 obtain methyl (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene-1-yl)piperidine-2-carboxylate (190 mg, 18%) as 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 mins; 220 / 254 nm; Rt1: 4.995 min; Rt2: 6.813 min) to obtain 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 oil.

[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-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (enantiomer 1, 60 mg, 0.160 mmol, 1.00 equiv.) and LiOH·H2O (20 mg, 0.480 mmol, 3.00 equiv.) was stirred at 60°C for 3 days in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that 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 over 7 min; 254 / 210 nm; RT: 6.55 min) to obtain the corresponding enantiomer (8a, 14.9 mg, 25%) of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid 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] + Analytical 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 at 2.00 min, retention at 95% for 0.60 min, 95% B to 10% B at 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-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylate (enantiomer 2, 53 mg, 0.14 mmol, 1.00 equiv.) and LiOH·H2O (18 mg, 0.480 mmol, 3.00 equiv.) was stirred at 60°C for 3 days in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that 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 over 7 minutes; 254 / 210 nm; RT: 6.55 min) to obtain the corresponding enantiomer (8b, 12.8 mg, 25%) of (2S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid 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] + Analytical 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 at 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B at 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] In 8.0 mL of MeCN, a solution of 1-chloro-5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene (980 mg, 3.620 mmol, 1.00 equiv.) and methyl (R)-piperidine-2-carboxylate (1.04 g, 7.240 mmol, 2.00 equiv.) was added, to which K2CO3 (2.0 g, 10.860 mmol, 3.00 equiv.) was added. The resulting mixture was stirred at 80°C for 2 days. LC-MS indicated 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 obtain methyl (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-indene-1-yl)piperidine-2-carboxylate (379 mg, 28%) as 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 mins; 220 / 254 nm; RT1: 5.802 min; RT2: 7.402 min; injection volume: 0.8 ml; number of runs: 4) to obtain 126 mg of chiral isomer 1 and 133 mg of chiral isomer 2 as oil. 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.) and LiOH·H2O (40 mg, 0.990 mmol, 3.00 equiv.) was stirred at 60°C for 3 days in THF (2.0 mL) and water (2.0 mL). LC-MS indicated that 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 over 7 min; 254 / 210 nm; RT: 6.53 min) to obtain the corresponding enantiomer (9a, 36.5 mg, 30%) of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid 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] + Analytical 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 at 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B at 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.) and LiOH·H2O (40 mg, 1.050 mmol, 3.00 equiv.) was stirred at 60°C for 3 days in THF (2.0 mL) and water (2.0 mL). LC-MS indicated that 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 over 7 min; 254 / 210 nm; RT: 6.70 min) to obtain the corresponding enantiomer (9b, 5 mg, 3.8%) of (2R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-2-carboxylic acid 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] + Analytical 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 at 2.00 min, retention at 95% for 0.60 min, 95% B to 10% B at 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 NaBH3CN (113 mg, 1,800 mmol, 3.00 equiv.) and ZnCl2 (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. Then, 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 added. The resulting mixture was stirred at 60°C for 72 hours. LC-MS indicated that the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was purified by flash C18 silica column chromatography (water (5 mM NH4HCO3) / ACN, eluted at 20 / 80) to obtain 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-azabicyclo[3.2.1]-octane-8-carboxylic acid [ka] LiOH·H2O (19 mg, 0.450 mmol, 3.00 equiv.) was added 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). The reaction mixture was stirred at 80°C for 48 hours. LC-MS indicated that 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 C18 flash column chromatography (water (5 mM NH4HCO3) / ACN, eluted at 35 / 65) to obtain (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 minutes, 60% B to 95% B in 0.5 minutes, hold at 95% for 0.6 minutes, 95% B to 5% B in 0.1 minutes; 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)

Chem.

[0218] Synthesis of tert-butyl 8-cyano-5-azapiro[2,5]octane-5-carboxylate

Chem.

[0219] Synthesis of 5-azaspiro[2,5]octane-8-carbonitride

Chem.

[0220] Synthesis of 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile [ka] SOCl2 (5.0 mL) was added 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). The reaction mixture was stirred at room temperature for 4 hours. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step. K2CO3 (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 product in MeCN (3.0 mL). The reaction mixture was stirred at room temperature for 12 hours. LCMS indicated that the reaction was complete. The solvent was removed under reduced pressure, and the remaining oil was purified by flash C18 silica column chromatography (water (5 mM NH4HCO3) / ACN, eluted at 25 / 75) to obtain 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-carbonitrilate (360 mg, 1.087 mmol, 1.00 equiv) in methanol (5.0 mL), H2O (5.0 mL) and H2SO4 (5.0 mL) were added. The reaction mixture was stirred at 90°C for 12 hours, and LC-MS indicated that the reaction was complete. The solvent was evaporated, and the remaining oil was purified by flash C18 silica column chromatography (eluting at 30 / 70 with water (5 mM NH4HCO3) / ACN) to obtain methyl 5-(5-bromo-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (200 mg, 50%) as the 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(PPh3)2Cl2 (30 mg, 0.040 mmol, 0.10 equiv), K2CO3 (181 mg, 1.320 mmol, 3.00 equiv), and CuI (4 mg, 0.020 mmol, 0.05 equiv) was stirred in 10.0 mL of DMF at 80°C under a nitrogen atmosphere for 12 hours. LCMS indicated that the reaction was complete. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was purified by flash C18 silica column chromatography (water (5 mM NH4HCO3) / ACN, eluted at 40 / 60) to obtain methyl 5-(5-((2-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylate (146 mg, 82%) as 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] LiOH·H2O (91 mg, 2.170 mmol, 3.00 equiv) was added 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). The reaction mixture was stirred at 80°C for 4 days. LCMS indicated that the reaction was complete. The 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 x 30 mL). The organic layer was dried over anhydrous Na2SO4 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 over 7 minutes; 254 / 210 nm) to obtain 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: from 10% B to 95% B in 1.4 minutes, hold at 95% for 0.8 minutes, from 95% B to 10% B in 0.03 minutes; 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)

Chem.

[0227] Synthesis of 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carbonitrile

Chem.

[0228] Synthesis of 5-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-5-azaspiro[2.5]octane-8-carboxylic acid

Chem.

[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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B over 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B over 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 NaBH3CN (753 mg, 11.99 mmol, 3.00 equiv.) and ZnCl2 (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. Then, 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 added. The resulting mixture was stirred at 60°C for 12 hours. LC-MS indicated that the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column silica gel chromatography (PE / Âi, elution at 1 / 1) to obtain 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] In 3 mL of THF and 0.5 mL of water, a solution of the 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.) was added to LiOH·H2O (46 mg, 1.100 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 24 hours. LC-MS indicated 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. LC-MS (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: CO2, mobile phase B: EtOH / ACN (1 / 1, 2 mM NH3-MeOH); flow rate: 45 mL / min; gradient: 50% B; 220 nm; RT: 5.98 min) to obtain chiral separation 1 (13a, 32.5 mg, 33%) of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B over 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B over 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: 23 min from 20% B to 20% B; 220 / 254 nm; RT1: 10.778 min; RT2: 15.769 min; injection volume: 1 mL; number of runs: 7) to separate the two isomers of methyl (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate (60 (mg) was obtained as 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] LiOH·H2O (24 mg, 0.600 mmol, 3.00 equiv.) was added 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). The resulting mixture was stirred at room temperature for 24 hours. LC-MS indicated that 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 flash C18 silica column chromatography (MeCN in water (0.05% NH4HCO3), 30% to 46% at 7 min; 70 mL / min, 254 / 210 nm) to obtain the corresponding enantiomer (13b, 46.9 mg, 78%) of (3S)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B over 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B over 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] In methanol (12.0 mL), 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.) were stirred, to which NaBH3CN (753 mg, 11.990 mmol, 3.00 equiv.) and ZnCl2 (2M in THF, 4.0 mL, 7.990 mmol, 2.00 equiv.) were added. The mixture was stirred at 60°C for 16 hours. The target product could be detected by LC-MS. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 40 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. 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 minutes; 254 / 210 nm) to obtain (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] A racemic mixture (400 mg) was divided 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 over 10 minutes; 220 / 254 nm; RT1: 5.741 min; RT2: 7.442 min; injection volume: 0.5 mL; number of runs: 15) to obtain 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] LiOH·H2O (17 mg, 0.410 mmol, 3.00 equiv.) was added 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). The mixture was stirred at room temperature for 2 hours under an air atmosphere. The target substance could be detected by LC-MS. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash chromatography using 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 minutes; 254 / 210 nm) to obtain the corresponding enantiomer (14a, 19.5 mg, 40%) of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid as a semi-solid.

[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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 95% B at 1.99 min, hold at 95% for 0.7 min, 95% B to 5% B at 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] LiOH·H2O (17 mg, 0.410 mmol, 3.00 equiv.) was added 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). The mixture was stirred at room temperature for 2 hours under an air atmosphere. The target substance could be detected by LC-MS. The resulting mixture was adjusted to pH 5-6 with 2N HCl and concentrated under reduced pressure. The residue was purified by flash chromatography using 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 minutes; 254 / 210 nm) to obtain the corresponding enantiomer (14b, 16.0 mg, 33%) of (3R)-1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid as a semi-solid.

[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] + Analytical 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 at 1.99 min, retention at 95% for 0.79 min, 95% B to 10% B at 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-azabicyclo[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), ethyl (1R,5R)-3-azabicyclo[3.1.0]hexane-1-carboxylate (77 mg, 0.498 mmol, 1.50 equiv.), NaCNBH3 (84 mg, 1.328 mmol, 4.00 equiv.), and ZnCl2 (2.0 M in THF, 0.33 mL, 0.664 mmol, 2.00 equiv.) were added. The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 48 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE / Âxy, eluted at 3 / 1) to obtain 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-azabicyclo[3.1.0]hexane-1-carboxylic acid [ka] LiOH·H2O (47 mg, 1.126 mmol, 4.00 equiv.) was added 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). The resulting mixture was stirred at room temperature for 72 hours. LC-MS indicated that 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 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 over 7 minutes; 254 / 210 nm; RT: 6.12 min) to obtain (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] +Analytical 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 at 2.0 min, hold at 95% for 0.7 min, 95% B to 5% B at 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 NaBH3CN (110 mg, 1.760 mmol, 4.00 equiv.) in methanol (2.0 mL), ZnCl2 (2M in 2-Me-THF, 0.44 mL, 0.880 mmol, 2.00 equiv.) was added. 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. LC-MS indicated 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 obtain 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·H2O (51 mg, 1.272 mmol, 6.00 equiv.) was stirred at 80°C for 14 hours in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and subsequently concentrated under vacuum. 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 over 7 minutes; 210 / 254 nm; RT: 6.42 min) to obtain (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] + Analytical 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 NaBH3CN (110 mg, 1.760 mmol, 4.00 equiv.) in methanol (2.0 mL), ZnCl2 (2M in 2-Me-THF, 0.44 mL, 0.880 mmol, 2.00 equiv.) was added. 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. LC-MS indicated 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 obtain 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)2Cl2 (1.4 g, 1.930 mmol, 0.05 equiv), and CuI (737 mg, 3.870 mmol, 0.10 equiv) was stirred at 45°C for 16 hours under a nitrogen atmosphere. TLC indicated that the reaction was complete, and the mixture was quenched with NaHCO3 (sat. aq, 500 mL) and extracted with DCM (500 mL x 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 obtain the target 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) and LiOH (2.2 g, 89.930 mmol, 3.00 equiv) was stirred at 25°C for 0.5 hours in THF (100 mL) and water (100 mL). TLC indicated that 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (MeCN:H2O = 2:3) to obtain the target 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) was stirred at 60°C for 12 hours under a nitrogen atmosphere. LCMS indicated that 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 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EA, 2 / 1) to obtain 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 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) was stirred at 60°C for 0.5 hours in THF (25.0 mL) and water (25.0 mL). LC-MS indicated that 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 minutes; 254 / 210 nm) to obtain each enantiomer (19, 3.31 g, 68%) of 1-(5-((3-fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid as a solid.

[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] +Analytical 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 over 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] XPhos Pd G3 (50 mg, 0.060 mmol, 0.10 equiv) was added 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). The flask was evacuated and flushed five times with nitrogen. The mixture was stirred overnight at 70°C under a nitrogen atmosphere. LC-MS indicated that the reaction was complete. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether, elution at 1 / 2), and one enantiomer (130 mg, 60%) of methyl 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate was obtained as 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] LiOH·H2O (30 mg, 0.710 mmol, 2.00 equiv.) was added 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 in THF (3.0 mL) and water (0.3 mL). The mixture was stirred overnight at room temperature. LC-MS indicated that 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: 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 over 7 min, holding at 47% B for 1 min; 254 / 210 nm; RT: 7.33 min) to obtain the corresponding enantiomer (20, 80.9 mg, 64%) of 1-(5-((2,5-difluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid 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] + Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 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]heptan-6-carboxylic acid(21) [ka] A solution of methyl 2-[5-[2-(2,6-dichlorophenyl)ethynyl]indan-1-yl]-2-azaspiro[3.3]-heptan-6-carboxylate (50 mg, 0.110 mmol, 1.00 equiv.) and LiOH (8 mg, 0.330 mmol, 3.00 equiv.) was stirred in THF (1.0 mL) and water (1.0 mL) at room temperature for 15 hours. LC-MS indicated that 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 over 7 minutes; 254 / 210 nm; RT: 6.63 min) to obtain 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-6-carboxylic acid (21, 14.3 mg, 29.5%) as a solid.

[0275] LCMS (ESI, m / z): 426 [M+H] +Analytical 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 over 1.2 min, hold at 100% B for 0.6 min, 100% B to 5% B over 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] In 10.0 mL of THF, 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) was stirred at 60°C under a nitrogen atmosphere for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with siRNA (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (PE:EA=1:1) to obtain methyl 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (350 mg, 55%) as 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 hour under a hydrogen atmosphere. LC-MS indicated that the reaction was complete. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain methyl 1-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (200 mg, crude) as oil. LC-MS (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·H2O (97 mg, 2.300 mmol, 5.00 equiv) was stirred at room temperature for 1 hour in water / THF (2 / 2 mL). LC-MS indicated that the reaction was complete. The pH of the solution was adjusted to 3-4 with 1N 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain 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] +Analytical 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 at 1.99 min, hold at 95% for 0.6 min, 95% B to 10% B at 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·H2O (97 mg, 2.300 mmol, 5.00 equiv) was stirred at room temperature for 1 hour in water / THF (2 / 2 mL). LC-MS indicated that the reaction was complete. The pH of the solution was adjusted to 3-4 with 1N 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 50% B over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain 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] + Analytical conditions: Column: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B 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 (600 mg, 1.45 mmol, 1.00 equiv) of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid was stirred at 150°C for 8 hours under microwave irradiation. LC-MS indicated that the reaction was complete. The solvent was removed under reduced pressure, and the residue was subjected to 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 over 27 mins; 220 / 254 nm; RT1: 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 over 7 mins; 254 / 210 nm; RT1: 6.43 The compound was purified in min) to obtain (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] +Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 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 (600 mg, 1.45 mmol, 1.00 equiv) of 1-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid was stirred at 150°C for 8 hours under microwave irradiation. LC-MS indicated that the reaction was complete. The solvent was removed under reduced pressure, and the residue was subjected to 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 over 27 mins; 220 / 254 nm; RT2: 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 over 7 mins; 254 / 210 nm; RT2: 6.25 The product was purified in min) to obtain a single enantiomer (24, 20 mg, 3.19%) of 1-(5-(2-(2,6-dichlorophenyl)-2-oxoethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid 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] + Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 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), 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.) were added. The resulting solution was stirred overnight at 80°C. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether, elution at 1 / 2), yielding methyl 1-(5-((2-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (512 mg, 87.9%) as 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] Pd / C (51 mg, 10% w / w) was added 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). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was filtered through Celite, and the filter cake was washed with methanol (3 x 50 mL). The mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting at ethyl acetate / petroleum ether, 1 / 2) to obtain methyl 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (457 mg, 77.1%) as 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 racemic mixture 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 minutes; 220 / 254 nm; RT1: 7.002 min; RT2: 9.054 min; injection volume: 1.1 mL; number of runs: 8) to obtain chiral isomer 1 (192 mg, 100% ee) and chiral isomer 2 (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.) was stirred at room temperature for 0.5 hours in THF (2 mL) and water (2 mL). LC-MS indicated that 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 over 10 minutes; 210 / 254 nm; RT: 7.68 min) to obtain each enantiomer of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (25a, 85.5 mg, 0.222 mmol, yield 49.1%) as a solid.

[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] +Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 0.2 min; 220 nm; RT: 1.655 min

[0297] Synthesis of each enantiomer 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) was stirred at room temperature for 0.5 hours in THF (2 mL) and water (2 mL). LC-MS indicated that 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 over 7 minutes; 210 / 254 nm; RT: 5.95 min) to obtain each enantiomer (25b, 108.1 mg, 61.8%) of 1-(5-(2-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid as a solid.

[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] +Analytical 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 at 1.39 min, hold at 95% for 0.7 min, 95% B to 10% B at 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 under a hydrogen atmosphere for 12 hours. LC-MS indicated that the reaction was complete. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain methyl 1-(5-(3-fluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, 50%) as oil. LC-MS (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·H2O (83 mg, 1.950 mmol, 5.00 equiv) in THF / water (1 / 1, 4 mL) was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The pH of the solution was adjusted to 3-4 with 1N 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 over 7 min; 210 / 254 nm; RT: 6.17 min) to obtain 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] +Analytical 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 at 1.39 min, hold at 95% for 0.7 min, 95% B to 10% B at 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.) was stirred at 80°C for 15 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The resulting solution was diluted with 20 mL of water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was 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 obtain methyl 1-(5-((3-chlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (580 mg, 50%) as 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 hour under an H2 atmosphere. TLC indicated that 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 obtain methyl 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (300 mg, 51%) as 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 mins; 220 / 254 nm; RT1: 7.219 min; RT2: 8.912 min), and one chiral isomer (110 mg, 100% ee) was obtained as 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. LC-MS indicated that the reaction was complete. The obtained 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 over 7 minutes; 254 / 210 nm; RT: 6.28 min) to obtain one enantiomer (27a, 47.5 mg, 45%) of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid as a solid.

[0314] LCMS (ESI, m / z): 384[M+H] + Analytical 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. LC-MS indicated that the reaction was complete. The obtained 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 over 7 minutes; 254 / 210 nm; RT: 6.28 min) to obtain the corresponding enantiomer (27b, 48.0 mg, 33%) of 1-(5-(3-chlorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid as a solid.

[0318] LCMS (ESI, m / z): 384 [M+H] + Analytical 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] In 4.0 mL of DMF, 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.) was added at room temperature to 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.). The resulting solution was stirred at 60°C for 12 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain 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), Pd / C (300 mg, 1.00 w / w) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 10 hours. LC-MS indicated that the reaction was complete. The resulting mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 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. LC-MS (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.) and LiOH.H2O (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 hour. LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and subsequently concentrated under vacuum. 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 over 7 minutes; 210 / 254 nm; RT: 4.77 min) to obtain one enantiomer (28a, 60.3 mg, 41%) of 1-(5-(2,6-difluorophenethyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid 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] + Analytical 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]heptan-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.) was stirred at 80°C for 15 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE = 50%) to obtain methyl 2-(5-((2,6-dichlorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-6-carboxylate (200 mg, 39.8%) as 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]heptan-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 under an H2 atmosphere for 15 hours. LC-MS indicated 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. LC-MS (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]heptan-6-carboxylate (30 mg, 0.070 mmol, 1.00 equiv.) and LiOH (5 mg, 0.210 mmol, 3.00 equiv.) was stirred in THF (1.0 mL) and water (1.0 mL) at room temperature for 1 hour. LC-MS indicated that 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 over 7 min, holding at 53% B for 1 min; 254 / 210 nm; RT: 7.92 min) to obtain the target product, 2-(5-(2,6-dichlorophenethyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-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 hours. LC-MS indicated that 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, 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 over 7 minutes; 254 / 210 nm; RT: 7.00 min) to obtain a 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] + Analytical 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 hours. LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 minutes; 254 / 210 nm; RT: 7.00 min) to obtain 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] + Analytical 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)Cl2 (82 mg, 0.112 mmol, 0.20 equiv.), and Cs2CO3 (548 mg, 1.68 mmol, 3.00 equiv.) was stirred at 90°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The resulting solution was diluted with 10 ml of water and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE = 30%) to obtain one enantiomer (90 mg, 44%) of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate as 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 hours. LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; 254 / 210 nm; RT: 6.42 min) to obtain the corresponding enantiomer (31a, 25.8 mg, 29%) of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid as a solid.

[0344] LCMS (ESI, m / z): 352 [M+H] + Analytical 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)Cl2 (82 mg, 0.112 mmol, 0.200 equiv.), and Cs2CO3 (548 mg, 1.680 mmol, 3.00 equiv.) was stirred at 90°C for 2 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The resulting solution was diluted with 20 mL of water and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EA / PE = 30%) to obtain the other enantiomer (130 mg, 64%) of methyl 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate as 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 hours. LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; 254 / 210 nm; RT: 6.42 min) to obtain the corresponding enantiomer (31b, 38.2 mg, 31%) of 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid as a solid.

[0350] LCMS (ESI, m / z): 352 [M+H] + Analytical 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] LiOH (23 mg, 0.960 mmol, 3.00 equiv.) was added to a solution of one enantiomer (131 mg, 0.320 mmol, 1.00 equiv.) of methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate in THF (2 mL) and water (2 mL). The resulting solution was stirred at room temperature for 30 minutes. LC-MS indicated that 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 over 10 minutes; 254 / 210 nm; RT: 8.80 min) to obtain one enantiomer (32a, 41 mg, 32.3%) of 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid 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] +Analytical 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 at 2.5 min, 60% B to 95% B at 0.5 min, hold at 95% B for 0.6 min, 95% B to 5% B at 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] In toluene (2 mL) and water (1 mL), 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.) were stirred, to which Pd(DTBPF)Cl2 (46.1 mg, 0.060 mmol, 0.100 equiv.) and K3PO4 (375 mg, 1.77 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 90°C for 4 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether, elution at 1 / 1 ratio) to obtain methyl 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (268 mg, 89.5%) as 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] LiOH (47 mg, 0.960 mmol, 3.00 equiv.) was added 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). The resulting solution was stirred at room temperature for 30 minutes. LC-MS indicated that 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 over 10 minutes; 254 / 210 nm; RT: 8.80 min) to obtain 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] +Analytical 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 over 2.0 min, hold at 95% B for 0.7 min, 95% B to 5% B over 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] 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.) was added to a stirred solution of 4-bromo-2-chloro-1-isopropenylbenzene (300 mg, 1,300 mmol, 1.00 equiv.), Pd(dppf)Cl2 (189 mg, 0.260 mmol, 0.20 equiv.), and CS2CO3 (1.27 g, 3.890 mmol, 3.00 equiv.) in 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90°C for 1 day. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / ethyl acetate, eluted at 6 / 1) to obtain 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] In 2 mL of MeOH, 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.) was stirred, and Pd / C (8 mg, 0.16 w / w) was added. The resulting mixture was evacuated and flushed three times with nitrogen, followed by hydrogen. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain methyl 1-(5-(3-chloro-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (37 mg) as the crude product, which was used directly in the next step. LC-MS (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] LiOH·H2O (11 mg, 0.2700 mmol, 3.00 equiv.) was added 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). The resulting mixture was stirred at room temperature for 3 hours. LC-MS indicated that 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 over 7 mins, holding at 41% B for 1 min; 210 / 254 nm; RT: 7.92 min) to obtain 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] +Analytical 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 over 2.0 min, hold at 95% B for 0.7 min, 95% B to 5% B over 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] In 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), NaBH3CN (1.82 g, 28.4 mmol, 4.00 equiv.) and ZnCl2 (1.9 M in THF, 7.11 mL, 14.2 mmol, 2.00 equiv.) were added. The resulting solution was stirred overnight at 80°C. LC-MS indicated that 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 x 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 (PE / Âxy, eluted at 3 / 1) to obtain methyl (3R)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (1.60 g, 69.4%) as 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 obtain chiral separation 1 enantiomer (1.40 g, 96.1% ee) with a retention time of 2.53 minutes and chiral separation 2 enantiomer (1.30 g, 99.2% ee) with a retention time of 2.88 minutes.

[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 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.), 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 hours under a nitrogen atmosphere. LCMS indicated that 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 (PE / Â, elution at 1 / 1) to obtain the corresponding enantiomer (100 mg, 54.6%) of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate as 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), an aqueous solution of LiOH·H2O (20.0 mg, 0.480 mmol, 3.00 equiv.) (0.5 mL) was added. The resulting solution was stirred at room temperature for 2 hours. 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: 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 over 7 minutes; 210 / 254 nm; RT: 6.38 min) to obtain each enantiomer of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylic acid (34a, 14.8 mg, yield 25.4%) as a solid.

[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] + Analytical conditions: Column: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B over 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B over 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 two enantiomers of chiral separation 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.), 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 hours under a nitrogen atmosphere. LCMS indicated that 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 (PE / Â, elution at 1 / 1) to obtain the corresponding enantiomer (100 mg, 54.6%) of methyl (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate as 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] 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.) was added to THF (2.5 mL) with an aqueous solution of LiOH·H2O (30.0 mg, 0.710 mmol, 3.00 equiv.) (0.5 mL). The resulting solution was stirred at 25°C for 2 hours. 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: 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 over 10 minutes, holding at 45% B for 1 minute; 210 / 254 nm; RT: 10.02 min) to obtain the respective enantiomers (34b, 49.5 mg, 51.1%) of (3R)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid as solids.

[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] +Analytical conditions: Column: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B over 2.0 min, hold at 95% for 0.6 min, 95% B to 10% B over 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 methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-pyrrolidine-3-carboxylate from 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 obtain chiral separation 1 enantiomer (1.10 g, ee=96.9%) with a retention time of 2.61 minutes and chiral separation 2 enantiomer (900 mg, ee=98.0%) with a retention time of 3.35 minutes.

[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 two chiral enantiomers (400 mg, 1.23 mmol, 1.00 equiv.) of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate in 1,4-dioxane (5.0 mL), bis(pinacorato)diborone (469 mg, 1.85 mmol, 1.5 equiv.), PdCl2(dppf)CH2Cl2 (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 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain the corresponding enantiomer (300 mg, 65%) 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 as 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), PdCl2(dppf)CH2Cl2 (88.0 mg, 0.110 mmol, 0.200 equiv.), and Cs2CO3 (527 mg, 1.620 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 80°C for 2 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain each enantiomer (100 mg, 46%) of methyl (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate as 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·H2O (53.0 mg, 1.25 mmol, 5.00 equiv.) was stirred at room temperature for 12 hours in THF (2 mL) and water (2 mL). LC-MS indicated that 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 over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain the respective enantiomers (35a, 20 mg, 21%) of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 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] + Analytical conditions: Column: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: Water (5 mM NH4HCO3), Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B over 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B over 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·H2O (53 mg, 1.250 mmol, 5.00 equiv.) in THF (4.0 mL) / water (4.0 mL) was stirred at room temperature for 12 hours. LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and subsequently concentrated under vacuum. 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 over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain (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] LiOH·H2O (27.6 mg, 0.660 mmol, 1.00 equiv.) was added 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). The resulting solution was stirred overnight at room temperature. LC-MS indicated that 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: 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 over 7 minutes; 254 / 210 nm; RT: 6.68 min) to obtain each enantiomer (36a, 14.8 mg, 30.6%) of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid as solids.

[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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B over 2.0 min, hold at 100% for 0.7 min, 100% B to 5% B over 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] Pd(dppf)Cl2·DCM (37.8 mg, 0.050 mmol, 0.10 equiv.) was added to a solution of two chiral 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.), K3PO4 (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). The reaction mixture was stirred overnight at 80°C under a nitrogen atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with EA. The solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column silica gel chromatography (DCM / MeOH, eluted at 15 / 1) to obtain the corresponding enantiomer (150 mg, 85.4%) of methyl (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate as 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] LiOH·H2O (55.3 mg, 1.32 mmol, 1.00 equiv.) was added 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). The resulting solution was stirred overnight at room temperature. LC-MS indicated that 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: 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 over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain the respective enantiomers (36b, 33.6 mg, 34.7%) of (3R)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid as solids.

[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] + Analytical conditions: Column: Shim-pack XR-ODS Column 3.0*50 mm, 2.2 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 20% B to 50% B at 2.7 min, 50% B to 95% B at 0.3 min, hold at 95% for 0.6 min, 95% B to 5% B at 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 NaBH3CN (3.64 g, 56.9 mmol, 4.00 equiv.) in methanol (20 mL), ZnCl2 (2M in 2-Me-THF, 14.2 mL, 28.4 mmol, 2.00 equiv.) was added. 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 overnight at 80°C. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with water (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 using PE:EA=3:1 to obtain methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (3.00 g, 65%) as 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). Chiral separation 1 enantiomer (1.10 g, ee=96.9%) was obtained with a retention time of 2.61 minutes, and chiral separation 2 enantiomer (900 mg, ee=98.0%) was obtained with a retention time of 3.35 minutes. 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 1,4-dioxane (5 mL), one enantiomer of chiral separation of methyl (3S)-1-(5-bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate (400 mg, 1.23 mmol, 1.00 equiv.), bis(pinacorato)diborone (469 mg, 1.85 mmol, 1.5 equiv.), PdCl2(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 hours under a nitrogen atmosphere. LC-MS indicated that 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 obtain the corresponding enantiomer (300 mg, 65%) 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 as 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.), PdCl2(dppf)·DCM (44.0 mg, 0.050 mmol, 0.200 equiv.), and Cs2CO3 (263 mg, 0.810 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 80°C for 2 hours under a nitrogen atmosphere. LCMS indicated 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 (EA:PE=2:3) to obtain each enantiomer (100 mg, 49%) of methyl (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylate as 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·H2O (53.0 mg, 1.25 mmol, 5.00 equiv.) in THF (2 mL) / water (2 mL) was stirred at room temperature for 12 hours. LC-MS indicated that 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 over 7 min; 254 / 210 nm; RT: 6.42 min) to obtain the respective enantiomers (37a, 36.6 mg, 37%) of (3S)-1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 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] + Analytical 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·H2O (53.0 mg, 1.25 mmol, 5.00 equiv.) was stirred at room temperature for 12 hours in THF (2 mL) and water (2 mL). LC-MS indicated that 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 over 7 minutes; 254 / 210 nm; RT: 6.42 min) to obtain the respective enantiomers (37b, 40.6 mg, 42%) of (3S)-1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-3-carboxylic acid 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)

change

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

change

[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.) was stirred at room temperature for 1 hour in THF (1 mL) and water (1 mL). LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; 254 / 210 nm; RT: 6.73 min) to obtain 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] +Analytical 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]heptan-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), TBSOTf (2.1 g, 7.843 mmol, 2.00 equiv.) was added dropwise at 0°C. The resulting solution was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The resulting solution was concentrated under reduced pressure. Crude methyl 2-azaspiro[3.3]heptane-6-carboxylate (700 mg) was used directly in the next step without further purification. LC-MS (ESI, m / z): 156 [MH] +

[0415] Synthesis of methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-6-carboxylate [ka] In 10 mL of methanol, a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (400 mg, 1.896 mmol, 1.00 equiv.), ZnCl2 (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.) was added, to which NaBH3CN (358 mg, 5.688 mmol, 3.00 equiv.) was added. The resulting solution was stirred overnight at 80°C under a nitrogen atmosphere. LC-MS indicated that 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash C18 silica chromatography (water (0.05% TFA) / ACN, eluted at 3 / 1) to obtain methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-6-carboxylate (400 mg, 60.3%) as 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] Pd(dppf)Cl2-DCM (44 mg, 0.054 mmol, 0.10 equiv.) was added 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.), Cs2CO3 (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). The reaction mixture was stirred overnight at 80°C under a nitrogen atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with Âtiol. The solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column silica gel chromatography (DCM / MeOH, eluted at 15 / 1) to obtain methyl 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-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] LiOH·H2O (50 mg, 1.180 mmol, 5.00 equiv.) was added to a solution of methyl 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-6-carboxylate (100 mg, 0.240 mmol, 1.00 equiv.) in THF (2.0 mL) and water (2.0 mL). The resulting solution was stirred overnight at room temperature. LC-MS indicated that 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: 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 over 7 minutes; 254 / 210 nm; RT: 5.93 min) to obtain 2-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-2-azaspiro[3.3]heptan-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] +Analytical 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 at 2.5 min, 65% B to 95% B at 0.5 min, retention 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), (3,5-dimethoxyphenyl)boronic acid (100 mg, 0.550 mmol, 2.00 equiv), Pd(dppf)Cl2 (22 mg, 0.030 mmol, 0.10 equiv), and Cs2CO3 (268 mg, 0.820 mmol, 3.00 equiv) were added. The reaction mixture was stirred at 80°C for 3 hours. LC-MS indicated that 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 over 7 min; 254 / 210 nm) to obtain a single enantiomer of methyl 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate (150 mg, yield 69%) as 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] LiOH·H2O (47 mg, 1.140 mmol, 3.00 equiv) was added 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). The reaction mixture was stirred at room temperature for 5 hours. LC-MS indicated that 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 over 7 min; 254 / 210 nm; RT: 5.95 min) to obtain a single enantiomer of 1-(5-(3,5-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (40, 35.6 mg, yield 23%) 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] +Analytical conditions: Column: Titank C18, 3.0*50 mm, 3.0 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B over 1.80 min, hold at 95% for 0.8 min, 95% B to 10% B over 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.), 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)Cl2 (60 mg, 0.080 mmol, 0.10 equiv.), and Cs2CO3 (794 mg, 2.440 mmol, 3.00 equiv.) was stirred at 90°C for 15 hours under an N2 atmosphere in 1,4-dioxane (5.0 mL) and water (0.5 mL). LC-MS indicated that the reaction was complete. The reaction mixture was diluted with 20 mL of water and then extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with hydrated 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 obtain a single enantiomer (120 mg, 53.6%) of methyl 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)-piperidine-4-carboxylate as 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.) was stirred at room temperature for 1 hour in THF (2 mL) and water (1 mL). LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 22% B over 8 minutes; 254 / 210 nm; RT: 7.53 min) to obtain one enantiomer (41, 24.6 mg, 23.4%) of the target product 1-(5-(2,3-dihydrobenzofuran-6-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid 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 at 1.7 min, 45% B to 95% B at 0.3 min, hold at 95% B for 0.7 min, 95% B to 10% B at 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]oxazole-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.) was stirred at room temperature for 0.5 hours in THF (1 mL) and water (1 mL). LC-MS indicated that 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·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 8% B to 38% B over 7 min; 254 / 210 nm; RT: 5.87 min) to obtain one enantiomer of 1-(5-(benzo[d]oxazole-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid (42, 9.1 mg, 0.024 mmol, yield 10.1%) 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]+ Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 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), 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.) were added. The resulting mixture was stirred overnight at 90°C. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (DCM / MEOH, eluted at 1 / 10), and one enantiomer (94 mg, 84.2%) of methyl 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylate was obtained as 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.) was stirred at room temperature for 0.5 hours in THF (1 mL) and water (1 mL). LC-MS indicated that 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 over 8 min; 254 / 210 nm; RT: 7.45 min) to obtain one enantiomer (43, 38.5 mg, 42.3%) of 1-(5-(2,3-dihydrobenzofuran-5-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-4-carboxylic acid 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] +Analytical 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 over 2.0 min, hold at 100% B for 0.7 min, 100% B to 5% B over 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] In a solution of 1,4-dioxane (2.0 mL) and water (0.2 mL), 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.) and indan-5-ylboronic acid (86 mg, 0.530 mmol, 1.20 equiv.) was added. Cs2CO3 (433 mg, 1.330 mmol, 3.00 equiv.) and Pd(dppf)Cl2 (72 mg, 0.090 mmol, 0.20 equiv.) were added. The resulting solution was stirred at 80°C for 3 hours under a nitrogen atmosphere. LC-MS indicated 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 obtain one enantiomer (140 mg, 84%) of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylate as oil. LCMS (ESI, m / z): 376 [M+H] +

[0437] Synthesis of 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biindene]-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·H2O (33 mg, 0.800 mmol, 3.00 equiv.) was stirred at room temperature for 12 hours in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and subsequently concentrated under vacuum. 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 over 8 minutes; 254 / 210 nm; RT: 6.32 min) to obtain one enantiomer (44, 29.7 mg, 30%) of 1-(2,2',3,3'-tetrahydro-1H,1'H-[5,5'-biinden]-1-yl)piperidine-4-carboxylic acid 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] +Analytical conditions: Column: Poroshell HPH-C18 Column 3.0*50 mm, 2.7 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 50% B at 2.0 min, 50% B to 95% B at 0.25 min, hold at 95% for 0.45 min, 95% B to 10% B at 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] In a solution of 1,4-dioxane (4.0 mL), 4-bromoindan (300 mg, 1.520 mmol, 1.00 equiv.) and bis(pinacolato)diborone (580 mg, 2.280 mmol, 1.50 equiv.) were added. AcOK (447 mg, 4.570 mmol, 3.00 equiv.) and Pd(dppf)Cl2 (124 mg, 0.150 mmol, 0.10 equiv.) were added at room temperature. The resulting solution was stirred at 80°C for 3 hours under a nitrogen atmosphere. LC-MS indicated 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 = 10 / 1) to obtain 2-(2,3-dihydro-1H-inden-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260 mg, 69%) as oil. LCMS (ESI, m / z): 245 [M+H] +

[0441] Synthesis of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biindene]-1'-yl)piperidine-4-carboxylate [ka] In 1,4-dioxane (5.0 mL) and water (0.5 mL), 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.) and 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.) are dissolved in 1,4-dioxane (5.0 mL) and water (0.5 mL), with Cs2CO3 (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 under a nitrogen atmosphere at 80°C for 3 hours. LC-MS indicated 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 obtain one enantiomer (200 mg, 66%) of methyl 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylate as oil. LC-MS (ESI, m / z): 376 [M+H] +

[0442] Synthesis of 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biindene]-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·H2O (34 mg, 0.810 mmol, 3.00 equiv.) was stirred at room temperature for 12 hours in THF (1.0 mL) and water (1.0 mL). LC-MS indicated that the reaction was complete. The solution was adjusted to pH 4-5 with 1N HCl and subsequently concentrated under vacuum. 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 over 8 minutes; 254 / 210 nm; RT: 6.32 min) to obtain one enantiomer (45, 47.8 mg, 49%) of 1-(2,2',3,3'-tetrahydro-1H,1'H-[4,5'-biinden]-1'-yl)piperidine-4-carboxylic acid 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] +Analytical 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 receptors were placed in a 500 cm³ area. 2 Cells were cultured in a culture dish, and once confluent, they were rinsed with cell lifting buffer (10 mM HEPES, 154 mM NaCl, 6.85 mM EDTA, pH 7.4) to detach them. Next, the cells were pelletized 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). Cell proteins were pelletized by centrifugation (48,000 xg, 4°C, 30 min). The resulting supernatant was discarded, the pellet was resuspended in membrane preparation buffer, homogenized a second time, and then centrifuged again 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), divided into fixed volumes, and stored at -80°C until use. Example B2. GTPγS binding assay

[0446] [ 35A functional binding assay of [S]-GTPγS was performed on a 96-well unbound surface plate with a final volume of 200 μL. The test compound was serially diluted with DMSO and added to the assay plate in a total volume of 0.4 μL using a Tecan D300E digital dispenser (printer). Control sphingosine-1-phosphate (S1P) was prepared separately by creating a 400 μM stock solution from 100 nmol S1P pellet in 10 mM Na2CO3 containing 2% β-cyclodextrin. S1P was serially diluted with complete assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.1% fatty acid-free bovine serum albumin (BSA), and 30 μg / mL saponin, pH 7.4) and transferred to wells already containing 0.4 μL of DMSO. Next, complete assay buffer was added to all wells except the nonspecific binding (NSB) wells up to a total volume of 40 μL. For the NSB wells, 40 μL / well of 50 μM GTPγS (Sigma Aldrich, St. Louis, Missouri, catalog number G8634) was added to the well 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, Missouri, catalog number G7127), and 2.5 mg / mL WGA PVT SPA beads complete buffer. The assay plate was then sealed and incubated at room temperature for 30 minutes with gentle agitation. Next, 1 nM [ 3540 μL / well of S]-GTPγS (PerkinElmer, Waltham, Massachusetts, catalog number NEG030X250UC) was added to the assay plate to a final concentration of 200 pM, and the plate was incubated at room temperature for 40 minutes with gentle agitation. The assay was terminated by centrifugation of the plate using an Eppendorf 5810R centrifuge (Eppendorf, Hamburg, Germany) at 1000 rpm for 3 minutes, and G protein-binding radioactivity was quantified using a MicroBeta2 microplate scintillation counter (PerkinElmer, Waltham, Massachusetts). Since G protein-binding radioactivity is directly correlated with receptor activation and binding to G proteins, this assay serves as an indicator of S1P5 agonism. The results are shown in Table 2. [Table 14] [Table 15]

[0447] Although the present invention is described in some detail with illustrations and examples for ease of understanding, the description and examples should not be construed as limiting the scope of the invention. All disclosures of patent and scientific documents cited herein are expressly incorporated herein in their entirety by reference.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, L is 【Chemistry 2】 or combination; X and Y are independently H, O, H ２ , or absent; 【Transformation 3】 It is a single, double, or triple bond; R １ C ６ -C １０ An aryl, a condensed bicyclic 8-10 membered heteroaryl, or a condensed bicyclic 8-10 membered heterocyclil, each of which may be appropriately substituted with 1-5 R' groups, where the heterocyclil 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 cycloalkyl; R ２ is H or C １ -C ６ It is alkyl; R ３ is, -(CH ２ ) ｘ -CO ２ H or 【Chemistry 4】 Is it; Alternatively, R ２ and R ３ The dashed line between them is R ２ and R ３ However, along with the nitrogen atom to which they are bonded, there are 1 to 5 R ４ This represents a ring structure that forms a 4-6 member heterocycline substituted with a group, where at least one R ４ The base is -CO ２ It is either H or -CO ２ Including the H portion; x is between 1 and 5; Each R ４ It is independently, -CO ２ H, Halo, or C １ -C ６ Is it alkyl? Or two R's ４ The group, along with the carbon atoms to which it is bonded, is -CO ２ Condensation, crosslinking, or spiro-C which may be appropriately substituted with H. ３ -C ５ [Forms cycloalkyl] Compounds of or pharmaceutically acceptable salts thereof.

2. L, 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. L is -C≡C-, -HC=CH-, or -CH ２ CH ２ - The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

4. L is -C(O)-CH ２ - or -CH ２ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is -C(O)-.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

6. R １ However, these are phenyl, phenyl condensed with a cycloalkyl group, a condensed bicyclic nine-membered heteroaryl, or a condensed bicyclic nine-membered heterocyclil, each of which may be appropriately substituted with 1 to 3 R' groups, where the heterocyclil and heteroaryl contain 1 to 2 heteroatoms selected from nitrogen and oxygen. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. Each R' independently produces a halo and C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, or C ３ -C ６ It is a cycloalkyl, A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. Each R' independently corresponds to Cl, F, methyl, ethyl, isopropyl, -CF ３ , -OCH ３ , or cyclopropyl, The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ but, 【Transformation 6】 That is, A compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt thereof.

10. R ２ However, H or C １ -C ３ It is alkyl; R ３ However, - (CH ２ ) ｘ -CO ２ H or 【Transformation 7】 And; x is between 1 and 3. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ２ However, it is either H or methyl; R ３ However, -CH ２ CO ２ H, -(CH ２ ) ２ CO ２ H, -(CH ２ ) ３ CO ２ H, or 【Transformation 8】 That is, The compound according to claim 10, or a pharmaceutically acceptable salt thereof. 【Request Item 12】 【Chemistry 9】 but, 【Chemistry 10】 That is, The compound according to claim 11, or a pharmaceutically acceptable salt thereof.

13. R ２ and R ３ However, along with the nitrogen atom to which they are bonded, there are 1 to 3 R ４ It forms a 4-6 member heterocycline substituted with a group, where at least one R ４ The base is -CO ２ It is either H or -CO ２ Including the H portion, A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

14. R ２ and R ３ However, together with the nitrogen atom to which they are bonded, they form azetidinyl, pyrrolidinyl, or piperidinyl, each of which contains 1 to 3 R atoms. ４ Substituted with a base, where at least one R ４ The base is -CO ２ It is either H or -CO ２ Including the H portion, The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. Each R ４ However, independently, -CO ２ H, Halo, or C １ -C ３ Is it alkyl? Or two R's ４ The group, along with the carbon atoms to which they are bonded, -CO ２ Condensation, crosslinking, or spiro-C which may be appropriately substituted with H. ３ -C ５ Forming a cycloalkyl group, Here, at least one R ４ group is -CO ２ H or contains a -CO ２ H moiety A compound according to any one of claims 1 to 9, 13, and 14, or a pharmaceutically acceptable salt thereof.

16. Each R ４ However, independently, -CO ２ It is H, F, or methyl, Or two R's ４ The groups, together with the carbon atoms to which they are bonded, form condensed cyclopropyl, spirocyclopropyl, spirocyclobutyl, or crosslinked cyclopentyl, which are respectively -CO ２ H may be substituted as appropriate. Here, at least one R ４ group is either -CO ２ H or contains a -CO ２ H moiety. The compound according to claim 15, or a pharmaceutically acceptable salt thereof. 【Request Item 17】 【Chemistry 11】 but, 【Chemistry 12】 That is, A compound according to any one of claims 1 to 9 and 13 to 16, or a pharmaceutically acceptable salt thereof.

18. The aforementioned compound is of formula (II): 【Chemistry 13】 A compound according to any one of claims 1 to 9 and 13 to 17, or a pharmaceutically acceptable salt thereof.

19. The compound is of formula (IIIa) or (IIIb): 【Chemistry 14】 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

20. A compound selected from the following or a pharmaceutically acceptable salt thereof, wherein "or1" indicates that the absolute stereochemistry has not been determined. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

22. A drug for modulating sphingosine 1-phosphate receptor 5 (S1P5), comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

23. A drug for treating neurological disorders, comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

24. The agent according to claim 23, wherein the neurological disease is Alzheimer's disease or multiple sclerosis.

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