Compounds for the treatment of neurodegenerative diseases

Abstract

Compounds and compositions for modulating S1P5 are provided herein. In some embodiments, the compounds and compositions are provided for the treatment of neurological disorders.

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 390,069, filed on July 18, 2022, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

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

Background Art

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate) is a bioactive sphingolipid synthesized by the metabolic turnover of sphingolipids in cells and by the extracellular action of secreted sphingosine kinase. S1P binds to and stimulates members of the endothelial 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 various cellular responses such as proliferation, cytoskeleton formation and migration, adhesion and tight junction formation, and morphogenesis.

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

[0005] Accordingly, in one aspect, compounds that modulate S1P5 for use in the treatment of neurodegenerative diseases are provided herein. SUMMARY OF THE INVENTION

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

[0007] This embodiment can be more fully understood by reference to the forms and examples for carrying out the invention, which are intended to be illustrative examples of non-limiting embodiments.

[0008] Embodiment A1. A compound of the following formula (I):

Chemical formula

Chemical formula

[0009] Embodiment A2. L is -C≡C-, -CH2CH2-, -CH2O-, or a bond, the compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof.

[0010] Embodiment A3. L is

Chemical formula

[0011] Embodiment A4. R 1 each independently is halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, the compound according to any one of Embodiments A1 to A3 or a pharmaceutically acceptable salt thereof.

[0012] Embodiment A5.

Chemical formula

[0013] Embodiment A6. R 2 is H, halo, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl; R 3a and R 3b are each H, the compound according to any one of Embodiments A1 to A5 or a pharmaceutically acceptable salt thereof.

[0014] Embodiment A7. R 2 and R 3aforms a fused cyclopentyl together with the carbon atom to which they are attached; R 3b is H, A compound according to any one of embodiments A1 - A5 or a pharmaceutically acceptable salt thereof.

[0015] Embodiment A8. R 2 and R 4 form a fused phenyl together with the carbon atom to which they are attached, A compound according to any one of embodiments A1 - A5 or a pharmaceutically acceptable salt thereof.

[0016] Embodiment A9. R 4 is H, halo, -CN, C1 - C3 alkyl, C1 - C3 haloalkyl, C1 - C3 alkoxy, or C3 - C6 cycloalkyl, A compound according to any one of embodiments A1 - A7 or a pharmaceutically acceptable salt thereof.

[0017] Embodiment A10. R 5 are each independently H, halo, -CN, C1 - C3 alkyl, C1 - C3 haloalkyl, C1 - C3 alkoxy, or C3 - C6 cycloalkyl, A compound according to any one of embodiments A1 - A9 or a pharmaceutically acceptable salt thereof.

[0018] Embodiment A11.

Chemical formula

[0019] Embodiment A12. R 6 is H; R 7 is C1 - C6 alkyl - OH, The compound according to any one of Embodiments A1 to A11 or a pharmaceutically acceptable salt thereof.

[0020] Embodiment A13. R 6 and R 7 together with the nitrogen atom to which they are attached

Chemical formula

[0021] Embodiment A14.

Chemical formula

[0022] Embodiment A15. The following formula (II):

Chemical formula

[0023] Embodiment A16. The following formula (III):

Chemical formula

[0024] Embodiment A17. A compound selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0025] Embodiment A18. A pharmaceutical composition comprising a compound described in any one of Embodiments A1 - A17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0026] Embodiment A19. A method of modulating sphingosine 1 - phosphate receptor 5 (S1P5), comprising contacting S1P5 with an effective amount of a compound described in any one of Embodiments A1 - A17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment A18.

[0027] Embodiment A20. A method of treating a neurological disease in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound described in any one of Embodiments A1 - A17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment A18, and optionally, wherein the neurological disease is Alzheimer's disease, multiple sclerosis, migraine, and amyotrophic lateral sclerosis.

Mode for Carrying Out the Invention

[0028] Definitions As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" should be construed as identifying the presence of the recited features or components, but not excluding the presence or addition of one or more other features, components, or groups thereof. Further, the terms "comprising" and "including" are intended to include examples subsumed by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0029] The term "consisting of" means that the subject of the patented invention has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent listing, except for those that are essential to the technical effect to be achieved.

[0030] As used herein, the term "or" should be construed as the inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C". An exception to this definition occurs only when the combination of elements, functions, steps, or acts is mutually exclusive in some way.

[0031] In this specification, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range is to be understood as including any integer value within the recited range, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer). Also, any numerical range recited herein with respect to any physical characteristic (such as polymer subunit, size, or thickness) is to be understood as including any integer within the recited range, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the recited range, value, or structure, unless otherwise specified.

[0032] An "alkyl" group has 1 to 10 carbon atoms (C1-C 10An alkyl group is typically a saturated, partially saturated, or unsaturated straight-chain or branched acyclic hydrocarbon having from 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, from 1 to 6 (C1-C6 alkyl), from 1 to 3 (C1-C3 alkyl), or from 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(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). The alkyl group can be substituted or unsubstituted.When an alkyl group described in this specification 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 halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, 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 -B(OH)2.In certain embodiments, when an alkyl group described herein is said to be "substituted", it is any substituent found in the representative compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or may be substituted with O(alkyl)aminocarbonyl.

[0033] The "alkyl-OH" group refers to an unbranched or branched alkyl group as defined above, where one or more hydrogen atoms are substituted by -OH. For example, "C1-C6 alkyl-OH" refers to C1-C6 alkyl substituted by one or more -OH groups. Alkyl-OH may contain multiple hydroxy groups bonded to the same carbon atom or multiple carbon atoms.

[0034] The "cycloalkyl" group has a monocyclic ring or multiple fused or bridged rings, optionally substituted, having 3 to 10 carbon atoms (C3-C 10It is 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 is 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl 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. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.

[0035] The "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms (C6-C 14 aryl) with 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 10It is included in the ring portion of the aryl-based group. Specific aryls include phenyl, biphenyl, naphthyl, and the like. 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 the like).

[0036] "Halogen" or "halo" is fluorine, chlorine, bromine, or iodine.

[0037] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more of the halogen radicals defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halogen radicals (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halogen radicals (C1-C3 haloalkyl). The halogen radicals may be exactly the same or may be different. Unless explicitly stated otherwise, the haloalkyl group may be optionally substituted.

[0038] 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, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guanylinyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups, among others. The heteroaryl group can be substituted or unsubstituted.

[0039] "Heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms selected from O, S, and N. In some embodiments, the 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. Heterocyclyl can be attached to other groups at any ring atom (i.e., at any carbon or heteroatom of the heterocyclic ring). The heterocycloalkyl group can be substituted or unsubstituted. The heterocyclyl group encompasses saturated and partially saturated ring systems. Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, and the ring may be fused to an aryl or heteroaryl ring, regardless of its attachment to the rest of the molecule. This phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]phenoxathiinyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono-substituted or multi-substituted (e.g., disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or hexasubstituted by various substituents such as those described below, or a disubstituted pyridyl or morpholinyl group, etc.).

[0040] The "alkoxy" group is -O-(alkyl), where alkyl is as defined above.

[0041] The "carboxy" group is a radical of the formula: -C(O)OH.

[0042] When a group (excluding an alkyl group) described in this specification is said to be "substituted", it may be substituted with any suitable substituent. Examples of substituents are those found in the representative compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0043] Embodiments of the present disclosure are intended to include pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers of the compounds provided herein (such as compounds of formula (I)).

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases such as inorganic acids and bases and organic acids and bases. Suitable base addition salts of the compounds 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, ethanesulfonic acid, formic acid, fumaric acid, phthalic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, examples of specific salts include hydrochloride, formate, and mesylate. Other examples are well known in the art, for example, see Remington’s Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0045] Unless otherwise indicated, as used herein, the terms "stereoisomer" or "stereoisomerically pure" 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 greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, or greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the 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.

[0046] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of such forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques (such as chiral columns or chiral resolving agents, etc.).See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. 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); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0047] 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 certain 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.

[0048] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of the isomers depends on the environment in which the compound is found and may vary, for example, depending on whether the compound is a solid or is in an organic or aqueous solution. For example, in an aqueous solution, pyrazole may exhibit the following isomers, which are called tautomers of each other. [Chem.]

[0049] As will be readily understood by those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present disclosure.

[0050] It should also be noted that the compounds disclosed herein may contain atomic isotopes in unnatural proportions at one or more of their atoms. For example, the compounds may be radiolabeled with radioactive isotopes (such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), etc.), or with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15It may be isotopically enriched, such as by (N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radioactive labels and isotopically enriched compounds are useful as therapeutic agents, such as cancer therapeutic agents, research reagents, such as binding assay reagents, and diagnostic agents, such as in vivo contrast agents. All isotopic variations of the compounds described herein are intended to be encompassed within the scope of the embodiments provided herein, whether radioactive or not. In some embodiments, isotopologues of the compounds disclosed herein are provided, for example, the isotopologue is a deuterium, carbon-13, and / or nitrogen-15 enriched compound. As used herein, "deuterated" means a compound in which at least one hydrogen (H) is replaced by deuterium (D or 2 represented by H), i.e., the compound is enriched with deuterium at at least one position.

[0051] Regardless of the stereoisomeric composition or isotopic composition, it is understood that each compound disclosed herein may be provided in any form of a pharmaceutically acceptable salt described herein. Similarly, it is understood that the isotopic composition may vary independently of the stereoisomeric composition of each compound referred to herein. Further, the isotopic composition is limited to the elements present in each compound or its salt disclosed herein, but otherwise may vary independently of the choice of pharmaceutically acceptable salt of each compound.

[0052] Note that if there is a discrepancy between the drawn structure and the name of that structure, the drawn structure should be given more weight.

[0053] As used herein, "treating" means reducing in whole or in part one or more of a disorder, disease, or condition, or symptoms associated with a disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is a neurodegenerative disease described herein, or a symptom thereof.

[0054] As used herein, "preventing" means a method of delaying and / or preventing in whole or in part the onset, recurrence, or spread of a disorder, disease, or condition; a method of preventing a subject from contracting a disorder, disease, or condition; or a method of reducing the risk that a subject will contract a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease described herein, or a symptom thereof.

[0055] The term "effective amount" as related to a compound disclosed herein means an amount capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof.

[0056] As used herein, the terms "subject" or "patient" include, but are not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment mammals, and in another embodiment humans. In one embodiment, the subject is a human having or at risk of having an S1P5-mediated disease, or a symptom thereof.

[0057] Although various features of the invention may be described in the context of a single embodiment, the features may be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may be implemented in a single embodiment.

[0058] Compounds In one embodiment, a compound of formula (I):

Chemical formula

Chemical formula

[0059] In some embodiments, L is -C≡C-, -HC=CH-, -CH2CH2-, -CH2O-,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0060] In some embodiments, R 1is, independently of each other, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 1 is, independently of each other, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 1 is, independently of each other, F, Cl, or cyclopropyl.

[0061] In some embodiments, R 1 is halo. In some embodiments, R 1 is Cl, F, or Br. In some embodiments, R 1 is Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Br.

[0062] In some embodiments, R 1 is -CN.

[0063] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is n-propyl. In some embodiments, R 1 is isopropyl.

[0064] In some embodiments, R 1 is C1-C6 haloalkyl. In some embodiments, R 1is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 1 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 1 is -CF3. In some embodiments, R 1 is -CHF2.

[0065] In some embodiments, R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R 1 is -OCH3. In some embodiments, R 1 is -OCH2CH3.

[0066] In some embodiments, R 1 is C3-C6 cycloalkyl. In some embodiments, R 1 is C3-C5 cycloalkyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl.

[0067] In some embodiments, x is from 0 to 5. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0. 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.

[0068] In some embodiments,

Chemical formula

[0069] In some embodiments, R 2 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. In some embodiments, R 2 is H, halo, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl. In some embodiments, R 2 is H, F, Cl, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

[0070] In some embodiments, R 2 is H.

[0071] In some embodiments, R 2 is halo. In some embodiments, R 2 is Cl, F, or Br. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Br.

[0072] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl.

[0073] In some embodiments, R 2 is C3-C6 cycloalkyl. In some embodiments, R 2 is C3-C5 cycloalkyl. In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl.

[0074] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 2 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 2is -CF3. In some embodiments, R 2 is -CHF2.

[0075] In some embodiments, R 2 and R 3a together with the carbon atom to which they are attached form a fused cyclopentyl. In some variations, R 3b is H.

[0076] In some embodiments, R 2 and R 4 together with the carbon atom to which they are attached form a fused phenyl.

[0077] In some embodiments, R 3a and R 3b are each H.

[0078] In some embodiments, R 4 is H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 4 is H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 4 is H, F, or -CH3.

[0079] In some embodiments, R 4 is H.

[0080] In some embodiments, R 4 is halo. In some embodiments, R 4 is Cl, F, or Br. In some embodiments, R 4 is Cl. In some embodiments, R 4 is F. In some embodiments, R 4 is Br.

[0081] In some embodiments, R 4 is -CN.

[0082] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C3 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl.

[0083] In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 4 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 4 is -CF3. In some embodiments, R 4 is -CHF2.

[0084] In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, R 4is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R 4 is -OCH3. In some embodiments, R 4 is -OCH2CH3.

[0085] In some embodiments, R 4 is C3-C6 cycloalkyl. In some embodiments, R 4 is C3-C5 cycloalkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4 is cyclopentyl. In some embodiments, R 4 is cyclohexyl.

[0086] In some embodiments, X 1 and X 2 are independently N or CR 5 . In some embodiments, X 1 and X 2 are independently CR 5 . In some embodiments, X 1 is N and X 2 is CR 5 . In some embodiments, X 1 is CR 5 and X 2 is N. In some embodiments, X 1 and X 2 are each N.

[0087] In some embodiments, R 5is, independently of each other, H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 5 is, independently of each other, H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl. In some embodiments, R 5 is, independently of each other, H, F, -CH3, -CH2CH3, or -CH(CH3)2.

[0088] In some embodiments, R 5 is H.

[0089] In some embodiments, R 5 is halo. In some embodiments, R 5 is Cl, F, or Br. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F. In some embodiments, R 5 is Br.

[0090] In some embodiments, R 5 is -CN.

[0091] In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 is isopropyl.

[0092] In some embodiments, R 5 is C1-C6 haloalkyl. In some embodiments, R 5 is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 5 is C1-C3 haloalkyl. In some embodiments, R 5 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 5 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF2.

[0093] In some embodiments, R 5 is C1-C6 alkoxy. In some embodiments, R 5 is C1-C3 alkoxy. In some embodiments, R 5 is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R 5 is -OCH3. In some embodiments, R 5 is -OCH2CH3.

[0094] In some embodiments, R 5 is C3-C6 cycloalkyl. In some embodiments, R 5 is C3-C5 cycloalkyl. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 5is cyclopentyl. In some embodiments, R 5 is cyclohexyl.

[0095] In some embodiments,

Chemical formula

[0096] In some embodiments, R 6 is H.

[0097] In some embodiments, R 7 is C1-C6 alkyl-OH. In some embodiments, R 7 is C1-C5 alkyl-OH. In some embodiments, R 7 is C1-C4 alkyl-OH. In some embodiments, R 7 is C3-C6 alkyl-OH. In some embodiments, R 7 is -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH2CH3, -C(CH3)(OH)CH2CH3, -CH(OH)CH(CH3)CH3, -CH2CH(OH)CH3, -CH(CH3)CH(OH)CH3, -CH2C(CH3)(OH)CH3, or -CH2C(OH)(CH3)2. In some embodiments, R 7 is -CH2C(OH)(CH3)2.

[0098] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl substituted with n R 8 groups. In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl substituted with n R 8 groups. In some embodiments, R 6 and R 7forms a 5-membered heterocyclyl substituted with n R groups together with the nitrogen atom to which they are attached. In some embodiments, R 8 and R 6 form a 6-membered heterocyclyl substituted with n R 7 groups together with the nitrogen atom to which they are attached. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with n R 8 groups. 8 groups.

[0099] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached

Chemical formula

[0100] In some embodiments, n is from 1 to 5. In some embodiments, n is from 1 to 4. In some embodiments, n is from 1 to 3. In some embodiments, n is from 1 to 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0101] In some embodiments, each R 8 is independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -OH, provided that at least one R 8 is -OH. In some embodiments, each R 8 is independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or -OH. In some embodiments, R 8is, independently, -CH3, -CH2CH3, -CFH2, -CF2H, -CF3, or -OH. In some embodiments, one R 8 is -OH.

[0102] In some embodiments, R 8 is halo. In some embodiments, R 8 is Cl, F, or Br. In some embodiments, R 8 is Cl. In some embodiments, R 8 is F. In some embodiments, R 8 is Br.

[0103] In some embodiments, R 8 is -CN.

[0104] In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is C1-C3 alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl.

[0105] In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 8 is C1-C3 haloalkyl. In some embodiments, R 8 is C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R8 is -CF3, -CHF2, -CH2F, -CFH2, -CF2H, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R 8 is -CF3. In some embodiments, R 8 is -CFH2. In some embodiments, R 8 is -CF2H.

[0106] In some embodiments, R 8 is C1-C6 alkoxy. In some embodiments, R 8 is C1-C3 alkoxy. In some embodiments, R 8 is -OCH3, -OCH2CH3, -OCH2CH2CH3, or -OCH(CH3)2. In some embodiments, R 8 is -OCH3. In some embodiments, R 8 is -OCH2CH3.

[0107] In some embodiments, R 8 is -OH.

[0108] In some embodiments, two or more R 8 groups are present, and one R 8 group is -OH. In some embodiments, two R 8 groups are present, and one R 8 group is -OH. In some embodiments, three R 8 groups are present, and one R 8 group is -OH.

[0109] In some embodiments,

Chemical formula

[0110] In some embodiments, the compound of formula (I) is a compound of formula (II): [Chemical formula] [wherein R 1 , R 4 , R 6 , R 7 , L, X 1 , X 2 , and x are as described for formula (I)] is.

[0111] In some embodiments, the compound of formula (I) is a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIg): [Chemical formula] [wherein R 1 , R 4 , R 6 , R 7 , X 1 , X 2 , and x are as described for formula (I)] is.

[0112] In some embodiments, the compound of formula (I) is a compound of formula (II-A) or (II-B): [Chemical formula] [wherein R 1 , R 4 , R 8 , L, X 1 , X 2 , n, and x are as described for formula (I), and [Chemical formula] is a 4- to 6-membered heterocyclyl] is.

[0113] In some embodiments, the compound of formula (I) is a compound of formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), or (IIG):

Chemical formula

[0114] In some embodiments, the compound of formula (I) is a compound of formula (III):

Chemical formula

[0115] In some embodiments, the compound of formula (I) is a compound of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg):

Chemical formula

[0116] In some embodiments, the compound of formula (I) is a compound of formula (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), or (IIIG): [Chemical formula] [wherein R 1 , R 2 , R 4 , R 8 , X 1 , X 2 , x, and n are as described for formula (I)] is.

[0117] In some embodiments, the compound of formula (I) is a compound of formula (III-A) or (III-B): [Chemical formula] [wherein R 1 , R 2 , R 4 , R 7 , R 8 , L, X 1 , X 2 , n, and x are as described for formula (I), and [Chemical formula] is a 4- to 6-membered heterocyclyl] is.

[0118] In some embodiments, the compound of formula (I) is a compound of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (IVg): [Chemical formula] [wherein R 1 , R 3a , R 3b , R 6 , R 7 , X 1 , X 2 , and x are as described for formula (I)] It is.

[0119] In the description of this specification, any description, modification, embodiment, or aspect of a part may be combined with any description, modification, embodiment, or aspect of other parts, and it is understood that any combination of descriptions is the same as if specifically and individually described. For example, for R in formula (I) 1 any description, modification, embodiment, or aspect provided herein regarding 2 R 3a R 3b R 4 R 6 R 7 R 8 X 1 X 2 x, and n may be combined with any description, modification, embodiment, or aspect, and any combination is the same as if specifically and individually described. All descriptions, modifications, 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 any description, modification, embodiment, or aspect is the same as if separately and individually described for all formulas. For example, all descriptions, modifications, 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 (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (II-A), (II-B), (IIA), (IIB), (IIC), (IID), (IIE), (IIF), (IIG), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), (IIIG), (III-A), (III-B), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), or (IVg), etc.) detailed herein, and any description, modification, embodiment, or aspect is the same as if separately and individually described for all formulas.

[0120] In some embodiments, a compound selected from the compounds described in Table 1, or a pharmaceutically acceptable salt thereof, is 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. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

Table 14

Table 15

Table 16

[0121] It is understood that, in this specification, combinations of substituents and / or variables of the formulas depicted are only permitted if such combinations result in stable compounds.

[0122] Furthermore, all compounds of formula (I) that exist in the free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid, by methods known to those skilled in the art. The salts of the compounds of formula (I) can be converted into their free base or acid forms by standard techniques.

[0123] Synthesis Methods The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or by the methods provided herein. By way of example and not limitation, the compounds of formula (I) can be prepared as outlined in Scheme 1, as well as in 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 reach the desired product.

Chemical formula

[0124] As outlined in Scheme 1, the compound of formula A can be synthesized via an intermediate b formed by coupling a bromine-substituted ring a with Boc-protected 3-iodoazetidine, followed by deprotection by reaction with aryl bromide c to form an intermediate d. Subsequently, when intermediate d and amine e are subjected to a Schiff base reaction, the compound of formula A is obtained.

[0125] As outlined in Scheme 1, the compound of formula B can be synthesized by forming intermediate g from the bromine-substituted ring a via coupling with aryl alkyne f, followed by reacting this with amine e in a Schiff base reaction. Alternatively, the bromine-substituted ring a can first react with amine e in a Schiff base reaction to form intermediate h, and then couple with aryl alkyne f to form formula B. Further hydrogenation of the compound of formula B gives the compound of formula C. The compound of formula C can also be prepared by coupling trifluoroborate salt l to intermediate a, followed by reductive amination with amine e.

[0126] As outlined in Scheme 1, the compound of formula D can be synthesized by reacting the bromine-substituted ring a with amine e to form intermediate h, followed by coupling this with the amine of azetidine aryl i in a coupling reaction.

[0127] As outlined in Scheme 1, the compound of formula E can be synthesized via two routes from intermediate h. One involves a two-step reaction, where first intermediate h is reacted with a dioxaborolane compound in a coupling reaction to form intermediate j, which is then further coupled with aryl bromide c to form the compound of formula E. The other involves a direct coupling reaction of intermediate h with dioxaborolane aryl k, which forms the compound of formula E.

Chemical Structure

[0128] Scheme 2 shows the synthetic route of the compound of formula F. Reaction of intermediate l with benzyl bromide m forms intermediate n, which is then coupled with amine o to form the compound of formula F.

[0129] Methods of Use Embodiments of the present disclosure provide a method of modulating sphingosine 1-phosphate receptor 5 (S1P5) in a subject in need of treatment, which comprises administering to the subject an effective amount of a compound of formula (I). Modulation of S1P5 (e.g., inhibition or activation) can be evaluated and demonstrated by various methods known in the art. Kits and commercially available assays can be utilized to determine whether S1P5 is modulated (e.g., inhibited or activated) and to what extent.

[0130] In one aspect, provided herein is a method of modulating S1P5, which comprises contacting S1P5 with an effective amount of a compound of formula (I) or any embodiment or variant thereof. In some embodiments, the compound of formula (I) inhibits S1P5. In other embodiments, the compound of formula (I) activates S1P5. In some embodiments, the compound of formula (I) is an agonist of S1P5. In some embodiments, the compound of formula (I) is an antagonist of S1P5.

[0131] 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) modulates the activity of S1P5 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 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%.

[0132] In another aspect, there is provided herein a method of treating a neurological disorder in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of formula (I). In some embodiments, there is provided herein a method of preventing a neurological disorder in a subject in need of prevention, the method comprising administering to the subject an effective amount of a compound of formula (I). Non-limiting examples of neurological disorders include Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), migraine, Bell's palsy, ataxia, cerebral aneurysm, epilepsy, stroke, 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.

[0133] In some embodiments, administration of a compound of formula (I) to a subject susceptible to a neurological disorder prevents the subject from developing symptoms of any neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject who does not yet exhibit symptoms of a neurological disorder prevents the subject from developing symptoms of any neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the degree of neurological disorder in the subject. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment stabilizes the neurological disorder (prevents or delays progression of the neurological disorder). In some embodiments, administration of a compound of formula (I) to a subject in need of treatment delays the onset or recurrence of a neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment slows the progression of a neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment provides a partial remission of the neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment provides a complete remission of the neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the dosage of one or more other drugs required to treat the neurological disorder. In some embodiments, 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 delays the progression of a 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 having a neurological disorder. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment extends the lifespan of a subject having a neurological disorder.

[0134] In one aspect, provided herein is a method for preventing a subject susceptible to a neurological disorder from developing symptoms of any neurological disorder, the method comprising administering a compound of formula (I) to the subject. In some embodiments, provided herein is a method for preventing a subject that does not yet exhibit symptoms of a neurological disorder from developing symptoms of any neurological disorder, the method comprising administering a compound of formula (I) to the subject.

[0135] In some aspects, provided herein is a method for reducing the degree of a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, provided herein is a method for stabilizing a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method prevents the worsening of a neurological disorder. In some embodiments, the method delays the worsening of a neurological disorder.

[0136] In another aspect, provided herein is a method for delaying the onset or recurrence of a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject.

[0137] In some embodiments, provided herein is a method for slowing the progression of a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method provides a partial remission of the neurological disorder. In some embodiments, the method provides a complete remission of the neurological disorder.

[0138] In a further aspect, provided herein is a method for reducing the dosage of one or more other drugs required to treat a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, provided herein is a method for enhancing the effect of another drug used to treat a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject.

[0139] A method for delaying the progression of a neurological disease in a subject, the method comprising administering to the subject a compound of formula (I), is also provided herein. In some embodiments, the method improves the quality of life of a subject having a neurological disease. In some embodiments, the method extends the lifespan of a subject having a neurological disease.

[0140] In another aspect, provided herein is a method for treating neurological symptoms caused by a disease in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of formula (I). In some embodiments, provided herein is a method for preventing neurological symptoms caused by a disease in a subject in need of prevention, the method comprising administering to the subject an effective amount of a compound of formula (I). In some embodiments, administration of a compound of formula (I) to a subject susceptible to a disease that causes neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administration of a compound of formula (I) to a subject who does not yet exhibit neurological symptoms of a disease that causes neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment reduces the degree of neurological symptoms caused by the disease in the subject. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment stabilizes (prevents or delays worsening of) 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 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 a partial remission of the disease that causes neurological symptoms. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment provides a complete remission of the disease that causes neurological symptoms. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment decreases the dosage of one or more other drugs required to treat the disease that causes neurological symptoms. 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 the disease that causes neurological symptoms.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 having a disease that causes neurological symptoms. In some embodiments, administration of a compound of formula (I) to a subject in need of treatment extends the lifespan of a subject having a disease that causes neurological symptoms. In some embodiments, the disease is Niemann-Pick disease.

[0141] In some embodiments, the compound of formula (I) is useful for treating Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile rheumatoid 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, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft-versus-host disease, organ transplant rejection (including but not limited to bone marrow and solid 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 polyangiitis of the kidney, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's disease, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, autoimmune polyglandular syndrome type I and autoimmune polyglandular syndrome type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthritis, arthrosis, Reiter's disease, psoriatic arthritis, ulcerative colitis-associated arthritis, enteropathic synovitis, Chlamydia, Yersinia and Salmonella-associated arthritis, atherosclerotic disease / arteriosclerosis, atopic allergy, autoimmune blistering diseases, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, pernicious anemia, juvenile pernicious anemia, myalgic encephalomyelitis / Chronic Fatigue Syndrome, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing cholangitis, autoimmune hepatitis of unknown origin, acquired immunodeficiency syndrome, acquired immunodeficiency-related diseases, hepatitis B, hepatitis C, unclassified immunodeficiency (unclassified hypogammaglobulinemia), dilated cardiomyopathy, infertility, female infertility, ovarian insufficiency, premature ovarian insufficiency, fibrotic lung disease, chronic wound healing, idiopathic interstitial pneumonia, post-inflammatory interstitial lung disease, fibrosis, interstitial pneumonia, interstitial lung disease associated with connective tissue disease, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, lung disease associated with Sjögren's disease,Lung diseases associated with ankylosing spondylitis, vasculitic diffuse lung diseases, lung diseases associated with hemosiderosis, drug-induced interstitial lung diseases, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung diseases, post-infectious interstitial lung diseases, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune hypoglycemia, B-type insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune diseases due to organ transplantation, chronic immune diseases due to organ transplantation, osteoarthritis, primary sclerosing cholangitis, psoriasis vulgaris type 1, psoriasis vulgaris type 2, idiopathic leukopenia, autoimmune neutropenia, renal diseases NOS, glomerulonephritides, microscopic polyangiitis of the kidney, Lyme disease, discoid lupus erythematosus, idiopathic or NOS male infertility, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, secondary pulmonary hypertension due to connective tissue disease, Goodpasture syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid diseases, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lens-induced uveitis, primary vasculitis, vitiligo, acute liver diseases, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiosyncratic liver diseases, 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 Th1-mediated diseases, acute and chronic pain (various types of pain), and cancers (e.g., lung, breast, gastric, bladder, colorectal, pancreatic, ovarian, prostate, and rectal cancers) and hematopoietic malignancies (leukemia and lymphoma), and hematopoietic malignancies (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infections, acute pancreatitis, acute renal failure, adenocarcinoma, atrial 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, anti-receptor hypersensitivity reaction, aortic aneurysm and peripheral 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 transplantation (BMT) rejection, foot block, Burkitt lymphoma, burns, cardiac arrhythmia, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammatory reaction, cartilage graft rejection, cerebellar cortical degeneration, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy-related disorders, chronic myelogenous leukemia (CML), chronic alcoholism, chronic inflammatory conditions, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal cancer, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture-negative sepsis, cystic fibrosis, cytokine therapy-related disorders, boxer dementia, demyelinating diseases, dengue hemorrhagic fever, dermatitis, skin diseases, diabetes, diabetes mellitus, diabetic atherosclerotic disorders, diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglia disorders of the brain, middle-aged Down syndrome, drug-induced movement disorders induced by drugs that block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrine disorders, laryngotracheobronchitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymus graft rejection, Friedreich ataxia, functional peripheral arterial disease, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, graft rejection of any organ or tissue, gram-negative bacterial sepsis, gram-positive bacterial sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, hemorrhage, hepatitis (type A), His bundle arrythmias, HIV infection / HIV neuropathy, Hodgkin's disease,Hyperkinesia, allergic reaction, allergic pneumonia, hypertension, hypokinesia, hypothalamic-pituitary-adrenal system evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, myasthenia, infantile spinal muscular atrophy, Takayasu arteritis, influenza A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi sarcoma, renal allograft rejection, Legionella, leishmaniasis, Hansen's disease, corticospinal tract lesion, fatty edema, hepatic allograft rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic, migraine, mitochondrial multisystem disease, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multisystem degeneration (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemia disorder, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative disease, neurogenic muscular atrophy, neutropenic fever, non-Hodgkin lymphoma, abdominal aortic and its branch occlusion, obstructive arterial disease, okt3 therapy, orchitis / epididymitis, orchitis / pyeloplasty reconstruction, organomegaly, osteoporosis, pancreatic allograft rejection, pancreatic cancer, tumor-associated syndrome / hypercalcemia associated with malignant tumor, parathyroid allograft rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic arterial disease, peripheral vascular disease, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuritis, organomegaly, endocrine abnormality, monoclonal gammopathy, and skin symptom syndrome), postperfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, pregnancy-induced hypertensive nephropathy, progressive supranuclear palsy, primary pulmonary hypertension, radiotherapy, Raynaud phenomenon and Raynaud disease, Raynaud 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 anemiaSkin allograft rejection, skin lesion syndrome, small intestine graft rejection, solid tumors, specific arrhythmias, spinocerebellar ataxia, spinocerebellar degeneration, streptococcal myositis, organic lesions of the cerebellum, subacute sclerosing panencephalitis, absence seizures, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory response syndrome, systemic juvenile idiopathic arthritis, T-cell or FAB ALL, ataxia telangiectasia, thrombotic occlusive vasculitis, thrombocytopenia, toxicity, transplantation, trauma / bleeding, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urinary tract sepsis, urticaria, valvular heart disease, aneurysms, vasculitis, venous disorders, 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-associated memory impairment (AAMI), anxiety attention deficit disorder, overall attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, central neuropathic pain syndrome, central post-stroke pain, chemotherapy-induced neuropathy, agnosia and dysfunction in mental disorders, agnosia associated with aging and neurodegeneration, agnosia associated with diabetes, agnosia in schizophrenia, complex regional pain syndrome, cognitive decline in Alzheimer's type 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, diseases associated with memory impairment, dizziness, drug 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, ischemia, learning, major depressive disorder, medullary thyroid cancer, Ménière's disease, metabolic syndrome, mild cognitive impairment, mood swings, motion sickness, pain in multiple sclerosis, narcolepsy, need for angiogenesis and neovascularization associated with skin graft angiogenesis and ischemia, need for neovascularization associated with wound healing, neuropathic pain, neuropathy, neuropathy secondary to tumor infiltration, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, pain in Parkinson's disease, pathological drowsiness, phantom limb pain, Pick's disease, polycystic ovary syndrome, post-traumatic stress disorder, postherpetic neuralgia, postmastectomy pain, postoperative painIt is useful for the treatment of disorders selected from psychotic depression, schizoaffective disorder, seizures, senile dementia, sepsis syndrome, sleep disorders, smoking cessation, neuropathic pain in subcategories such as spinal cord injury pain, steroid acute psychosis, peripheral neuropathic pain syndrome, substance abuse such as alcohol abuse, syndrome X, Tourette syndrome, treatment-resistant depression, trigeminal neuralgia, type II diabetes, rotational vertigo, and vestibular disorders.

[0142] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically or parenterally in conventional dosage forms (such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions, etc.).

[0143] The compounds disclosed in this specification can be administered orally, topically, or parenterally to a subject in conventional pharmaceutical forms (such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions, etc.). Suitable formulations can be prepared by generally used methods using conventional organic or inorganic additives, such as additives (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, 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), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol), etc. The effective amount of the compound of formula (I) in the pharmaceutical composition may be at a level that exhibits the desired effect. For example, in unit doses for both oral and parenteral administration, it is from about 0.005 mg / kg (subject's body weight) to about 10 mg / kg (subject's body weight).

[0144] The dosage of the compound of formula (I) to be administered to a subject can vary quite widely and may depend on the judgment of the treating physician. Generally, the compounds disclosed herein can be administered 1 to 4 times a day at a dosage of from about 0.001 mg / kg (of the subject's body weight) to about 10 mg / kg (of the subject's body weight), although the above dosages may vary appropriately depending on the age, weight, and medical condition of the subject and the type of administration. In one embodiment, the dosage is from about 0.001 mg / kg (of the subject's body weight) to about 5 mg / kg (of the subject's body weight), from about 0.01 mg / kg (of the subject's body weight) to about 5 mg / kg (of the subject's body weight), from about 0.05 mg / kg (of the subject's body weight) to about 1 mg / kg (of the subject's body weight), from about 0.1 mg / kg (of the subject's body weight) to about 0.75 mg / kg (of the subject's body weight) or from about 0.25 mg / kg (of the subject's body weight) to about 0.5 mg / kg (of the subject's body weight). In one embodiment, one dosage is given per day. In any given case, the amount of the compound of formula (I) administered is determined by factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0145] In some embodiments, the compound of formula (I) is administered to a subject at a dosage of 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.

[0146] In another embodiment, unit dosage formulations are provided herein that contain from about 0.1 mg to 500 mg, from about 1 mg to 250 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 1 mg to about 25 mg, or from about 1 mg to about 10 mg of the compound of formula (I).

[0147] In certain embodiments, unit dosage formulations are provided herein that contain about 0.1 mg or 100 mg of the compound of formula (I).

[0148] In another embodiment, unit dosage formulations are provided herein that contain a compound of formula (I) in an amount 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.

[0149] The compound of formula (I) can be administered once, twice, three times, four times, or more times per day. In certain embodiments, a dosage of 100 mg or less is administered as a once-daily dosage, and a dosage greater than 100 mg is administered twice daily in an amount equal to half of the total daily amount.

[0150] The compound of formula (I) can be administered orally for reasons of 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.

[0151] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracranially, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is left to the discretion of the healthcare provider and may depend in part on the site of the disease.

[0152] In one embodiment, capsules are provided herein that contain a compound of formula (I) without additional carriers, additives, or vehicles.

[0153] In another embodiment, a composition is provided herein comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, where the pharmaceutically acceptable carrier or vehicle may include additives, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0154] The composition can be in the form of tablets, chewable tablets, capsules, solutions, injectable solutions, troches, suppositories, and suspensions, and the like. The composition can be formulated to contain a daily dose, or a convenient sub-portion of a daily dose, in dosage 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 pharmaceutical chemistry. Capsules can be prepared by mixing the compound of formula (I) with a suitable carrier or diluent and filling a suitable amount of the mixture into capsules. Common carriers and diluents include, but are not limited to, inert powdered substances (such as various types of starch, etc.), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose, etc.), wheat flour, and similar edible powders.

[0155] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate a diluent, a binder, a lubricant, and a disintegrant, as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride, etc.), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars (such as lactose, fructose, glucose, and the like). Natural and synthetic rubbers are also convenient, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0156] Lubricants may be necessary in the formulation of tablets to prevent the tablet and pestle from sticking to the dye. Lubricants can be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hardened vegetable oils. Tablet disintegrants are substances that swell when wet, disintegrate the tablet, and release the compound. These include starch, clay, cellulose, algin, and rubber. More particularly, for example, corn starch and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Tablets can be coated with sugar as a flavor and filler or with a film-forming protective agent to modify the dissolution characteristics of the tablets. The composition may also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

[0157] 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 the addition of wax to slightly increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycols of various molecular weights are widely used.

[0158] The effect of the compound of formula (I) can be delayed or extended by an appropriate formulation. For example, pellets that dissolve slowly of the compound of formula (I) can be prepared and incorporated into tablets or capsules or as a sustained-release implant device. Techniques also include creating pellets with multiple different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be made long-acting by dissolving or suspending the compound of formula (I) in an oily or emulsified vehicle that allows it to disperse slowly into the serum.

[0159] Exemplary Embodiments The present disclosure is further described by the following embodiments. Each feature of the embodiments can be combined with any of the other suitable and practical embodiments.

[0160] Embodiment 1. A compound of the following formula (I):

Chemical formula

Chemical formula

[0161] Embodiment 2. L is -C≡C-, -CH2CH2-, or -CH2O-, a compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 3. L is

Chemical Structure

[0163] Embodiment 4. L is a bond, a compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 5. R 1 each independently is halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, The compound according to any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 6. R 1 is each independently F, Cl, or cyclopropyl; The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 7. x is 0, 1, or 2; The compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 8.

Chemical formula

[0168] Embodiment 9. R 2 is H, halo, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl; The compound according to any one of Embodiments 1 to 8 or a pharmaceutically acceptable salt thereof.

[0169] Embodiment 10. R 2 is H, F, Cl, -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl; The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof.

[0170] Embodiment 11. R 2 and R 3a together with the carbon atom to which they are attached form a fused cyclopentyl; R 3b is H; The compound according to any one of Embodiments 1 to 8 or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 12. R 3a and R 3b are each H, The compound according to any one of Embodiments 1 to 10 or a pharmaceutically acceptable salt thereof.

[0172] Embodiment 13. R 2 and R 4 together with the carbon atom to which they are attached form a condensed phenyl, The compound according to any one of Embodiments 1 to 8 and 12 or a pharmaceutically acceptable salt thereof.

[0173] Embodiment 14. R 4 is H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, The compound according to any one of Embodiments 1 to 12 or a pharmaceutically acceptable salt thereof.

[0174] Embodiment 15. R 4 is H, F, or -CH3, The compound according to Embodiment 14 or a pharmaceutically acceptable salt thereof.

[0175] Embodiment 16. X 1 and X 2 are independently CR 5 is, The compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt thereof.

[0176] Embodiment 17. X 1 is N; X 2 is CR 5 is, The compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt thereof.

[0177] Embodiment 18. X 1 is CR 5 ; X 2 is N, The compound according to any one of Embodiments 1 to 15 or a pharmaceutically acceptable salt thereof.

[0178] Embodiment 19. R 5 is each independently H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, The compound according to any one of Embodiments 1 to 18 or a pharmaceutically acceptable salt thereof.

[0179] Embodiment 20. R 5 is each independently H, F, -CH3, -CH2CH3, or -CH(CH3)2, The compound according to Embodiment 19 or a pharmaceutically acceptable salt thereof.

[0180] Embodiment 21. [Chemical formula] The compound according to any one of Embodiments 1 to 20 or a pharmaceutically acceptable salt thereof.

[0181] Embodiment 22. R 6 is H; R 7 is C1-C6 alkyl-OH, The compound according to any one of Embodiments 1 to 21 or a pharmaceutically acceptable salt thereof.

[0182] Embodiment 23. R 6 is H; R 7 is -CH2C(OH)(CH3)2, The compound according to Embodiment 22 or a pharmaceutically acceptable salt thereof.

[0183] Embodiment 24. R 6 and R 7 together with the nitrogen atom to which they are attached

Chemical formula

[0184] Embodiment 25. R 8 each independently is halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or -OH The compound according to Embodiment 24 or a pharmaceutically acceptable salt thereof.

[0185] Embodiment 26. R 8 each independently is -CH3, -CH2CH3, -CFH2, -CF2H, -CF3, or -OH The compound according to Embodiment 25 or a pharmaceutically acceptable salt thereof.

[0186] Embodiment 27. n is 2 The compound according to any one of Embodiments 1 to 21 and 24 to 26 or a pharmaceutically acceptable salt thereof.

[0187] Embodiment 28. One R 8 is -OH The compound according to Embodiment 27 or a pharmaceutically acceptable salt thereof.

[0188] Embodiment 29.

Chemical formula

[0189] Embodiment 30. The following formula (II):

Chemical formula

[0190] Embodiment 31. The following formula (II-A) or (II-B):

Chemical formula

Chemical formula

[0191] Embodiment 32. The following formula (III):

Chemical formula

[0192] Embodiment 33. The following formula (III-A) or (III-B):

Chemical formula

Chemical formula

[0193] Embodiment 34. A compound selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0194] Embodiment 35. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 34, and a pharmaceutically acceptable excipient.

[0195] Embodiment 36. A method for regulating sphingosine 1-phosphate receptor 5 (S1P5), comprising contacting S1P5 with an effective amount of a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 35.

[0196] Embodiment 37. A method for treating a neurological disorder in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 35.

[0197] Embodiment 38. The method according to Embodiment 37, wherein the neurological disorder is Alzheimer's disease, multiple sclerosis, migraine, and amyotrophic lateral sclerosis.

Examples

[0198] The following examples are presented as illustrations, not limitations. Compounds were named using the automatic name generation tool provided by ChemBiodraw Ultra (CambridgeSoft), which generates a systematic name of the chemical structure while supporting the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art may modify the procedures described in the examples to reach the target product.

[0199] Salts of the compounds described herein can be prepared by standard methods (such as encapsulation of an acid (e.g., TFA, formic acid, or HCl) into the mobile phase during chromatographic purification, or stirring of the product after chromatographic purification with an acid solution (e.g., aqueous HCl solution), etc.).

[0200] As used in part 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 has not been determined.

[0201] The following abbreviations may be relevant to this application. Abbreviations

Table 17

[0202] Synthesis Examples Example S1.1-(5-((2-Fluorophenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (1a&1b)

Chemical Structure

Chemical Structure

[0203] Chiral Resolution of 1-(5-Bromoinden-1-yl)-3-methylazetidin-3-ol

Chemical Structure

[0204] Synthesis of 1-[5-[2-(2-Fluorophenyl)ethynyl]inden-1-yl]-3-methylazetidin-3-ol (1a)

Chemical Structure

[0205] LCMS (ESI, m / z): 322 [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 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.569 min

[0206] 11H NMR (400 MHz, DMSO-d6) δ 7.64-7.60 (m, 1H), 7.50-7.45 (m, 1H), 7.42 (s, 1H), 7.37-7.25 (m, 4H), 5.16 (s, 1H), 3.84-3.81 (m, 1H), 3.19-3.17 (m, 1H), 3.13-3.09 (m, 2H), 2.96 (d, J = 6.4 Hz, 1H), 2.91 (t, J = 8.0 Hz, 1H), 2.79-2.72 (m, 1H), 2.09-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.32 (s, 3H)

[0207] Synthesis of 1-[5-[2-(2-Fluorophenyl)ethynyl]inden-1-yl]-3-methylazetidin-3-ol (1b) [Chemical formula] In DMF (2 mL), to a stirred solution of 1-(5-bromoindan-1-yl)-3-methylazetidin-3-ol (100 mg, 0.35 mmol, 1 equiv.) were added 1-ethynyl-2-fluorobenzene (213 mg, 1.77 mmol, 5 equiv.), Pd(PPh3)2Cl2 (25 mg, 0.04 mmol, 0.1 equiv.), CuI (14 mg, 0.07 mmol, 0.2 equiv.), and K2CO3 (143 mg, 1.06 mmol, 3 equiv.). The resulting mixture was stirred at 80 °C overnight. 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 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: 40% B to 60% B in 7 min; 210 / 254 nm; RT: 6.52 min) to give 1-[5-[2-(2-fluorophenyl)ethynyl]indan-1-yl]-3-methylazetidin-3-ol (25.3 mg, 22%) as a white solid.

[0208] LCMS (ESI, m / z): 322 [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: from 10% B to 95% B in 2.00 min, held at 95% for 0.60 min, from 95% B to 10% B in 0.15 min; 254 nm; RT: 1.569 min

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.60 (m, 1H), 7.50 - 7.45 (m, 1H), 7.42 (s, 1H), 7.36 - 7.25 (m, 4H), 5.16 (s, 1H), 3.84 - 3.81 (m, 1H), 3.19 - 3.17 (m, 1H), 3.13 - 3.09 (m, 2H), 2.96 (d, J = 6.8 Hz, 1H), 2.91 (t, J = 8.0 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.09 - 2.00 (m, 1H), 1.87 - 1.79 (m, 1H), 1.32 (s, 3H)

[0210] Example S2.1-[5-[2-(3-Fluorophenyl)ethynyl]inden-1-yl]-3-methylazetidin-3-ol (2a&2b)

Chem.

Chem.

[0211] LCMS (ESI, m / z): 322 [M+H] + . Analytical conditions: column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (0.05% TFA); flow rate: 1.20 mL / min; gradient: 5% B to 100% B in 2.00 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.05 min; 254 nm; RT: 1.294 min

[0212] 11H NMR (400 MHz, DMSO-d6) δ 7.50-7.44 (m, 1H), 7.42-7.38 (m, 3H), 7.37-7.34 (m, 1H), 7.30-7.25 (m, 2H), 5.16 (s, 1H), 3.84-3.81 (m, 1H), 3.19-3.17 (m, 1H), 3.13-3.09 (m, 2H), 2.96 (d, J = 6.8 Hz, 1H), 2.91 (t, J = 8.0 Hz, 1H), 2.79-2.72 (m, 1H), 2.09-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.32 (s, 3H)

[0213] Synthesis of 1-[5-[2-(3-Fluorophenyl)ethynyl]inden-1-yl]-3-methylazetidin-3-ol (2b) [Chemical formula] In DMF (2 mL), to a stirred solution of 1-(5-bromoindan-1-yl)-3-methylazetidin-3-ol (100 mg, 0.35 mmol, 1 equiv.) were added 1-ethynyl-3-fluorobenzene (213 mg, 1.77 mmol, 5 equiv.), Pd(PPh3)2Cl2 (25 mg, 0.04 mmol, 0.1 equiv.), CuI (14 mg, 0.07 mmol, 0.2 equiv.), and K2CO3 (143 mg, 1.06 mmol, 3 equiv.). The resulting mixture was stirred at 80 °C overnight. 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 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: 45% B to 75% B in 7 min; 254 / 210 nm; RT: 6.32 min) to give 1-[5-[2-(3-fluorophenyl)ethynyl]indan-1-yl]-3-methylazetidin-3-ol (85.9 mg, 74%) as a white solid.

[0214] LCMS (ESI, m / z): 322 [M+H] + . Analytical conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 2.00 min, hold at 100% for 0.70 min, from 100% B to 5% B in 0.05 min; 254 nm; RT: 1.292 min

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.44 (m, 1H), 7.42 - 7.37 (m, 3H), 7.36 - 7.34 (m, 1H), 7.30 - 7.25 (m, 2H), 5.17 (s, 1H), 3.84 - 3.81 (m, 1H), 3.19 - 3.17 (m, 1H), 3.14 - 3.09 (m, 2H), 2.96 (d, J = 6.4 Hz, 1H), 2.91 (t, J = 8.0 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.09 - 2.00 (m, 1H), 1.87 - 1.79 (m, 1H), 1.32 (s, 3H)

[0216] Example S3.1-(5-((2,6-Dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3a&3b)

Chem.

Chem.

[0217] Synthesis of 1-(5-((2,6-Dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol [Chemical formula] In methanol (2 mL), a mixture of NaCNBH3 (82 mg, 1.30 mmol, 4 equiv.) and ZnCl2 (4 M in 4Me-THF, 0.17 mL, 0.65 mmol, 2 equiv.) was stirred at room temperature for 30 minutes. Next, 3-methylazetidin-3-ol (57 mg, 0.650 mmol, 2 equiv.) and 5-[(2,6-dichlorophenyl)methoxy]indan-1-one (100 mg, 0.33 mmol, 1 equiv.) were added. The resulting mixture was stirred at 60 °C overnight. LCMS indicated that the reaction was complete. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 65% B in 7 min; 210 / 254 nm; RT: 6.59 min) to give 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (100 mg, 80%) as a white solid. LCMS (ESI, m / z): 378 [M+H] +

[0218] Chiral Resolution of 1-(5-((2,6-Dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3a)

Chem.

[0219] LCMS (ESI, m / z): 378 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 50 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: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 0.916 min

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.55 (m, 2H), 7.49 - 7.45 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.0, 2.4 Hz, 1H), 5.18 (s, 2H), 5.14 (s, 1H), 3.75 - 3.73 (m, 1H), 3.19 - 3.17 (m, 1H), 3.09 - 3.06 (m, 2H), 2.95 - 2.87 (m, 2H), 2.74 - 2.67 (m, 1H), 2.08 - 1.97 (m, 1H), 1.86 - 1.79 (m, 1H), 1.31 (s, 3H)

[0221] Chiral Resolution of 1-(5-((2,6-Dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3b)

Chemical formula

[0222] LCMS (ESI, m / z): 378 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 50 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: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 0.911 min

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.55 (m, 2H), 7.49 - 7.45 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.0, 2.4 Hz, 1H), 5.18 (s, 2H), 5.14 (s, 1H), 3.75 - 3.73 (m, 1H), 3.19 - 3.17 (m, 1H), 3.10 - 3.06 (m, 2H), 2.95 - 2.87 (m, 2H), 2.74 - 2.67 (m, 1H), 2.08 - 1.97 (m, 1H), 1.86 - 1.79 (m, 1H), 1.31 (s, 3H)

[0224] Example S4.1-(5-(4-Cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (4a&4b)

Chem.

Chem.

[0225] Synthesis of 1-[5-(3-chloro-4-fluoropropylphenyl)indan-1-yl]-3-methylazetidin-3-ol

Chemical Structure

[0226] Chiral resolution of 1-[5-(3-chloro-4-fluoropropylphenyl)indan-1-yl]-3-methylazetidin-3-ol (4a)

Chemical Structure

[0227] LCMS (ESI, m / z): 338 [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: from 10% B to 95% B in 2.00 min, held at 95% for 0.60 min, from 95% B to 10% B in 0.15 min; 254 nm; RT: 1.690 min

[0228] 1 H NMR (400 MHz, methanol-d4) δ 7.49 (s, 1H), 7.43 - 7.38 (m, 2H), 7.32 (dd, J = 8.0, 2.0 Hz, 1H), 7.27 (dd, J = 12.0, 2.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 4.04 - 4.01 (m, 1H), 3.48 - 3.42 (m, 2H), 3.40 - 3.38 (m, 1H), 3.25 - 3.23 (m, 1H), 3.17 - 3.09 (m, 1H), 2.92 - 2.85 (m, 1H), 2.30 - 2.21 (m, 1H), 2.15 - 2.08 (m, 1H), 1.98 - 1.91 (m, 1H), 1.48 (s, 3H), 1.05 - 1.00 (m, 2H), 0.79 - 0.75 (m, 2H)

[0229] Chiral resolution of 1-[5-(3-chloro-4-fluoropropylphenyl)indan-1-yl]-3-methylazetidin-3-ol (4b) [Chemical formula] The racemate was separated by chiral HPLC (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 45 mL / min; Gradient: from 5% B to 5% B in 24 min; Wavelength: 220 / 254 nmn), and the first elution peak (47.2 mg, Rt: 21.712 min) was obtained as a white solid.

[0230] LCMS (ESI, m / z): 338 [M+H] + . Analysis conditions: Column: EVO C18, 3.0*50 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: from 10% B to 95% B in 2.00 min, held at 95% for 0.60 min, from 95% B to 10% B in 0.15 min; 254 nm; RT: 1.687 min

[0231] 1 H NMR (400 MHz, methanol-d4) δ 7.49 (s, 1H), 7.43 - 7.37 (m, 2H), 7.31 (dd, J = 8.0, 2.0 Hz, 1H), 7.27 (dd, J = 12.0, 2.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 4.03 - 4.00 (m, 1H), 3.47 - 3.42 (m, 2H), 3.39 - 3.37 (m, 1H), 3.24 - 3.22 (m, 1H), 3.17 - 3.09 (m, 1H), 2.91 - 2.84 (m, 1H), 2.29 - 2.20 (m, 1H), 2.15 - 2.08 (m, 1H), 1.97 - 1.90 (m, 1H), 1.48 (s, 3H), 1.04 - 0.99 (m, 2H), 0.78 - 0.75 (m, 2H)

[0232] Example S5. 1-(5-(3-chlorocyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (5a&5b)

Chem.

Chem.

[0233] Synthesis of 1-[5-(3-chlorocyclopropylphenyl)indan-1-yl]-3-methylazetidin-3-ol [Chemical formula] A mixture of NaCNBH3 (133 mg, 2.12 mmol, 4 equiv.) and ZnCl2 (2 M in 4Me-THF, 0.53 mL, 1.06 mmol, 2 equiv.) in methanol (3 mL) was stirred at room temperature for 30 min. Next, 3-methylazetidin-3-ol (92 mg, 1.06 mmol, 2 equiv.) and 5-(3-chloro-4-cyclopropylphenyl)indan-1-one (150 mg, 0.53 mmol, 1 equiv.) were added. The resulting mixture was stirred at 60 °C overnight. LCMS indicated that the reaction was complete. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: SunFire Prep C18 OBD Column, 19×150 mm, 5 μm; mobile phase A: water (0.05% HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B in 10 min; 254 / 210 nm; Rt: 8.19 min) to give 1-[5-(3-chloro-4-cyclopropylphenyl)indan-1-yl]-3-methylazetidin-3-ol (120 mg, 64%) as a yellow solid. LCMS (ESI, m / z): 354 [M+H] +

[0234] Chiral resolution of 1-[5-(3-chlorocyclopropylphenyl)indan-1-yl]-3-methylazetidin-3-ol (5a) [Chemical formula] The racemate was separated by SFC (column: Lux 5 μm Cellulose-4, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 60 mL / min; gradient: 50% B; 220 nm) to give the first eluted peak (29.0 mg, Rt: 5.59 min) as a yellow solid.

[0235] LCMS (ESI, m / z): 354 [M+H] +Analysis conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 2.00 min, hold at 100% for 0.70 min, from 100% B to 5% B in 0.05 min; 254 nm; RT: 1.645 min

[0236] 1 H NMR (300 MHz, methanol-d4) δ 7.64 - 7.61 (m, 3H), 7.57 - 7.53 (m, 1H), 7.48 (dd, J = 8.1, 1.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.96 (dd, J = 7.8, 1.8 Hz, 1H), 4.31 - 4.16 (m, 3H), 4.08 (d, J = 10.5 Hz, 1H), 3.29 - 3.21 (m, 1H), 3.10 - 3.00 (m, 1H), 2.64 - 2.51 (m, 1H), 2.29 - 2.19 (m, 2H), 1.56 (s, 3H), 1.10 - 1.03 (m, 2H), 0.77 - 0.71 (m, 2H)

[0237] Chiral resolution of 1-[5-(3-chlorocyclopropylphenyl)indan-1-yl]-3-methylazetidin-3-ol (5b)

Chemical formula

[0238] LCMS (ESI, m / z): 354 [M + H] +Analysis conditions: Column: Shim-pack XR-ODS, 3.0 * 50 mm, 2.2 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 2.00 min, hold at 100% for 0.70 min, from 100% B to 5% B in 0.05 min; 254 nm; RT: 1.652 min

[0239] 1 H NMR (300 MHz, methanol-d4) δ 7.64 - 7.61 (m, 3H), 7.57 - 7.54 (m, 1H), 7.48 (dd, J = 8.1, 1.8 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 4.96 (dd, J = 7.8, 3.0 Hz, 1H), 4.31 - 4.16 (m, 3H), 4.08 (d, J = 10.5 Hz, 1H), 3.29 - 3.21 (m, 1H), 3.10 - 3.01 (m, 1H), 2.64 - 2.51 (m, 1H), 2.28 - 2.19 (m, 2H), 1.56 (s, 3H), 1.10 - 1.03 (m, 2H), 0.77 - 0.72 (m, 2H)

[0240] Example S6. 1-(5-(3-chlorocyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (6)

Chemical formula

[0241] 1 H NMR (400 MHz, chloroform-d) δ 7.60-7.59 (m, 1H), 7.45-7.38 (m, 4H), 6.99 (d, J = 8.0 Hz, 1H), 4.38-4.35 (m, 1H), 3.15-3.07 (m, 2H), 2.93-2.57 (m, 4H), 2.52-2.43 (m, 1H), 2.28-2.14 (m, 3H), 1.98-1.85 (m, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.09-1.00 (m, 2H), 0.77-0.742 (m, 2H)

[0242] LCMS (ESI, m / z): 382 [M+H] +Analysis conditions: Column: HALO C18, 3.0*30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.50 mL / min; Gradient: from 5% B to 100% B in 1.30 min, hold at 100% for 0.50 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.998 min

[0243] Example S7. 1-(5-(3-chlorocyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (7)

Chem.

[0244] 1H NMR (400 MHz, chloroform-d) δ 7.59 (s, 1H), 7.54-7.50 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.03-7.01 (m, 1H), 5.03-4.93 (m, 1H), 3.31-3.11 (m, 5H), 2.70-2.46 (m, 3H), 2.29-2.23 (m, 1H), 1.40 (m, 3H), 1.28 (s, 2H), 1.11-1.06 (m, 2H), 0.78-0.74 (m, 2H)

[0245] LCMS (ESI, m / z): 368 [M+H] + Analysis conditions: Column: HALO C18, 3.0*30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.50 mL / min; Gradient: 5% B to 100% B in 1.30 min, hold at 100% for 0.50 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 0.993 min

[0246] Example S8. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (8) [ka] Synthesis of tert-butyl 3-(1-oxoindan-5-yl)azetidine-1-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (60 g, 211 mmol, 4.00 equiv.) in DMF (900 mL) was added zinc powder (22.5 g, 344 mmol, 7.00 equiv.). The mixture solution was stirred at 80 °C for 2 h. Next, 5-bromoindan-1-one (10.5 g, 49.8 mmol, 1.00 equiv.), Pd2(dba)3 (4.5 g, 4.97 mmol, 0.10 equiv.), and tri-m-tolylphosphane (3.0 g, 9.95 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was filtered. The filtrate was diluted with water (2 L) and extracted with ethyl acetate (5 x 400 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (eluting with dichloromethane / methanol, 20 / 1) to give tert-butyl 3-(1-oxoindan-5-yl)azetidine-1-carboxylate (4.5 g, 31%) as an off-white solid. LCMS (ESI, m / z): 288 [M+H] +

[0247] Synthesis of 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one [Chemical formula] To a solution of tert-butyl 3-(1-oxo-2,3-dihydro-1H-inden-5-yl)azetidine-1-carboxylate (600 mg, 1.50 mmol, 1.00 equiv.) in DCM (5 mL) was added TBSOTf (0.4 mL, 2.25 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 1 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated in vacuo. The crude product was purified by C18 flash column (eluting with water / ACN, 5 / 95) to give 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 77%) as a white solid. LCMS (ESI, m / z): 188 [M+H] +

[0248] Synthesis of 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one

Chem.

[0249] Synthesis of 1-[5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-yl]-4-methylpiperidin-4-ol (8)

Chem.

[0250] LCMS (ESI, m / z): 431 [M+H] + Analysis conditions: Column: HALO C18 Column 3.0*30 mm, 2.0 μm; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.20 mL / min; Gradient: 5% B to 100% B in 1.2 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.893 min

[0251] 11H NMR (300 MHz, DMSO-d6) δ 7.27 - 7.21 (m, 5H), 6.74 (t, J = 8.1 Hz, 1H), 4.82 (t, J = 8.1 Hz, 2H), 4.40 - 4.32 (m, 2H), 4.24 (t, J = 7.2 Hz, 2H), 4.04 (s, 1H), 3.79 - 3.69 (m, 1H), 2.91 - 2.68 (m, 2H), 2.56 - 2.38 (m, 2H), 2.21 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.49 - 1.34 (m, 4H), 1.08 (s, 3H)

[0252] Example S9.1 - (5-(1-(2,6-Dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (9) [Chemical formula] In methanol (2.0 mL), to a stirred solution of 5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-one (60 mg, 0.18 mmol, 1.00 equiv.) and 3-methylpyrrolidin-3-ol (54 mg, 0.54 mmol, 3.00 equiv.) were added NaBH3CN (34 mg, 0.54 mmol, 3.00 equiv.) and ZnCl2 (2 M in THF, 0.18 mL, 0.36 mmol, 2.00 equiv.). The mixture solution was stirred at 80 °C overnight. LCMS indicated that the reaction was complete. The reaction was quenched with water (10 mL) and extracted with dichloromethane (2 x 10 mL). The organic layer was concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge C18 OBD Prep Column, 5 μm, 19*250 mm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 60% B to 90% B in 9 min; wavelength: 254 / 220 nm; RT: 8.12 min) to give 1-[5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-yl]-3-methylpyrrolidin-3-ol (66.1 mg, 86%) as a pale orange semi-solid.

[0253] LCMS (ESI, m / z): 417 [M+H] + . Analytical conditions: Column: HALO C18 Column 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: from 5% B to 65% B in 1.7 min, from 65% B to 100% B in 0.3 min, held at 100% for 0.6 min, from 100% B to 5% B in 0.10 min; 254 nm; RT: 1.495 min

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.18 (m, 5H), 6.75 (t, J = 8.0 Hz, 1H), 4.82 (t, J = 8.0 Hz, 2H), 4.46 - 4.44 (m, 1H), 4.34 (t, J = 7.6 Hz, 2H), 4.10 (t, J = 6.0 Hz, 1H), 3.78 - 3.70 (m, 1H), 2.95 - 2.88 (m, 1H), 2.77 - 2.67 (m, 2H), 2.63 - 2.54 (m, 1H), 2.52 - 2.45 (m, 1H), 2.09 - 2.00 (m, 2H), 1.73 - 1.60 (m, 2H), 1.22 (s, 3H)

[0255] Example S10.1 - (5-(3-Chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (10a&10b)

Chem.

Chem.

[0256] Synthesis of 5-(3-Chloro-4-cyclopropylphenyl)-7-methylindan-1-ol [Chemical formula] To a stirred solution of 5-(3-chloro-4-cyclopropylphenyl)-7-methylindan-1-one (500 mg, 1.68 mmol, 1.00 equiv.) in methanol (5 mL) was added NaBH4 (191 mg, 5.05 mmol, 3.00 equiv.). The resulting mixture was stirred at 0 °C for 2 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated in vacuo. The residue was purified by C18 silica flash column chromatography (eluting with water / acetonitrile, 2 / 3) to afford 5-(3-chloro-4-cyclopropylphenyl)-7-methylindan-1-ol (350 mg, 69%) as a pale yellow oil. LCMS (ESI, m / z): 299 [M+H] +

[0257] Synthesis of 1-Chloro-5-(3-chloro-4-cyclopropylphenyl)-7-methylindan

Chem.

[0258] Synthesis of 1-[5-(3-chloro-4-cyclopropylphenyl)-7-methylindan-1-yl]-3-methylazetidin-3-ol

Chem.

[0259] Chiral resolution of 1-[5-(3-Chloro-4-cyclopropylphenyl)-7-methylindan-1-yl]-3-methylazetidin-3-ol (10a)

Chem.

[0260] 1 H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.1, 2.1 Hz, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 5.11 (s, 1H), 4.08-4.04 (m, 1H), 3.12 (d, J = 6.0 Hz, 1H), 3.06-2.91 (m, 4H), 2.80-2.71 (m, 1H), 2.42 (s, 3H), 2.22-2.10 (m, 2H), 1.96-1.84 (m, 1H), 1.32 (s, 3H), 1.07-1.00 (m, 2H), 0.77-0.72 (m, 2H)

[0261] LCMS (ESI, m / z): 368 [M+H] +Analysis conditions: Column: L‐column3 C18 Column 3.0*30 mm, 2.0 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.5000 mL / min; Gradient: 30% B to 80% B in 1.80 min, 80% B to 95% B in 0.5 min, hold at 95% for 0.5 min, 95% B to 10% B in 0.1 min; 254 nm; RT: 2.006 min

[0262] Chiral resolution of 1-[5-(3-Chloro-4-cyclopropylphenyl)-7-methylindan-1-yl]-3-methylazetidin-3-ol (10b) [ka] The racemate (80 mg) was purified by Prep-Chiral HPLC (Column: Lux 5 μm Cellulose-2, 2.12*25 cm, 5 μm; Mobile phase A: Hex (0.2% DEA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 2% B to 2% B in 25 min; 220 / 254 nm; RT2: 22.478 min) to give 1-[5-(3-chloro-4-cyclopropylphenyl)-7-methylindan-1-yl]-3-methylazetidin-3-ol (33.4 mg, 41%) as an off-white solid.

[0263] 11H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.1, 2.1 Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 5.11 (s, 1H), 4.06 (d, J = 6.6 Hz, 1H), 3.12 (d, J = 6.0 Hz, 1H), 3.06 - 2.94 (m, 4H), 2.80 - 2.72 (m, 1H), 2.42 (s, 3H), 2.22 - 2.10 (m, 2H), 1.96 - 1.84 (m, 1H), 1.32 (s, 3H), 1.07 - 1.00 (m, 2H), 0.77 - 0.72 (m, 2H)

[0264] LCMS (ESI, m / z): 368 [M+H] + . Analytical conditions: Column: EVO C18, 2.1 * 30 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: from 10% B to 95% B in 1.20 min, hold at 95% for 0.58 min, from 95% B to 10% B in 0.05 min; 254 nm; RT: 1.157 min

[0265] Example S11.1 - (5-(3-Chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (11)

Chemical formula

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (m, 1H), 7.47 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.00-4.97 (m, 1H), 3.41-3.38 (m, 1H), 3.33-3.19 (m, 2H), 3.13-3.00 (m, 2H), 2.93-2.86 (m, 1H), 2.58-2.56 (m, 4H), 2.41-2.30 (m, 1H), 2.22-2.15 (m, 1H), 1.84-1.74 (m, 2H), 1.69-1.60 (m, 2H), 1.15 (s, 3H), 1.07-1.02 (m, 2H), 0.78-0.74 (m, 2H)

[0267] 1919F NMR (282 MHz, DMSO-d6) δ -74.202

[0268] LCMS (ESI, m / z): 396 [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: from 80% B to 95% B in 1.80 min, hold at 95% for 0.80 min, from 95% B to 10% B in 0.15 min; 254 nm; RT: 1.289 min

[0269] Example S12.1 - (5-(3-Chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (12)

Chemical Structure

[0270] 1 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.52 (m, 1H), 7.45 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.14 - 4.97 (m, 1H), 3.43 - 3.37 (m, 3H), 3.28 - 3.22 (m, 1H), 3.14 - 3.03 (m, 1H), 2.97 - 2.79 (m, 1H), 2.60 - 2.57 (m, 4H), 2.44 - 2.33 (m, 1H), 2.22 - 2.15 (m, 1H), 2.12 - 1.80 (m, 2H), 1.38 - 1.33 (m, 3H), 1.08 - 1.02 (m, 2H), 0.78 - 0.73 (m, 2H)

[0271] 19 19F NMR (282 MHz, DMSO-d6) δ -74.011

[0272] 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: from 80% B to 95% B in 1.80 min, hold at 95% for 0.80 min, from 95% B to 10% B in 0.15 min; 254 nm; RT: 1.079 min

[0273] Example S13.1 - (5-((3-Fluorophenyl)ethynyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (13a&13b) [Chemical formula] Synthesis of 5-[2-(3-Fluorophenyl)ethynyl]-7-methylindan-1-one [Chemical formula] In DMF (10.0 mL), a solution of 1-ethynyl-3-fluorobenzene (533 mg, 4.44 mmol, 2.00 equiv.), 5-bromo-7-methylinden-1-one (500 mg, 2.220 mmol, 1.00 equiv.), K2CO3 (919 mg, 6.66 mmol, 3.00 equiv.), CuI (21 mg, 0.11 mmol, 0.05 equiv.), and Pd(PPh3)2Cl2 (155 mg, 0.22 mmol, 0.10 equiv.) was stirred at 80 °C for 16 h. LCMS indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with PE / EtOAc, 3 / 1) to afford 5-[2-(3-fluorophenyl)ethynyl]-7-methylinden-1-one (500 mg, 85%) as an off-white solid. LCMS (ESI, m / z): 265 [M+H] +

[0274] Synthesis of 1-[5-[2-(3-Fluorophenyl)ethynyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol [Chemical formula] In methanol (10 mL), a solution of 5-[2-(3-fluorophenyl)ethynyl]-7-methylindan-1-one (500 mg, 1.89 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (164 mg, 1.89 mmol, 1.00 equiv.), ZnCl2 (2 M in THF, 1.9 mL, 3.78 mmol, 2.00 equiv.), and NaBH3CN (363 mg, 5.68 mmol, 3.00 equiv.) was stirred at 80 °C for 16 h. LCMS indicated completion of the reaction. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 1:1) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol (80 mg, 12%) as an off-white solid. LCMS (ESI, m / z): 336 [M+H] +

[0275] Chiral resolution of 1-[5-[2-(3-Fluorophenyl)ethynyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol (13a) [Chemical formula] The racemate (80 mg) was purified by Prep-Chiral (column: Lux 5 μm Cellulose-2, 2.12 × 25 cm, 5 μm; mobile phase A: Hex (0.1% DEA)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 25 min; 220 / 254 nm; RT1: 17.904 min) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol (the first eluted peak, 17.7 mg, 21%) as an off-white solid.

[0276] 11H NMR (300 MHz, DMSO-d6) δ 7.52-7.45 (m, 1H), 7.41-7.37 (m, 2H), 7.31-7.24 (m, 2H), 7.18 (s, 1H), 5.12 (s, 1H), 4.08 (d, J = 6.6 Hz, 1H), 3.11 (d, J = 6.3 Hz, 1H), 3.02 (d, J = 6.3 Hz, 1H), 2.98-2.90 (m, 3H), 2.79-2.71 (m, 1H), 2.38 (s, 3H), 2.19-2.12 (m, 1H), 1.96-1.83 (m, 1H), 1.32 (s, 3H)

[0277] 19F NMR (376 MHz, DMSO-d6) δ -112.515

[0278] LCMS (ESI, m / z): 336 [M+H] + . Analytical conditions: Column: L-column3 C18 Column 3.0*30 mm, 2.0 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.5000 mL / min; Gradient: from 30% B to 95% B in 2.19 min, hold at 95% for 0.6 min, from 95% B to 10% B in 0.03 min; 254 nm; RT: 1.701 min

[0279] Chiral resolution of 1-[5-[2-(3-Fluorophenyl)ethynyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol (13b)

Chem.

[0280] 1 H NMR (300 MHz, DMSO-d6) δ 7.52-7.45 (m, 1H), 7.41-7.37 (m, 2H), 7.31-7.24 (m, 2H), 7.18 (s, 1H), 5.12 (s, 1H), 4.08 (d, J = 6.6 Hz, 1H), 3.10 (d, J = 6.0 Hz, 1H), 3.02 (d, J = 6.0 Hz, 1H), 2.98-2.90 (m, 3H), 2.79-2.71 (m, 1H), 2.38 (s, 3H), 2.19-2.12 (m, 1H), 1.96-1.83 (m, 1H), 1.32 (s, 3H)

[0281] 19 F NMR (376 MHz, DMSO-d6) δ -112.173

[0282] LCMS (ESI, m / z): 336 [M+H] + . Analytical conditions: column: L‐column3 C18 Column 3.0*30 mm, 2.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: 30% B to 95% B in 2.19 min, hold at 95% for 0.6 min, 95% B to 10% B in 0.03 min; 254 nm; RT: 1.702 min

[0283] Example S14.1 - (5-(2,6-Dichlorophenethyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (14a&14b)

Chem.

Chem.

[0284] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol

Chem.

[0285] Chiral resolution of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methylinden-1-yl]-3-methylazetidin-3-ol (14a) [Chemical formula] The racemate (100 mg) was purified by Prep-Chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: from 98% B to 98% B in 15 min; 220 / 254 nm; RT1: 10.221 min) to give the desired isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methylindan-1-yl]-3-methylazetidin-3-ol (the first eluted peak, 27.7 mg, 27%) as an off-white solid.

[0286] 11H NMR (300 MHz, DMSO-d6) δ 7.50 - 7.47 (m, 2H), 7.33 - 7.27 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 5.10 (s, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.13 - 3.07 (m, 3H), 3.02 - 2.90 (m, 4H), 2.73 - 2.65 (m, 3H), 2.35 (s, 3H), 2.15 - 2.08 (m, 1H), 1.93 - 1.80 (m, 1H), 1.31 (s, 3H)

[0287] LCMS (ESI, m / z): 390 [M+H] + . Analytical conditions: Column: HALO C18 Column 3.0*30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: from 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.994 min

[0288] Chiral resolution of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methylinden-1-yl]-3-methylazetidin-3-ol (14b)

Chem.

[0289] 11H NMR (300 MHz, DMSO-d6) δ 7.51-7.47 (m, 2H), 7.33-7.27 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 5.09 (s, 1H), 4.01 (d, J = 6.6 Hz, 1H), 3.12-3.07 (m, 3H), 3.01-2.90 (m, 4H), 2.73-2.64 (m, 3H), 2.35 (s, 3H), 2.15-2.08 (m, 1H), 1.92-1.83 (m, 1H), 1.31 (s, 3H)

[0290] LCMS (ESI, m / z): 390 [M+H] + . Analytical conditions: Column: HALO C18 Column 3.0*30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: from 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.994 min

[0291] Example S15. 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (15a&15b)

Chem.

Chem.

[0292] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-7-methylinden-1-one [Chemical Formula] A solution of 5-hydroxy-7-methylindan-1-one (450 mg, 2.77 mmol, 1.00 equiv.), 2-(bromomethyl)-1,3-dichlorobenzene (732 mg, 3.05 mmol, 1.10 equiv.), and K2CO3 (1.1 mg, 8.32 mmol, 3.00 equiv.) in MeCN (10 mL) was stirred at 60 °C for 2 h. LCMS indicated the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluting with water / acetonitrile, 1:6) to give 5-[(2,6-dichlorophenyl)methoxy]-7-methylindan-1-one (600 mg, 67% yield) as an off-white solid. LCMS (ESI, m / z): 321 [M+H] +

[0293] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methylinden-1-yl]-3-methylazetidin-3-ol [Chemistry] A solution of 5-[(2,6-dichlorophenyl)methoxy]-7-methyl-1-indanone (600 mg, 1.87 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (162 mg, 1.87 mmol, 1.00 equiv.), ZnCl2 (2 M in THF, 1.8 mL, 3.74 mmol, 2.00 equiv.), and NaBH3CN (358 mg, 5.60 mmol, 3.00 equiv.) in methanol (15 mL) was stirred at 80 °C for 16 h. LCMS indicated the completion of the reaction. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluting with water / acetonitrile, 1:2) to afford 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-1-indanyl]-3-methylazetidin-3-ol (150 mg, 20%) as an off-white solid. LCMS (ESI, m / z): 392 [M+H] +

[0294] Chiral resolution of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methylinden-1-yl]-3-methylazetidin-3-ol (15a) [Chemistry] The racemate (120 mg) was purified by SFC (column: Lux 5 μm Celluloes-3, 3 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2 M NH3-MeOH); flow rate: 80 mL / min; gradient: 30% B; 220 nm; RT1: 4.21 min) to afford the desired isomer 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-1-indanyl]-3-methylazetidin-3-ol (the first eluting peak, 33.1 mg, 27%) as an off-white solid.

[0295] 11H NMR (300 MHz, DMSO-d6) δ 7.59-7.56 (m, 2H), 7.47 (dd, J = 9.0, 6.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.17 (s, 2H), 5.10 (s, 1H), 3.99 (d, J = 6.3 Hz, 1H), 3.09 (d, J = 6.0 Hz, 1H), 3.02-2.89 (m, 4H), 2.73-2.64 (m, 1H), 2.33 (s, 3H), 2.14-2.07 (m, 1H), 1.94-1.82 (m, 1H), 1.31 (s, 3H)

[0296] LCMS (ESI, m / z): 392 [M+H] + . Analytical conditions: Column: HALO C18 Column 3.0*30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: from 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.923 min

[0297] Chiral resolution of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methylinden-1-yl]-3-methylazetidin-3-ol (15b)

Chemical formula

[0298] 1 1H NMR (300 MHz, DMSO-d6) δ δ 7.59 - 7.56 (m, 2H), 7.47 (dd, J = 9.3, 6.3 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.17 (s, 2H), 5.09 (s, 1H), 3.99 - 3.95 (m, 1H), 3.09 - 3.05 (m, 1H), 3.01 - 2.90 (m, 4H), 2.73 - 2.64 (m, 1H), 2.33 (s, 3H), 2.14 - 2.07 (m, 1H), 1.94 - 1.82 (m, 1H), 1.31 (s, 3H)

[0299] LCMS (ESI, m / z): 392 [M+H] + . Analytical conditions: Column: HALO C18 Column 3.0*30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: from 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.931 min

[0300] Example S16. 1-(5-(3-chloro-4-cyclopropylphenyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (16a&16b)

Chem.

Chem.

[0301] Synthesis of 1-[5-(3-chloro-4-cyclopropylphenyl)-4-methylinden-1-yl]-3-methylazetidin-3-ol [Chemical formula] In methanol (8 mL), a mixture of 5-(3-chloro-4-cyclopropylphenyl)-4-methylindan-1-one (250 mg, 0.84 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (109 mg, 1.26 mmol, 1.50 equiv.), ZnCl2 (1.1 mL, 2 M in 4Me-THF, 2.11 mmol, 2.50 equiv.), and NaBH3CN (215 mg, 3.37 mmol, 4.00 equiv.) was stirred at 60 °C for 12 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water / acetonitrile, 1 / 3) to afford 1-[5-(3-chloro-4-cyclopropylphenyl)-4-methylindan-1-yl]-3-methylazetidin-3-ol (165 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 368 [M+H] +

[0302] Chiral resolution of 1-[5-(3-chloro-4-cyclopropylphenyl)-4-methylinden-1-yl]-3-methylazetidin-3-ol (16a) [Chemical formula] The racemate (80 mg) was purified by Prep-Chiral HPLC (column: Lux 5 μm Cellulose-2, 12*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 2% B to 2% B in 21 min; 254 / 220 nm; RT1: 16.824 min) to afford 1-[5-(3-chloro-4-cyclopropylphenyl)-4-methylindan-1-yl]-3-methylazetidin-3-ol (9.9 mg, 12%) as an off-white solid.

[0303] LCMS (ESI, m / z): 368 [M+H] +Analysis conditions: Column: L-column3 C18 Column 3.0*30 mm, 2.0 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.5000 mL / min; Gradient: from 30% B to 80% B in 1.80 min, from 80% B to 95% B in 0.5 min, hold at 95% for 0.5 min, from 95% B to 10% B in 0.1 min; 254 nm; RT: 1.771 min

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 2.0 Hz, 1H), 7.18 - 7.13 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.19 (s, 1H), 3.87 (s, 1H), 3.20 - 3.00 (m, 3H), 2.90 - 2.84 (m, 2H), 2.77 - 2.69 (m, 1H), 2.21 - 2.14 (m, 1H), 2.10 (s, 3H), 2.09 - 2.04 (m, 1H), 1.91 - 1.84 (m, 1H), 1.32 (s, 3H), 1.06 - 1.01 (m, 2H), 0.77 - 0.73 (m, 2H)

[0305] Chiral resolution of 1-[5-(3-chloro-4-cyclopropylphenyl)-4-methylinden-1-yl]-3-methylazetidin-3-ol (16b)

Chem.

[0306] LCMS (ESI, m / z): 368 [M+H] + . Analytical conditions: Column: L-column3 C18 Column 4.6*100 mm, 3.0 μm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: from 30% B to 80% B in 6.00 min, from 80% B to 95% B in 2.00 min, from 95% B to 10% B in 2.00 min; 254 nm; RT: 6.295 min

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 3.83 - 3.80 (m, 1H), 3.21 - 3.17 (m, 1H), 3.09 (s, 2H), 2.94 (d, J = 6.4 Hz, 1H), 2.91 - 2.83 (m, 1H), 2.75 - 2.67 (m, 1H), 2.21 - 2.15 (m, 1H), 2.10 (s, 3H), 2.07 - 2.00 (m, 1H), 1.89 - 1.82 (m, 1H), 1.32 (s, 3H), 1.06 - 0.99 (m, 2H), 0.77 - 0.73 (m, 2H)

[0308] Example S17. 1-(5-((3-fluorophenyl)ethynyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (17a&17b)

Chem.

Chem.

[0309] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol [Chemical formula] In methanol (10 mL), a solution of 5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-one (300 mg, 1.14 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (198 mg, 2.28 mmol, 2.00 equiv.), ZnCl2 (1.14 mL, 2 M in 4Me-THF, 2.27 mmol, 2.00 equiv.), and NaBH3CN (291 mg, 4.54 mmol, 3.00 equiv.) was stirred at 80 °C for 3 h. LCMS indicated the completion of the reaction. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 2:3) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (350 mg, 92%) as a yellow solid. LCMS (ESI, m / z): 356 [M+H] +

[0310] Chiral resolution of 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (17a) [Chemical formula] The racemate (350 mg) was separated by chiral HPLC (column: Lux 5 μm Cellulose-2, 3*15 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 5% B to 5% B in 71 min; wavelength: 220 / 254 nm; RT1: 13.238 min; RT2: 27.446 min) to give the isomers. The first eluting peak compound was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 35% B in 10 min, hold at 35% B for 2 min; wavelength: 254 / 220 nm; RT: 10.38 min) to give the desired isomer 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylindan-1-yl]-3-methylazetidin-3-ol (71.7 mg, 20.3%) as a white solid.

[0311] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H, H FA ), 7.51-7.45 (m, 1H), 7.43-7.39 (m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.30-7.25 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.18 (br, 1H), 3.87-3.85 (m, 1H), 3.22-3.20 (m, 1H), 3.14-3.10 (m, 2H), 2.97 (d, J = 6.4 Hz, 1H), 2.92-2.84 (m, 1H), 2.77-2.70 (m, 1H), 2.38 (s, 3H), 2.10-2.01 (m, 1H), 1.89-1.81 (m, 1H), 1.32 (s, 3H)

[0312] LCMS (ESI, m / z): 336 [M+H] +Analysis conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.921 min

[0313] Chiral resolution of 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (17b) [Chemical formula] The racemate (350 mg) was separated by chiral HPLC (Column: Lux 5 μm Cellulose-2, 3 * 15 cm, 5 μm; Mobile phase A: HEX (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: from 5% B to 5% B in 71 min; Wavelength: 220 / 254 nm; RT1: 13.238 min; RT2: 27.446 min), and the target isomer 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (the second elution peak, 118.6 mg, 33.6%) was obtained as a white solid.

[0314] 11H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.45 (m, 1H), 7.43 - 7.39 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 5.14 (s, 1H), 3.84 - 3.82 (m, 1H), 3.18 - 3.17 (m, 1H), 3.11 - 3.07 (m, 2H), 2.95 (d, J = 6.8 Hz, 1H), 2.92 - 2.83 (m, 1H), 2.77 - 2.70 (m, 1H), 2.38 (s, 3H), 2.09 - 2.00 (m, 1H), 1.88 - 1.81 (m, 1H), 1.32 (s, 3H)

[0315] LCMS (ESI, m / z): 336 [M+H] + . Analytical conditions: Column: HALO C18, 3.0*30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.922 min

[0316] Example S18. 1-(5-(2,6-dichlorophenethyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (18a&18b)

Chem.

Chem.

[0317] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol [Chemical formula] In methanol (5 mL), a solution of 5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-1-indanone (400 mg, 1.25 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (218 mg, 2.51 mmol, 2.00 equiv.), ZnCl2 (1.25 mL, 2 M in 4Me-THF, 2.51 mmol, 2.00 equiv.), and NaBH3CN (321 mg, 5.01 mmol, 4.00 equiv.) was stirred at 80 °C for 3 h. LCMS indicated the completion of the reaction. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep C18 OBD Column, 30 × 100 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 65% B to 85% B in 7 min; 254 / 220 nm; RT: 4.68 min) to give 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-1-indanyl]-3-methylazetidin-3-ol (390 mg, 80%) as a white solid. LCMS (ESI, m / z): 390 [M+H] +

[0318] Chiral resolution of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (18a)

Chem.

[0319] 1 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.13 (s, 1H), 3.78 - 3.75 (m, 1H), 3.18 - 3.16 (m, 1H), 3.06 - 3.00 (m, 4H), 2.92 - 2.80 (m, 2H), 2.77 - 2.66 (m, 3H), 2.25 (s, 3H), 2.04 - 1.95 (m, 1H), 1.85 - 1.78 (m, 1H), 1.30 (s, 3H)

[0320] LCMS (ESI, m / z): 390 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 1.003 min

[0321] Chiral resolution of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methylinden-1-yl]-3-methylazetidin-3-ol (18b)

Chem.

[0322] 1 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.19 (s, 1H), 3.77 - 3.74 (m, 1H), 3.18 - 3.16 (m, 1H), 3.06 - 3.00 (m, 4H), 2.92 - 2.80 (m, 2H), 2.76 - 2.66 (m, 3H), 2.24 (s, 3H), 2.04 - 1.95 (m, 1H), 1.84 - 1.78 (m, 1H), 1.30 (s, 3H)

[0323] LCMS (ESI, m / z): 390 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 0.990 min

[0324] Example S19. 1-(5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (19a&19b)

Chem.

Chem.

[0325] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-4-methylinden-1-one

Chemical Structure

[0326] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylinden-1-yl]-3-methylazetidin-3-ol [Chemistry] In methanol (5 mL), a solution of 5-[(2,6-dichlorophenyl)methoxy]-4-methylindan-1-one (300 mg, 0.93 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (162 mg, 1.87 mmol, 2.00 equiv.), ZnCl2 (1.2 mL, 2M in 4Me-THF, 2.33 mmol, 2.50 equiv.), and NaBH3CN (239 mg, 3.74 mmol, 4.00 equiv.) was stirred at 60 °C for 12 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluting with water / acetonitrile, 1:1) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylindan-1-yl]-3-methylazetidin-3-ol (300 mg, 81%) as a yellow solid. LCMS (ESI, m / z): 392 [M+H] +

[0327] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylinden-1-yl]-3-methylazetidin-3-ol (19a) [Chemistry] The racemate (150 mg) was purified by Prep-Chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12 × 25 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 90% B to 90% B in 15 min; 220 / 254 nm; RT1: 11.889 min) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylindan-1-yl]-3-methylazetidin-3-ol (37.7 mg, 24%) as an off-white solid.

[0328] 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.48 (dd, J = 9.0, 6.9 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 5.20 (s, 2H), 5.15 (s, 1H), 3.79-3.75 (m, 1H), 3.23-3.20 (m, 1H), 3.10-3.08 (m, 2H), 2.96-2.94 (m, 1H), 2.87-2.76 (m, 1H), 2.71-2.62 (m, 1H), 2.08-2.02 (m, 1H), 2.00 (s, 3H), 1.87-1.80 (m, 1H), 1.32 (s, 3H)

[0329] LCMS (ESI, m / z): 392 [M+H] + Analysis conditions: Column: L‐column3 C18 Column 3.0*30 mm, 2.0 μm; Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 30% B to 80% B in 1.80 min, 80% B to 95% B in 0.5 min, hold at 95% for 0.5 min, 95% B to 10% B in 0.1 min; 210 nm; RT: 1.461 min

[0330] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylinden-1-yl]-3-methylazetidin-3-ol (19b) [ka] The racemate (150 mg) was purified by Prep-Chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12*25 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: from 90% B to 90% B in 15 min; 220 / 254 nm; RT1: 13.499 min) to obtain 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methylinden-1-yl]-3-methylazetidin-3-ol (36.1 mg, 23%) as an off-white solid.

[0331] 1 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.55 (m, 2H), 7.46 (dd, J = 9.0, 6.9 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 5.19 (s, 2H), 3.80-3.77 (m, 1H), 3.24-3.21 (m, 1H), 3.11-3.08 (m, 2H), 2.97-2.95 (m, 1H), 2.87-2.76 (m, 1H), 2.70-2.61 (m, 1H), 2.09-2.02 (m, 1H), 2.00 (s, 3H), 1.88-1.78 (m, 1H), 1.33 (s, 3H)

[0332] LCMS (ESI, m / z): 392 [M+H] + . Analytical conditions: column: L-column3 C18 Column 3.0*30 mm, 2.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.50 mL / min; gradient: from 30% B to 80% B in 1.80 min, from 80% B to 95% B in 0.5 min, held at 95% for 0.5 min, from 95% B to 10% B in 0.1 min; 210 nm; RT: 1.462 min

[0333] Example S20. 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20a&20b) [Chemistry] Synthesis of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol [Chemistry] In methanol (5 mL), a solution of 5-[(2,6-dichlorophenyl)methoxy]-4-methyl-1-indanone (120 mg, 0.37 mmol, 1.00 equiv.), 1-amino-2-methyl-2-propanol (66 mg, 0.75 mmol, 2.00 equiv.), NaHB3CN (94 mg, 1.49 mmol, 4.00 equiv.), and ZnCl2 (2 M in 4Me-THF, 0.37 mL, 0.75 mmol, 2.00 equiv.) was stirred at 80 °C for 15 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (40 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluting with PE / EtOAc, 1:3) to give 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methyl-2-propanol (120 mg, 81%) as a yellow oil. LCMS (ESI, m / z): 394 [M+H] +

[0334] Chiral resolution of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20a) [Chemistry] The racemate (120 mg) was separated by chiral HPLC (column: XBridge Prep C18 OBD Column, 30*100 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 48% B to 73% B in 9 min, 73% B; wavelength: 254 / 220 nm; RT: 8.85 min), and the target isomer 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (the first elution peak, 31.1 mg, 25%, 100% e.e.) was obtained as a yellow oil.

[0335] 1 H NMR (400 MHz, methanol-d4) δ 7.48 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.37 (dd, J = 8.8, 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 4.29 (t, J = 6.4 Hz, 1H), 3.02 - 2.95 (m, 1H), 2.80 - 2.72 (m, 1H), 2.64 (d, J = 2.8 Hz, 2H), 2.44 - 2.36 (m, 1H), 2.09 (s, 3H), 1.98 - 1.91 (m, 1H), 1.25 (s, 3H), 1.24 (s, 3H)

[0336] LCMS (ESI, m / z): 394 [M+H] + . Analytical conditions: column: HALO C18 Column 3.0*30 mm, 2.7 μm; mobile phase A: water / 0.05% TFA, mobile phase B: acetonitrile / 0.05% TFA; flow rate: 1.50 mL / min; gradient: from 5% B to 100% B in 1.19 min, held at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 0.962 min

[0337] Chiral resolution of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20b)

Chem.

[0338] 1 H NMR (400 MHz, methanol - d4) δ 7.48 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.37 (dd, J = 8.8, 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.29 (s, 2H), 4.28 (t, J = 6.4 Hz, 1H), 3.02 - 2.94 (m, 1H), 2.79 - 2.71 (m, 1H), 2.64 (d, J = 2.0 Hz, 2H), 2.44 - 2.35 (m, 1H), 2.09 (s, 3H), 1.98 - 1.89 (m, 1H), 1.25 (s, 3H), 1.24 (s, 3H)

[0339] LCMS (ESI, m / z): 394 [M + H] +Analysis conditions: Column: HALO C18 Column 3.0*30 mm, 2.7 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.50 mL / min; Gradient: from 5% B to 100% B at 1.19 min, hold at 100% for 0.6 min, from 100% B to 5% B at 0.03 min; 210 nm; RT: 0.964 min

[0340] Example S21. 1-(5-(3-chloro-4-cyclopropylphenyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (21a&21b)

Chem.

Chem.

[0341] Synthesis of 1-[5-(3-chloro-4-cyclopropylphenyl)-6-methylinden-1-yl]-3-methylazetidin-3-ol

Chem.

[0342] Chiral resolution of 1-[5-(3-chloro-4-cyclopropylphenyl)-6-methylinden-1-yl]-3-methylazetidin-3-ol (21a)

Chemical Structure

[0343] 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 5.14 (s, 1H), 3.80-3.77 (m, 1H), 3.21-3.19 (m, 1H), 3.16-3.09 (m, 2H), 2.96-2.93 (m, 1H), 2.91-2.85 (m, 1H), 2.74-2.70 (m, 1H), 2.18 (s, 3H), 2.17-2.15 (m, 1H), 2.05-1.98 (m, 1H), 1.86-1.80 (m, 1H), 1.33 (s, 3H), 1.06-1.01 (m, 2H), 0.77-0.73 (m, 2H)

[0344] LCMS (ESI, m / z): 368 [M+H] + Analysis conditions: Column: EVO C18, 2.1*30 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 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 1.073 min

[0345] Chiral resolution of 1-[5-(3-chloro-4-cyclopropylphenyl)-6-methylinden-1-yl]-3-methylazetidin-3-ol (21b) [Chem.] A mixture of isomers (175 mg) was separated by chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12 * 25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: 5% B to 5% B in 22 min; wavelength: 220 / 254 nm; RT1: 9.35 min; RT2: 17.19 min) to obtain the desired isomer (58.3 mg, 32.9%, 99.1% ee) as a white solid.

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 5.14 (s, 1H), 3.80 - 3.77 (m, 1H), 3.21 - 3.18 (m, 1H), 3.16 - 3.09 (m, 2H), 2.96 - 2.93 (m, 1H), 2.91 - 2.85 (m, 1H), 2.74 - 2.71 (m, 1H), 2.18 (s, 3H), 2.17 - 2.15 (m, 1H), 2.05 - 1.98 (m, 1H), 1.86 - 1.79 (m, 1H), 1.33 (s, 3H), 1.06 - 1.01 (m, 2H), 0.77 - 0.73 (m, 2H)

[0347] LCMS (ESI, m / z): 368 [M+H] +Analysis conditions: Column: EVO C18, 2.1 * 30 mm, 2.6 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: from 10% B to 95% B in 1.20 min, hold at 95% for 0.58 min, from 95% B to 10% B in 0.05 min; 254 nm; RT: 1.070 min

[0348] Example S22. 1-(5-((3-fluorophenyl)ethynyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (22a&22b)

Chem.

Chem.

[0349] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol

Chem.

[0350] 1 Chiral resolution of 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol (22a) [Chemical formula] The racemate (380 mg) was separated by chiral HPLC (column: CHIRALPAK IG, 2 * 25 cm, 5 μm; mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: from 3% B to 3% B in 21 min; wavelength: 220 / 254 nm; RT1: 13.944 min; RT2: 16.488 min), and the target isomer 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol (the first elution peak, 108.5 mg, 28%, 100% e.e.) was obtained as a white solid.

[0351] 1 H NMR (400 MHz, methanol-d4) δ 7.44 - 7.38 (m, 2H), 7.35 - 7.33 (m, 1H), 7.27 - 7.23 (m, 2H), 7.15 - 7.10 (m, 1H), 4.00 - 3.97 (m, 1H), 3.47 - 3.41 (m, 2H), 3.37 (d, J = 8.0 Hz, 1H), 3.22 (d, J = 8.0 Hz, 1H), 3.09 - 3.01 (m, 1H), 2.84 - 2.77 (m, 1H), 2.50 (s, 3H), 2.26 - 2.17 (m, 1H), 1.95 - 1.87 (m, 1H), 1.48 (s, 3H)

[0352] LCMS (ESI, m / z): 336 [M + H] + . Analytical conditions: column: HALO C18, 3.0 * 30 mm, 2.7 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (0.05% TFA); flow rate: 1.20 mL / min; gradient: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.927 min

[0353] Chiral resolution of 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol (22b)

Chemical Structure

[0354] 1 H NMR (400 MHz, methanol-d4) δ 7.44-7.38 (m, 2H), 7.36-7.33 (m, 1H), 7.27-7.24 (m, 2H), 7.16-7.10 (m, 1H), 4.01-3.98 (m, 1H), 3.47-3.42 (m, 2H), 3.38 (d, J = 8.0 Hz, 1H), 3.23 (d, J = 8.0 Hz, 1H), 3.09-3.01 (m, 1H), 2.85-2.77 (m, 1H), 2.50 (s, 3H), 2.27-2.18 (m, 1H), 1.95-1.88 (m, 1H), 1.48 (s, 3H)

[0355] LCMS (ESI, m / z): 336 [M+H] + . Analytical conditions: column: L‐column3 C18 Column 3.0 * 30 mm, 2.0 μm; mobile phase A: water / 5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.5000 mL / min; gradient: from 40% B to 80% B in 2.00 min, from 80% B to 95% B in 0.25 min, hold at 95% for 0.55 min, from 95% B to 10% B in 0.05 min; 254 nm; RT: 1.318 min

[0356] Example S23. 1-(5-(2,6-dichlorophenethyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (23a&23b)

Chem.

Chem.

[0357] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-1-indanyl]-3-methylazetidin-3-ol

Chem.

[0358] Chiral separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-1-indanyl]-3-methylazetidin-3-ol (23a) [Chemical formula] The racemate (190 mg) was separated by chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12 * 25 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: from 95% B to 95% B in 13 min; 220 / 254 nm; RT1: 8.824 min; RT2: 11.342 min) to obtain the target isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol (25 mg, 12.9%, 99.7% e.e.) as a white solid.

[0359] 1 H NMR (400 MHz, methanol-d4) δ 7.39 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 3.99 - 3.96 (m, 1H), 3.48 - 3.37 (m, 3H), 3.23 (d, J = 7.6 Hz, 1H), 3.16 - 3.11 (m, 2H), 3.06 - 2.99 (m, 1H), 2.87 - 2.83 (m, 2H), 2.81 - 1.73 (m, 1H), 2.41 (s, 3H), 2.25 - 2.16 (m, 1H), 1.93 - 1.85 (m, 1H), 1.48 (s, 3H)

[0360] LCMS (ESI, m / z): 390 [M + H] + . Analytical conditions: column: HALO C18, 3.0 * 30 mm, 2.7 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (0.05% TFA); flow rate: 1.20 mL / min; gradient: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 1.000 min

[0361] Chiral separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-1-indanyl]-3-methylazetidin-3-ol (23b) [Chemical formula] The racemate (190 mg) was separated by chiral HPLC (column: Lux 5 μm Cellulose-2, 2.12 * 25 cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: from 95% B to 95% B in 13 min; 220 / 254 nm; RT1: 8.824 min; RT2: 11.342 min) to obtain the target isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methylinden-1-yl]-3-methylazetidin-3-ol (31.3 mg, 16.3%, 98.9% e.e.) as a white solid.

[0362] 1 H NMR (400 MHz, methanol-d4) δ 7.39 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 4.06 - 4.03 (m, 1H), 3.53 - 3.43 (m, 3H), 3.29 (d, J = 8.0 Hz, 1H), 3.16 - 3.12 (m, 2H), 3.06 - 2.99 (m, 1H), 2.87 - 2.82 (m, 2H), 2.80 - 1.75 (m, 1H), 2.41 (s, 3H), 2.27 - 2.18 (m, 1H), 1.95 - 1.87 (m, 1H), 1.48 (s, 3H)

[0363] LCMS (ESI, m / z): 390 [M+H] +Analysis conditions: Column: HALO C18, 3.0*30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.995 min

[0364] Example S24. 1-(5-((2,6-dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (24a&24b)

Chem.

Chem.

[0365] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-6-methyl-1-indanone

Chem.

[0366] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-1-indanyl]-3-methylazetidin-3-ol [Chemical formula] A solution of ZnCl2 (2.0 M in THF, 0.65 mL, 1.31 mmol, 2.00 equiv.), NaBH3CN (167 mg, 2.62 mmol, 4.00 equiv.), 5-[(2,6-dichlorophenyl)methoxy]-6-methylindan-1-one (210 mg, 0.65 mmol, 1.00 equiv.), and 3-methylazetidin-3-ol (114 mg, 1.31 mmol, 2.00 equiv.) in methanol (5 mL) was stirred at 80 °C overnight. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by C18 silica flash chromatography (eluting with water / acetonitrile, 1:1) to afford 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methylindan-1-yl]-3-methylazetidin-3-ol (110 mg, 42.9%) as a pale yellow solid. LCMS (ESI, m / z): 336 [M+H] +

[0367] Chiral separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-1-indanyl]-3-methylazetidin-3-ol (24a)

Chem.

[0368] 1 H NMR (400 MHz, methanol-d4) δ 7.49-7.46 (m, 2H), 7.37 (dd, J = 9.2, 7.6 Hz, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 5.30 (s, 2H), 4.04-4.01 (m, 1H), 3.51-3.48 (m, 2H), 3.43 (d, J = 8.0 Hz, 1H), 3.29 (d, J = 8.0 Hz, 1H), 3.12-3.06 (m, 1H), 2.88-2.81 (m, 1H), 2.30-2.21 (m, 1H), 2.13 (s, 3H), 1.97-1.90 (m, 1H), 1.48 (s, 3H)

[0369] LCMS (ESI, m / z): 392 [M+H] +Analysis conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.30 min, hold at 100% for 0.50 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 0.955 min

[0370] Chiral separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-1-indanyl]-3-methylazetidin-3-ol (24b) [Chemical formula] The racemate (110 mg) was separated by chiral HPLC (Column: CHIRALPAK IA, 2 * 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3 - MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: from 2% B to 2 B% in 19 min; 220 / 254 nm; RT1: 10.127 min; RT2: 11.859 min), and the target isomer 1 - [5 - [(2,6 - dichlorophenyl)methoxy] - 6 - methylinden - 1 - yl] - 3 - methylazetidin - 3 - ol (the second elution peak, 21.7 mg, 19.5%, 97.6% e.e.) was obtained as a white solid.

[0371] 1 H NMR (400 MHz, methanol - d4) δ 7.49 - 7.46 (m, 2H), 7.37 (dd, J = 9.2, 7.6 Hz, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 5.30 (s, 2H), 4.01 - 3.98 (m, 1H), 3.48 - 3.45 (m, 2H), 3.39 (d, J = 8.0 Hz, 1H), 3.25 (d, J = 8.0 Hz, 1H), 3.13 - 3.06 (m, 1H), 2.87 - 2.80 (m, 1H), 2.29 - 2.20 (m, 1H), 2.13 (s, 3H), 1.96 - 1.89 (m, 1H), 1.48 (s, 3H)

[0372] LCMS (ESI, m / z): 392 [M+H] + . Analytical conditions: Column: HALO C18, 3.0*30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.30 min, hold at 100% for 0.50 min, from 100% B to 5% B in 0.03 min; 210 nm; RT: 0.950 min

[0373] Example S25. 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25a&25b) [Chemical formula] Synthesis of 1-(4-bromo-3,5-dimethylphenyl)-3-chloropropan-1-one [Chemical formula] To a stirred solution of 3-chloropropanoyl chloride (1.37 g, 10.8 mmol, 1.00 equiv.) and AlCl3 (2.0 g, 15.2 mmol, 1.50 equiv.) in DCM (40 mL) was added dropwise a solution of 2-bromo-1,3-dimethylbenzene (2 g, 10.8 mmol, 1.00 equiv.) in DCM (4 mL) at 0 °C. The resulting mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with ice water (40 mL) and concentrated HCl (5 mL) and stirred for 15 min. The mixture was then extracted with DCM (3 * 20 mL). The combined organic layers were concentrated under reduced pressure to give a mixture of isomers containing 1-(4-bromo-3,5-dimethylphenyl)-3-chloropropan-1-one as a crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): 275 [M+H] +

[0374] Synthesis of 5-bromo-4,6-dimethyl-1-indanone [Chemical formula] In concentrated H2SO4 (5 mL), a solution of the isomer mixture (containing 1-(4-bromo-3,5-dimethylphenyl)-3-chloropropan-1-one) (1.3 g, 4.72 mmol, 1.00 equiv.) was stirred at 90 °C for 1 h. Next, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with PE:EtOAc = 12:1), and a mixture of isomers of 5-bromo-4,6-dimethylindan-1-one (800 mg, 70%) was obtained as a white solid, which was separated by achiral SFC (column: Green Sep Naphthyl, 3 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 80 mL / min; gradient: isocratic 30% B; wavelength: 254 nm; RT1 (min): 3.63; RT2 (min): 4.18) to obtain the target isomer 5-bromo-4,6-dimethylindan-1-one (400 mg, 50%, 99% e.e.) as a white solid. LCMS (ESI, m / z): 239[M+H] +

[0375] Synthesis of 1-(5-bromo-4,6-dimethyl-1-indanyl)-3-methylazetidin-3-ol [Chemical formula] In methanol (10 mL), a solution of 5-bromo-4,6-dimethyl-1-indanone (400 mg, 1.67 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (145 mg, 1.67 mmol, 1.00 equiv.), ZnCl2 (2 M in 4Me-THF, 1.6 mL, 3.35 mmol, 2.00 equiv.), and NaH3BCN (421 mg, 6.69 mmol, 4.00 equiv.) was placed in a 25 mL round-bottom flask. The resulting solution was stirred at 60 °C for 15 h. LCMS indicated the completion of the reaction. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 2:3) to afford 1-(5-bromo-4,6-dimethyl-1-indanyl)-3-methylazetidin-3-ol (200 mg, 39%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H] +

[0376] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol [Chemical formula] In 1,4-dioxane (10 mL) and water (1 mL), a solution of 1-(5-bromo-4,6-dimethylinden-1-yl)-3-methylazetidin-3-ol (190 mg, 0.61 mmol, 1.00 equiv.), 2-(3-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (170 mg, 0.61 mmol, 1.00 equiv.), Cs2CO3 (598 mg, 1.84 mmol, 3.00 equiv.), and Pd(dppf)Cl2 (44 mg, 0.060 mmol, 0.10 equiv.) was stirred at 90 °C for 4 h under a N2 atmosphere. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 1:1) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (200 mg, 85%) as a yellow oil. LCMS (ESI, m / z): 382[M+H] +

[0377] Chiral separation of 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25a)

Chemical formula

[0378] 11H NMR (400 MHz, methanol-d4) δ 7.09 - 7.04 (m, 3H), 6.95 - 6.89 (m, 1H), 4.01 - 3.98 (m, 1H), 3.47 - 3.43 (m, 2H), 3.38 - 3.35 (m, 1H), 3.24 - 3.21 (m, 1H), 3.03 - 2.95 (m, 1H), 2.81 - 2.74 (m, 1H), 2.29 - 2.18 (m, 2H), 1.99 (s, 3H), 1.97 - 1.94 (m, 1H), 1.92 (s, 3H), 1.48 (d, J = 2.4 Hz, 3H), 1.09 - 1.04 (m, 2H), 0.78 - 0.74 (m, 2H)

[0379] LCMS (ESI, m / z): 382 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 70% B in 1.70 min, from 70% B to 95% B in 0.30 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.10 min; 220 nm; RT: 1.545 min

[0380] Chiral Resolution of 1-(5-(3-Chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25b)

Chem.

[0381] 1 1H NMR (400 MHz, methanol-d4) δ 7.10 - 7.05 (m, 3H), 6.95 - 6.90 (m, 1H), 4.02 - 3.99 (m, 1H), 3.46 - 3.43 (m, 2H), 3.39 - 3.37 (m, 1H), 3.24 - 3.21 (m, 1H), 3.03 - 2.95 (m, 1H), 2.81 - 2.74 (m, 1H), 2.29 - 2.18 (m, 2H), 2.00 (s, 3H), 1.97 - 1.94 (m, 1H), 1.92 (s, 3H), 1.48 (d, J = 2.0 Hz, 3H), 1.09 - 1.04 (m, 2H), 0.78 - 0.74 (m, 2H)

[0382] LCMS (ESI, m / z): 382 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 220 nm; RT: 1.033 min

[0383] Example S26. 1-(5-(3-Chloro-4-cyclopropylphenyl)-4,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (26a&26b)

Chem.

Chem.

[0384] Synthesis of 5-Bromo-4,7-dimethylindan-1-one [Chemical formula] A solution of 1-(4-bromo-2,5-dimethylphenyl)-3-chloropropan-1-one (2.8 g, 10.8 mmol, 1 equiv.) in concentrated H2SO4 (8 mL) was stirred at 90 °C for 1 h. Next, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with PE:EtOAc = 12:1) to give 5-bromo-4,7-dimethylinden-1-one (2 g, 76.7%) as a yellow solid. LCMS (ESI, m / z): 239[M+H] +

[0385] Synthesis of 1-(5-Bromo-4,7-dimethylindan-1-yl)-3-methylazetidin-3-ol [Chemical formula] In methanol (20 mL), a solution of NaCNBH3 (1.27 g, 33.46 mmol, 4 equiv.) and ZnCl2 (4.2 mL, 2 M in 4Me-THF, 8.36 mmol, 1 equiv.) was stirred at room temperature for 0.5 h. Next, 5-bromo-4,7-dimethylindan-1-one (2 g, 8.36 mmol, 1 equiv.) and 3-methylazetidin-3-ol (1.46 g, 16.7 mmol, 2 equiv.) were added. The resulting mixture was stirred at 60 °C for 12 h. LCMS indicated that the reaction was complete. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 1:1) to give 1-(5-bromo-4,7-dimethylindan-1-yl)-3-methylazetidin-3-ol (500 mg, 19.2%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H] +

[0386] Synthesis of 1-[5-(3-Chloro-4-cyclopropylphenyl)-4,7-dimethylindan-1-yl]-3-methylazetidin-3-ol [Chemical formula] In 1,4-dioxane (5 mL) and water (0.5 mL), a mixture of 1-(5-bromo-4,7-dimethylinden-1-yl)-3-methylazetidin-3-ol (500 mg, 1.61 mmol, 1 equiv.), 2-(3-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (898 mg, 3.22 mmol, 2 equiv.), Pd(dppf)Cl2 (118 mg, 0.16 mmol, 0.1 equiv.), and Cs2CO3 (1.57 g, 4.84 mmol, 3 equiv.) was stirred at 90 °C overnight. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 1:1) to give 1-[5-(3-chloro-4-cyclopropylphenyl)-4,7-dimethylinden-1-yl]-3-methylazetidin-3-ol (300 mg, 48.7%) as a yellow oil. LCMS (ESI, m / z): 382 [M+H] +

[0387] Chiral Resolution of 1-[5-(3-Chloro-4-cyclopropylphenyl)-4,7-dimethylindan-1-yl]-3-methylazetidin-3-ol (26a) [Chemical formula] The racemate (300 mg) was purified by chiral HPLC (column: Lux 5 μm Celluloes-3, 2.12*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: from 2% B to 2% B in 20 min; 220 / 254 nm; RT1: 6.271 min; RT2: 13.587 min) to obtain the enantiomers. The first eluted peak enantiomer was purified by Prep-HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 65% B to 95% B in 7 min; 254 / 210 nm; RT1: 5.68 min) to obtain 1-[5-(3-chloro-4-cyclopropylphenyl)-4,7-dimethylinden-1-yl]-3-methylazetidin-3-ol (67.6 mg, 22.3%) as a white solid.

[0388] 1 H NMR (300 MHz, methanol-d4) δ 7.24 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 7.8, 1.5 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 4.14-4.11 (m, 1H), 3.30-3.27 (m, 2H), 3.24-3.21 (m, 1H), 3.16 (d, J = 7.2 Hz, 1H), 3.10-2.99 (m, 1H), 2.80-2.72 (m, 1H), 2.40 (s, 3H), 2.28-2.12 (m, 2H), 2.10 (s, 3H), 2.07-1.98 (m, 1H), 1.45 (s, 3H), 1.08-1.01 (m, 2H), 0.76-0.71 (m, 2H)

[0389] LCMS (ESI, m / z): 382 [M+H] +Analysis conditions: Column: YMCMeteoricCore C18 BIO, 2.1 * 30 mm, 2.7 μm; Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 1.20 mL / min; Gradient: from 10% B to 95% B in 1.20 min, hold at 95% for 0.58 min, from 95% B to 10% B in 0.05 min; 254 nm; RT: 1.186 min

[0390] Chiral Resolution of 1-[5-(3-Chloro-4-cyclopropylphenyl)-4,7-dimethylindan-1-yl]-3-methylazetidin-3-ol (26b) [Chemical formula] The racemate (300 mg) was purified by chiral HPLC (Column: Lux 5 μm Celluloes - 3, 2.12 * 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3 - MeOH)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: from 2% B to 2% B in 20 min; 220 / 254 nm; RT1: 6.271 min; RT2: 13.587 min) to obtain the enantiomers. The second eluted peak enantiomer was purified by Prep - HPLC (Column: XBridge Prep OBD C18 Column, 30 * 150 mm 5 μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: from 65% B to 95% B in 7 min; 254 / 210 nm; RT1: 8.32 min) to obtain 1 - [5 - (3 - chloro - 4 - cyclopropylphenyl)-4,7 - dimethylinden - 1 - yl]-3 - methylazetidin - 3 - ol (63.4 mg, 21.0%) as a white solid.

[0391] 11H NMR (300 MHz, methanol-d4) δ 7.24 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 7.8, 1.5 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (s, 1H), 4.14 - 4.11 (m, 1H), 3.30 - 3.27 (m, 2H), 3.24 - 3.21 (m, 1H), 3.16 (d, J = 6.9 Hz, 1H), 3.10 - 2.99 (m, 1H), 2.80 - 2.72 (m, 1H), 2.41 (s, 3H), 2.28 - 2.12 (m, 2H), 2.11 (s, 3H), 2.07 - 1.97 (m, 1H), 1.45 (s, 3H), 1.08 - 1.02 (m, 2H), 0.76 - 0.71 (m, 2H)

[0392] LCMS (ESI, m / z): 382 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.0 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 1.045 min

[0393] Example S27. 1-(5-(3-Chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27a&27b)

Chemical Structure

Chemical Structure

[0394] Synthesis of 5-Bromo-6,7-dimethyl-2,3-dihydro-1H-inden-1-one [Chemical formula] In concentrated H2SO4 (10 mL), a solution of the isomer mixture (containing 1-(4-bromo-2,3-dimethylphenyl)-3-chloropropan-1-one) (2.6 g, 9.44 mmol, 1.00 equiv.) was stirred at 90 °C for 1 h. Next, the reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with PE:EtOAc = 12:1), and the isomer mixture (1.2 g, 55%) was obtained as a white solid. This was separated by achiral SFC (column: Green Sep Naphthyl, 3 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 70 mL / min; gradient: isocratic 15% B; wavelength: 254 nm; RT1 (min): 5.72; RT2 (min): 6.23; sample solvent: DCM--HPLC; injection volume: 1 mL; number of runs: 40) to obtain the target isomer 5-bromo-6,7-dimethyl-2,3-dihydro-1H-inden-1-one (530 mg, 44%, 99% e.e.) as a white solid. LCMS (ESI, m / z): 239[M+H] +

[0395] Synthesis of 1-(5-Bromo-4,6-dimethylindan-1-yl)-3-methylazetidin-3-ol [Chemical formula] In methanol (10 mL), a solution of 5-bromo-6,7-dimethyl-2,3-dihydro-1H-inden-1-one (530 mg, 1.71 mmol, 1.00 equiv.), 3-methylazetidin-3-ol (158 mg, 1.71 mmol, 1.00 equiv.), ZnCl2 (2 M in 4Me-THF, 1.8 mL, 3.42 mmol, 2.00 equiv.), and NaH3BCN (430 mg, 6.84 mmol, 4.00 equiv.) was stirred at 60 °C for 15 h. LCMS indicated the completion of the reaction. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 2:3) to afford 1-(5-bromo-4,6-dimethylinden-1-yl)-3-methylazetidin-3-ol (120 mg, 17%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H] +

[0396] Synthesis of 1-(5-(3-Chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol [Chemical formula] In 1,4-dioxane (10 mL) and water (1 mL), a solution of 1-(5-bromo-4,6-dimethyl-1-indanyl)-3-methylazetidin-3-ol (120 mg, 0.39 mmol, 1.00 equiv.), 2-(3-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (170 mg, 0.39 mmol, 1.00 equiv.), Cs2CO3 (598 mg, 1.46 mmol, 3.00 equiv.), and Pd(dppf)Cl2 (44 mg, 0.04 mmol, 0.10 equiv.) was stirred at 90 °C for 4 h under a N2 atmosphere. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether, 1:1) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (60 mg, 85%) as a yellow oil. LCMS (ESI, m / z): 382 [M+H] +

[0397] Chiral Resolution of 1-(5-(3-Chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27a)

Chem.

[0398] 11H NMR (400 MHz, methanol-d4) δ 7.23 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.22 (d, J = 6.4 Hz, 1H), 3.30 - 3.27 (m, 2H), 3.24 - 3.23 (m, 1H), 3.19 (d, J = 7.6 Hz, 1H), 3.16 - 3.09 (m, 1H), 2.78 - 2.72 (m, 1H), 2.40 (s, 3H), 2.28 - 2.21 (m, 1H), 2.17 - 2.13 (m, 1H), 2.12 (s, 3H), 2.07 - 2.02 (m, 1H), 1.45 (s, 3H), 1.08 - 1.03 (m, 2H), 0.77 - 0.72 (m, 2H)

[0399] LCMS (ESI, m / z): 382 [M+H] + . Analytical conditions: Column: HALO C18, 3.0 * 30 mm, 2.7 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.20 mL / min; Gradient: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 1.027 min

[0400] Chiral Resolution of 1-(5-(3-Chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27b)

Chemical Structure

[0401] 1 H NMR (400 MHz, methanol-d4) δ 7.23 (d, J = 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.22 (d, J = 6.4 Hz, 1H), 3.32 - 3.30 (m, 2H), 3.25 - 3.23 (m, 1H), 3.19 (d, J = 7.6 Hz, 1H), 3.13 - 3.09 (m, 1H), 2.78 - 2.72 (m, 1H), 2.40 (s, 3H), 2.28 - 2.21 (m, 1H), 2.16 - 2.13 (m, 1H), 2.12 (s, 3H), 2.08 - 2.02 (m, 1H), 1.45 (s, 3H), 1.08 - 1.03 (m, 2H), 0.77 - 0.73 (m, 2H)

[0402] LCMS (ESI, m / z): 382 [M+H] + . Analytical conditions: column: HALO C18, 3.0 * 30 mm, 2.7 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (0.05% TFA); flow rate: 1.20 mL / min; gradient: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 1.024 min

[0403] Example S28. 1-(4-((2,6-difluorophenyl)ethynyl)benzyl)-3-methylazetidin-3-ol (28)

Chem.

Chem.

[0404] Synthesis of 1-[[4-[2-(2,6-difluorophenyl)ethynyl]phenyl]methyl]-3-methylazetidin-3-ol (28)

Chem.

[0405] LCMS (ESI, m / z): 314 [M+H] + Analysis conditions: Column: Shim-pack Scepter C18 3.0*50 mm, 3.0 μm; Mobile phase A: Water (0.04% NH3·H2O), Mobile phase B: Acetonitrile; Flow rate: 1.50 mL / min; Gradient: 10% B to 95% B in 2.00 min, hold at 95% for 0.60 min, 95% B to 10% B in 0.20 min; 254 nm; RT: 1.632 min

[0406] 11H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.70 - 7.53 (m, 5H), 7.28 (t, J = 8.4 Hz, 2H), 6.10 (s, 1H), 4.46 - 4.40 (m, 2H), 4.02 - 3.89 (m, 4H), 1.43 (s, 3H)

[0407] Example S29. 1-(4-((3-fluorophenyl)ethynyl)benzyl)-3-methylazetidin-3-ol (29) Synthesis of 1-[[4-[2-(3-fluorophenyl)ethynyl]phenyl]methyl]-3-methylazetidin-3-ol (29)

Chem.

[0408] LCMS (ESI, m / z): 296 [M+H] +Analysis conditions: Column: Shim-pack Scepter C18 3.0*50 mm, 3.0 μm; Mobile phase A: water (0.04% NH3·H2O), Mobile phase B: acetonitrile; Flow rate: 1.50 mL / min; Gradient: from 10% B to 95% B in 2.00 min, hold at 95% for 0.60 min, from 95% B to 10% B in 0.20 min; 254 nm; RT: 1.673 min

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.51-7.47 (m, 1H), 7.45-7.41 (m, 2H), 7.34-7.29 (m, 1H), 6.16 (br, 1H), 4.43 (s, 2H), 4.13-3.86 (m, 4H), 1.43 (s, 3H)

[0410] Example S30. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-4-methylpiperidin-4-ol (30)

Chem.

Chem.

[0411] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-4-piperidyl] acetate

Chemical formula

[0412] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methylpiperidin-4-ol (30)

Chem.

[0413] LCMS (ESI, m / z): 405 [M + H] + . Analytical conditions: column: HALO C18, 3.0 * 30 mm, 2.7 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile (0.05% TFA); flow rate: 1.20 mL / min; gradient: 5% B to 70% B in 1.70 min, 70% B to 95% B in 0.30 min, hold at 95% for 0.60 min, 95% B to 5% B in 0.10 min; 254 nm; RT: 1.427 min

[0414] 11H NMR (400 MHz, methanol-d4) δ 7.42 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.72 (t, J = 8.0 Hz, 1H), 4.92 - 4.89 (m, 2H), 4.44 - 4.40 (m, 2H), 3.80 - 3.73 (m, 1H), 3.58 (s, 2H), 2.59 - 2.49 (m, 4H), 1.68 - 1.59 (m, 4H), 1.22 (s, 3H)

[0415] Example S31. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (31)

Chem.

Chem.

[0416] Synthesis of [1-[[4-(azetidin-3-yl)phenyl]methyl]-3-methylazetidin-3-yl] acetate [Chemical formula] To a stirred solution of tert-butyl 3-[4-[(3-acetoxy-3-methylazetidin-1-yl)methyl]phenyl]azetidine-1-carboxylate (200 mg, 0.53 mmol, 1.00 equiv.) in DCM (4 mL) was added TBSOTf (0.3 mL, 1.60 mmol, 3.00 equiv.). The reaction mixture was stirred at room temperature for 30 minutes. LCMS indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water (0.05% FA) / MeCN, 7 / 3) to afford [1-[[4-(azetidin-3-yl)phenyl]methyl]-3-methylazetidin-3-yl] acetate (140 mg, 95% yield) as an off-white solid. LCMS (ESI, m / z): 275 [M+H] +

[0417] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methylazetidin-3-yl] acetate

Chem.

[0418] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methylazetidin-3-ol (31)

Chem.

[0419] 1 H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H, H FA ), 7.55 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.73 (t, J = 8.0 Hz, 1H), 4.91 (t, J = 8.0 Hz, 2H), 4.44 - 4.41 (m, 2H), 4.26 (s, 2H), 3.95 (d, J = 10.4 Hz, 2H), 3.84 - 3.75 (m, 3H), 1.52 (s, 3H)

[0420] LCMS (ESI, m / z): 377 [M + H] +Analysis conditions: Column: HALO C18 Column 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 60% B in 1.8 min, 60% B to 100% B in 0.15 min, hold at 100% for 0.7 min, 100% B to 5% B in 0.15 min; 254 nm; RT: 1.538 min

[0421] Example S32. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)-4-methylpiperidin-4-ol (32) [ka] Synthesis of 1-[(4-bromophenyl)methyl]-4-methylpiperidin-4-ol [ka] To a stirred solution of [1-[(4-bromophenyl)methyl]-4-methyl-4-piperidyl] acetate (600 mg, 1.84 mmol, 1.00 equiv.) in methanol (5 mL) was added CHONa (2 M in MeOH, 0.9 mL, 1.84 mmol, 1.00 equiv.). The mixture was stirred at 25 °C for 16 h. LCMS indicated the reaction was complete. The resulting solution was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was concentrated in vacuo. The residue was purified by C18 silica flash column chromatography (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 3) to give 1-[(4-bromophenyl)methyl]-4-methylpiperidin-4-ol (300 mg, 57% yield) as an off-white solid. LCMS (ESI, m / z): 284[M+H] +

[0422] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-4-methylpiperidin-4-ol (32) [ka] In tert-butanol (4 mL), to a stirred solution of 1-[(4-bromophenyl)methyl]-4-methylpiperidin-4-ol (200 mg, 0.70 mmol, 1.00 equiv.) and 3-(2,6-dichlorophenyl)azetidine (142 mg, 0.70 mmol, 1.00 equiv.) was added BrettPhos Pd G3 (63 mg, 0.07 mmol, 1.00 equiv.) and K2CO3 (291 mg, 2.11 mmol, 1.00 equiv.). The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was 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 (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B to 40% B in 7 min; wavelength: 254 / 220 nm; RT1: 5.7 min) to give 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-4-methylpiperidin-4-ol (14.6 mg, 5%) as an off-white solid.

[0423] 1 H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H, H FA ), 7.39 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 4.78 - 4.69 (m, 1H), 4.50 (t, J = 8.0 Hz, 2H), 4.24 (t, J = 8.0 Hz, 2H), 4.17 (s, 2H), 3.24 - 3.18 (m, 4H), 1.82 - 1.78 (m, 4H), 1.29 (s, 3H)

[0424] LCMS (ESI, m / z): 405 [M+H] +Analysis conditions: Column: HALO C18 Column 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: from 5% B to 60% B in 1.80 min, from 60% B to 100% B in 0.15 min, hold at 100% for 0.70 min, from 100% B to 5% B in 0.15 min; 254 nm; RT: 1.540 min

[0425] Example S33. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)-3-methylazetidin-3-ol (33)

Chem.

Chem.

[0426] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methylazetidin-3-ol (33)

Chem.

[0427] 1 H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.47 (d, J = 7.8 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.47 (d, J = 7.8 Hz, 2H), 4.59-4.54 (m, 1H), 4.43 (t, J = 7.8 Hz, 2H), 3.99 (t, J = 7.8 Hz, 2H), 3.49 (s, 2H), 3.16 (d, J = 6.6 Hz, 2H), 2.90 (d, J = 6.6 Hz, 2H), 1.34 (s, 3H)

[0428] LCMS (ESI, m / z): 377 [M+H] +Analysis conditions: Column: HALO C18 3.0*30 mm, 2.0 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile (0.05% TFA); Flow rate: 1.50 mL / min; Gradient: from 5% B to 60% B in 1.80 min, from 60% B to 100% B in 0.15 min, held at 100% for 0.40 min, from 100% B to 5% B in 0.70 min; 254 nm; RT: 1.505 min

[0429] Example S34. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-4-methylpiperidin-4-ol (34) [Chem.] Synthesis of tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidyl)methyl]-3,5-dimethylphenyl]azetidine-1-carboxylate [Chem.] A solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.9 g, 6.77 mmol, 5.00 equiv.) and Zn (775 mg, 11.9 mmol, 7.00 equiv.) in DMF (30 mL) was stirred at 60 °C for 2 h. Next, [1-[(4-bromo-2,6-dimethylphenyl)methyl]-4-methyl-4-piperidyl] acetate (600 mg, 1.69 mmol, 1.00 equiv.), Pd2(dba)3 (155 mg, 0.17 mmol, 0.10 equiv.), and tri-m-tolylphosphane (102 mg, 0.34 mmol, 0.20 equiv.) were added. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was filtered through Celite and the filter cake was washed with MeCN (3 * 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water (5 mM NH4HCO3) / MeCN, 1 / 6) to give tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidyl)methyl]-3,5-dimethylphenyl]azetidine-1-carboxylate (700 mg, 95%) as an off-white solid. LCMS (ESI, m / z): 431 [M+H]+

[0430] Synthesis of [1-[[4-(azetidin-3-yl)-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidyl] acetate

Chem.

[0431] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidyl] acetate

Chem.

[0432] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethylphenyl]methyl]-4-methylpiperidin-4-ol (34)

Chemical Structure

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.0 Hz, 2H), 7.02 (s, 2H), 6.74 (t, J = 8.0 Hz, 1H), 4.80 (t, J = 8.0 Hz, 2H), 4.33 (t, J = 7.2 Hz, 2H), 4.08 (s, 1H), 3.71-3.63 (m, 1H), 3.38 (s, 2H), 2.43-2.35 (m, 3H), 2.33 (s, 6H), 2.32-2.29 (m, 1H), 1.44-1.32 (m, 4H), 1.08 (s, 3H)

[0434] LCMS (ESI, m / z): 433 [M+H] +Analysis conditions: Column: HALO C18 Column 2.0*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: from 5% B to 100% B in 1.20 min, held at 100% for 0.60 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.917 min

[0435] Example S35. 1-(4-((2,6-dichlorophenyl)ethynyl)benzyl)-3-methylazetidin-3-ol (35)

Chem.

Chem.

[0436] Synthesis of 1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-ol

Chem.

[0437] Synthesis of [1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-yl] acetate [Chemical formula] To a stirred solution of 1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-ol (820 mg, 2.89 mmol, 1.00 equiv.) in DCM (10 mL) were added TEA (1.0 mL, 5.77 mmol, 2.00 equiv.), Ac2O (1.1 mL, 11.54 mmol, 4.00 equiv.), and DMAP (35 mg, 0.29 mmol, 0.10 equiv.). The reaction mixture was stirred at room temperature overnight. LCMS indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water (5 mM NH4HCO3) / MeCN, 1 / 9) to afford [1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-yl] acetate (830 mg, 88.0%) as an off-white solid. LCMS (ESI, m / z): 326 [M+H] +

[0438] Synthesis of tert-butyl 3-[4-[(3-acetoxy-3-methylazetidin-1-yl)methyl]-3,5-dimethylphenyl]azetidine-1-carboxylate [Chemical formula] A mixture of [1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-yl] acetate (430 mg, 1.32 mmol, 1.00 equiv.) and zinc powder (603 mg, 9.23 mmol, 7.00 equiv.) in DMF (3 mL) was stirred at 60 °C for 2 h. Next, Pd2(dba)3 (121 mg, 0.13 mmol, 0.10 equiv.) and tri(o-tolyl)phosphine (39 mg, 0.13 mmol, 0.10 equiv.) were added at room temperature. The resulting mixture was stirred at 80 °C for 3 h. LCMS indicated that the reaction was complete. The reaction mixture was filtered through Celite and the filter cake was washed with MeCN (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water (5 mM NH4HCO3) / MeCN, 1 / 6) to afford tert-butyl 3-[4-[(3-acetoxy-3-methylazetidin-1-yl)methyl]-3,5-dimethylphenyl]azetidine-1-carboxylate (210 mg, 39%) as an off-white solid. LCMS (ESI, m / z): 403 [M+H] +

[0439] Synthesis of [1-[[4-(azetidin-3-yl)-2,6-dimethylphenyl]methyl]-3-methylazetidin-3-yl] acetate

Chemical Structure

[0440] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethylphenyl]methyl]-3-methylazetidin-3-ol (35)

Chemical Structure

[0441] LCMS (ESI, m / z): 405 [M+H] + . Analytical conditions: column: Shim‐pack Scepter C18 3.0*50 mm, 3.0 μm; mobile phase A: water (0.04% NH3·H2O), mobile phase B: acetonitrile; flow rate: 1.50 mL / min; gradient: 60% B to 95% B in 2.00 min, hold at 95% for 0.80 min, 95% B to 10% B in 0.10 min; 254 nm; RT: 1.685 min

[0442] 11H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 8.0 Hz, 2H), 7.01 (s, 2H), 6.74 (t, J = 8.0 Hz, 1H), 5.11 (s, 1H), 4.80 (t, J = 8.0 Hz, 2H), 4.34-4.30 (m, 2H), 3.70-3.62 (m, 1H), 3.56 (s, 2H), 3.07-3.05 (m, 2H), 2.94-2.92 (m, 2H), 2.35 (s, 6H), 1.29 (s, 3H)

[0443] Example S36. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)-4-methylpiperidin-4-ol (36) [Chemistry] Synthesis of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidyl] acetate [Chemistry] To a stirred solution of [1-[(4-bromo-2,6-dimethylphenyl)methyl]-4-methyl-4-piperidyl] acetate (140 mg, 0.40 mmol, 1.00 equiv.) and 3-(2,6-dichlorophenyl)azetidine (79 mg, 0.40 mmol, 1.00 equiv.) in tert-butanol (4 mL) were added BrettPhos Pd G3 (35 mg, 0.04 mmol, 0.10 equiv.) and K2CO3 (163 mg, 1.19 mmol, 3.00 equiv.). The mixture solution was stirred at 80 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 silica flash column chromatography (eluting with water (5 mM NH4HCO3) / MeCN, 1 / 3) to give [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidyl] acetate (60 mg, 31%) as an off-white solid. LCMS (ESI, m / z): 475 [M+H] +

[0444] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methylpiperidin-4-ol (36) [Chem.] In methanol (2 mL), CH3ONa (2 M in MeOH, 0.5 mL, 1.04 mmol, 8.00 equiv.) was added to a stirred solution of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidyl] acetate (60 mg, 0.13 mmol, 1.00 equiv.). The mixture solution was stirred at 25 °C for 16 h. LCMS indicated that the reaction was complete. The resulting solution was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 72% B to 90% B in 8 min; wavelength: 254 / 220 nm; RT: 7.3 min) to give 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methylpiperidin-4-ol (6.4 mg, 11%) as an off-white solid.

[0445] 1 H NMR (300 MHz, methanol-d4) δ 7.38 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 1H), 6.26 (s, 2H), 4.60-4.52 (m, 1H), 4.46 (t, J = 7.5 Hz, 2H), 4.05 (t, J = 7.5 Hz, 2H), 3.47 (s, 2H), 2.55-2.49 (m, 4H), 2.34 (s, 6H), 1.59-1.56 (m, 4H), 1.20 (d, 3H)

[0446] LCMS (ESI, m / z): 433 [M+H] +Analysis conditions: Column: HALO C18 Column 3.0*30 mm, 2.0 um; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: from 5% B to 100% B in 1.2 min, hold at 100% for 0.6 min, from 100% B to 5% B in 0.03 min; 254 nm; RT: 0.902 min

[0447] Example S37. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (37)

Chem.

Chem.

[0448] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-3-methylazetidin-3-ol (37)

Chem.

[0449] LCMS (ESI, m / z): 405 [M+H] + . Analytical conditions: Shim-pack Scepter C18, 3.0*33 mm, 3.0 μm; mobile phase A: water / 5 mM NH4HCO3. Mobile phase B: ACN; flow rate: 1.50 mL / min; gradient: from 50% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, from 95% B to 15% B in 0.15 min; 254 nm; RT: 1.164 min

[0450] 11H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.15 (s, 2H), 5.07 (s, 1H), 4.51 (q, J = 8.0 Hz, 1H), 4.39 (t, J = 7.6 Hz, 2H), 3.95 (t, J = 7.6 Hz, 2H), 3.46 (s, 2H), 3.03 (d, J = 6.0 Hz, 2H), 2.88 (d, J = 6.0 Hz, 2H), 2.28 (s, 6H), 1.29 (s, 3H)

[0451] LC-MS method in the following examples Method 1: Information about the method: Column: Kinetex XB - C18 (75 x 3.0)mm, 2.6 μm; Mobile phase: A: 5mm ammonium formate pH 3.3:ACN (98:02); Mobile phase: B: ACN: Buffer (98:02); Flow rate: 1.0 mL / min Method 2: Information about the method: Column: XBridge C8 (50x4.6mm) 5 μm; Mobile phase: A: 0.1% TFA in H2O; Mobile phase: B: 0.1% TFA in ACN; Flow rate: 1.5mL / min Method 3: Column: Aquity Uplc BEH C18 (50 x 3.0)mm, 1.7μm; Mobile phase: A: 0.1% FA in water; Mobile phase: B: 0.1% TFA in ACN; Flow rate: 1.0 mL / min

[0452] Example S38. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-ethylazetidin-3-ol (38)

Chemical formula

Chemical formula

[0453] Synthesis of 4-(azetidin-3-yl)-2,6-dimethylbenzaldehyde [Chemical formula] In anhydrous dichloromethane (40 mL), trifluoroacetic acid (5.32 mL, 69.1 mmol) was added to a stirred solution of tert-butyl 3-(4-formyl-3,5-dimethylphenyl)azetidine-1-carboxylate (2 g, 6.91 mmol) at 0 °C. Next, the reaction mixture was stirred at ambient temperature and the progress of the reaction was monitored by TLC analysis. After 1 hour, TLC analysis indicated that the conversion of the starting material was complete. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was triturated with diethyl ether to afford 4-(azetidin-3-yl)-2,6-dimethylbenzaldehyde (1.96 g, 98% yield) as a brown semi-solid. LCMS method 1; LCMS (ESI, m / z): 190.0 [M+H] +

[0454] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde

Chemical Structure

[0455] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-ethylazetidin-3-ol (38)

Chem.

[0456] 11H NMR (400 MHz, MeOD): 7.19 - 7.23 (m, 4H), 6.73 (t, J = 8.00 Hz, 1H), 4.86 - 4.90 (m, 2H), 4.38 - 4.42 (m, 4H), 4.00 - 4.02 (m, 2H), 3.77 - 3.80 (m, 2H), 3.68 - 3.72 (m, 1H), 2.48 (s, 6H), 1.79 - 1.84 (m, 2H), 0.94 - 0.98 (m, 3H). LCMS method 1; LCMS (ESI, m / z): 419.0 [M+H] +

[0457] Example S39. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(fluoromethyl)azetidin-3-ol (39) [Chemical formula] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(fluoromethyl)azetidin-3-ol (39) [Chemical formula] To a stirred solution of 3-(fluoromethyl)azetidin-3-ol and HCl (79 mg, 0.561 mmol) in MeOH (8 mL) was added sodium bicarbonate (94 mg, 1.122 mmol), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to give the free amine. To the free amine 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (150 mg, 0.449 mmol) (see Synthesis Example 1) in MeOH (6 mL) was added zinc chloride (73.4 mg, 0.539 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (28.2 mg, 0.449 mmol) was added, and the mixture was heated to 65 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (60 mL) and washed with saturated ammonium chloride solution and water (60 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (information on method: diluent: THF:acetonitrile (30:70); column: Xbridge C8 (250 x 19) mm, 5 micron; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). The required fractions were concentrated and lyophilized to give the title compound 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(fluoromethyl)azetidin-3-ol (5 mg, 0.011 mmol, 2.55% yield, 96.8% purity) as an off-white solid.

[0458] 11H NMR (400 MHz, MeOD): δ 7.19 (d, J = 8.00 Hz, 2H), 7.09 (s, 2H), 6.71 (t, J = 8.40 Hz, 1H), 4.89 (m, 3H), 4.55 (s, 1H), 4.40 - 4.43 (m, 1H), 4.37 - 4.39 (m, 2H), 3.83 (s, 2H), 3.67 (m, 1H), 3.47 - 3.49 (m, 2H), 3.16 (s, 2H), 2.43 (s, 6H) LCMS method 1; LCMS (ESI, m / z): 425.0 [M+H] +

[0459] Example S40. 1-(4-(1-(2,6-Dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol (40) [Chemical formula] Synthesis of 1-(4-(1-(2,6-Dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol (40) [Chemical formula] To a stirred solution of 3-(difluoromethyl)azetidin-3-ol (in 10 mL of MeOH) and HCl (100 mg, 0.627 mmol) was added sodium bicarbonate (106 mg, 1.257 mmol), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to give the free amine. To the free amine 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (168 mg, 0.503 mmol) (see Synthesis Example 1) in MeOH (6 mL) was added zinc chloride (68.5 mg, 0.503 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (106 mg, 1.257 mmol) was added, and the mixture was heated to 65 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (60 mL) and washed with saturated ammonium chloride solution and water (60 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (information on method: diluent: THF:water:ACN (50:20:30); column: Zorbax C18 (50 x 21.5) mm, 5 micron; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). The required fractions were concentrated and lyophilized to give the title compound 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol, formate (30 mg, 0.061 mmol, 12.17% yield) as a white solid.

[0460] 11H NMR (400 MHz, MeOD): δ 7.12 - 7.20 (m, 4H), 6.72 (t, J = 19.20 Hz, 1H), 4.39 (t, J = 14.00 Hz, 2H), 3.97 - 3.98 (m, 2H), 3.72 (t, J = 25.60 Hz, 3H), 3.33 - 3.39 (m, 2H), 2.44 (s, 6H). Note: 2H are merged with the solvent peak. LCMS method 1; LCMS (ESI, m / z): 443.0 [M+H] +

[0461] Example S41. 1-(4-(1-(2,6-Dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(trifluoromethyl)azetidin-3-ol (41) [Chemical formula] Synthesis of 1-(4-(1-(2,6-Dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(trifluoromethyl)azetidin-3-ol (41) [Chemical formula] In MeOH (6 mL), zinc chloride (122 mg, 0.898 mmol) was added to a stirred solution of 3-(trifluoromethyl)azetidin-3-ol (158 mg, 1.122 mmol) and 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (250 mg, 0.748 mmol) (see Synthesis Example 1), and the mixture was stirred at 25 °C for 1 hour. After 1 hour, sodium cyanoborohydride (70.5 mg, 1.122 mmol) was added and the mixture was heated to 65 °C for 12 hours. The reaction mixture was diluted with dichloromethane (60 mL) and washed with saturated ammonium chloride solution and water (60 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography using silica gel of 100 - 200 mesh and 5 - 25% EtOAc / petroleum ether. The required fractions were evaporated to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(trifluoromethyl)azetidin-3-ol (55 mg, 0.119 mmol, 15.94% yield) as an off-white solid.

[0462] 1 H NMR (400 MHz, DMSO-d6): δ 7.23 (d, J = 8.0 Hz, 2H), 7.02 (s, 2H), 6.85 (s, 1H), 6.74 (t, J = 8.0 Hz, 1H), 4.80 (t, J = 8.4 Hz, 2H), 4.32 (t, J = 7.2 Hz, 2H), 3.67-3.64 (m, 3H), 3.46 (d, J = 9.2 Hz, 2H), 3.19 (d, J = 8.4 Hz, 2H), 2.35 (s, 6H). LCMS method 1; LCMS (ESI, m / z): 461.0 [M+H] +

[0463] Example S42. 1-(4-(1-(2,6-Difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (42)

Chem.

Chem.

[0464] Synthesis of 1-(4-(1-(2,6-Difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (42) [Chemical formula] To a stirred solution of 3-methylazetidin-3-ol, TFA salt (200 mg, 0.9 mmol) in MeOH (5 mL) was added sodium bicarbonate (167 mg, 1.99 mmol.), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to give the free amine. To the free amine 4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (200 mg, 0.664 mmol) in 5 ml of MeOH was added zinc chloride (90 mg, 0.664 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (62 mg, 0.9 mmol.) was added and the mixture was heated to 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:acetonitrile (50:50); column: Sunfire C18 (150 x 19)mm, 5 micron; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile) to give 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol, formate salt (38 mg, 14% yield, 99.8% purity) as a white solid.

[0465] 1 H NMR (400 MHz, DMSO-d6): δ 7.181 (s, 2H), 6.81 - 6.86 (m, 2H), 6.68 - 6.73 (m, 1H), 4.53 - 4.57 (m, 2H), 0.00 (s, 2H), 4.12 - 4.16 (m, 2H), 3.93 - 3.95 (m, 2H), 3.87 - 3.83 (m, 1H), 3.77 - 3.79 (m, 2H), 2.49 (s, 6H), 1.503 (s, 3H). LCMS method 1; LCMS (ESI, m / z): 373.2 [M+H] +

[0466] Example S43. 1-(2,6-Dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol (43) [Chemistry] Synthesis of 2,6-Dimethyl-4-(1-phenylazetidin-3-yl)benzaldehyde [Chemistry] In anhydrous 1,4 - dioxane (10 mL), cesium carbonate (3.5 g, 11.03 mmol) was added to a solution of 4-(azetidin - 3 - yl)-2,6 - dimethylbenzaldehyde, TFA salt (1 g, 3.68 mmol) and iodobenzene (750 mg, 3.68 mmol). Next, the reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (307 mg, 0.368 mmol), and heated to 80 °C. After 16 hours, TLC analysis showed that the conversion of the starting material was complete. The reaction mixture was then cooled to room temperature, filtered through a celite pad, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel flash column chromatography (230 - 400 mesh) eluting with 0 - 20% ethyl acetate in petroleum ether to give 2,6 - dimethyl - 4-(1 - phenylazetidin - 3 - yl)benzaldehyde (302 mg, 31.1% yield) as a yellow solid. LCMS method 1; LCMS (ESI, m / z): 266.2 [M + H] +

[0467] Synthesis of 1-(2,6-Dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol (43) [Chemistry] To a stirred solution of 3-methylazetidin-3-ol (157 mg, 1.80 mmol) in MeOH (10 mL) were added 2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzaldehyde (400 mg, 1.507 mmol) and zinc chloride (247 mg, 1.507 mmol), and the mixture was stirred at RT for 1 h. After 1 h, sodium cyanoborohydride (95 mg, 1.507 mmol) was added and the mixture was heated at 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:acetonitrile (30:70); Gemini NX C18 (50 x 21.2)mm, 10 micron, mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile) to give 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol, formate salt (51 mg, 0.131 mmol, 8.70% yield, 98.4% purity) as a white solid. 1 1H-NMR (400 MHz, MeOD): δ 7.19 - 7.23 (m, 2H), 7.12 (s, 2H), 6.75 (t, J = 7.60 Hz, 1H), 6.54 - 6.56 (m, 2H), 4.24 (t, J = 7.60 Hz, 2H), 4.19 (s, 2H), 3.76 - 3.89 (m, 5H), 3.62 (d, J = 9.60 Hz, 2H), 2.44 (s, 6H), 1.48 (s, 3H). LCMS method 2; LCMS (ESI, m / z): 337.2 [M+H] +

[0468] Example S44. 1-(4-(1-(2-Fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (44)

Chem.

[0469] Synthesis of 4-(1-(2-Fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde

Chemical Structure

[0470] Synthesis of 1-(4-(1-(2-Fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (44) [Chemical formula] In MeOH (5 mL), sodium bicarbonate (178 mg, 2.118 mmol) was added to a stirred solution of 3-methylazetidin-3-ol and TFA (213 mg, 1.059 mmol), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to afford the free amine. Zinc chloride (96 mg, 0.706 mmol) was added to the free amine 4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (200 mg, 0.706 mmol) in 5 mL of MeOH, and the mixture was stirred at rt for 1 h. After 1 h, sodium cyanoborohydride (66.5 mg, 1.059 mmol) was added and the mixture was heated at 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (information on method: diluent: THF:acetonitrile (30:70); column: Xbridge C18 (150 x 19)mm, 5 micron; mobile phase A: 5 mM ammonium formate in water; mobile phase B: acetonitrile) to give 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol, formate (68 mg, 0.170 mmol, 24.03% yield, 99.9% purity) as a white solid.

[0471] 1 1H NMR (400 MHz, MeOD): δ 7.19 (s, 2H), 6.95 - 7.06 (m, 2H), 6.74 - 6.79 (m, 1H), 6.63 - 6.65 (m, 1H), 4.43 (s, 2H), 4.33 - 4.37 (m, 2H), 4.02 (d, J = 11.20 Hz, 2H), 3.84 - 3.93 (m, 5H), 2.47 (s, 6H), 1.51 (s, 3H). LCMS method 1; LCMS (ESI, m / z): 355.2 [M+H] +

[0472] Example S45. 1-(4-(1-(3-Fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (45)

Chem.

Chem.

[0473] Synthesis of tert-butyl 3-(4-((3-acetoxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate

Chem.

[0474] Synthesis of 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate [Chemical Formula] In anhydrous dichloromethane (40 mL), trifluoroacetic acid (2.7 mL, 69.1 mmol) was added to a stirred solution of tert-butyl 3-(4-((3-acetoxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate (1.5 g, 3.7 mmol) at 0 °C. The reaction mixture was then stirred at ambient temperature and the progress of the reaction was monitored by TLC analysis. After 1 hour, TLC analysis indicated that the conversion of the starting material was complete. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was triturated with diethyl ether to afford a quantitative amount of 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate, TFA as a quantitative amount of a brown semi-solid. LCMS Method 1; LCMS (ESI, m / z): 303.0 [M+H] +

[0475] Synthesis of 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate [Chemical Structure] In anhydrous 1,4-dioxane (8 mL), cesium carbonate (0.96 g, 2.97 mmol) was added to a solution of 4-(1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl) acetate, TFA salt (300 mg, 0.98 mmol) and 1-fluoro-3-iodobenzene (356 mg, 1.48 mmol). The reaction mixture was then degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (83 mg, 0.09 mmol) to the reaction mixture, and heated to 80 °C. After 16 hours, TLC analysis showed that the conversion of the starting material was complete. The reaction mixture was then cooled to room temperature, filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by silica gel flash column chromatography (230 - 400 mesh) eluting with 0 - 20% ethyl acetate in petroleum ether to give 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate (60 mg, 16% yield) as a yellow semi-solid. LCMS method 1; LCMS (ESI, m / z): 397.4 [M+H] +

[0476] Synthesis of 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (45) [Chemical formula] To a stirred solution of 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate (60 mg, 0.151 mmol) in methanol (5 mL) was added sodium methoxide (20.44 mg, 0.378 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by Prep. HPLC (information on method: diluent: THF:water:ACN (50:10:40); column: Symmetry C8 (300 x 19)mm, 7 micron; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile) to give 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol, formate (18 mg, 29% yield, 99.8% purity) as a white solid.

[0477] 1 1H NMR (400 MHz, MeOD): 7.16 - 7.21 (m, 3H), 6.41 - 6.46 (m, 1H), 6.32 - 6.34 (m, 1H), 6.24 - 6.31 (m, 1H), 4.29 - 4.44 (m, 2H), 4.26 - 4.28 (m, 2H), 4.01 - 4.03 (m, 2H), 3.82 - 3.93 (m, 5H), 2.47 (s, 6H), 1.51 (s, 3H). LCMS method 1; LCMS (ESI, m / z): 355.2 [M+H] +

[0478] Example S46. 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (46)

Chem.

Chem.

[0479] Synthesis of 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (46) [Chemical Structure Diagram] In MeOH (10 mL), to a stirred solution of 3-methylazetidin-3-ol (123 mg, 1.34 mmol) was added 4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (400 mg, 1.177 mmol) and zinc chloride (192 mg, 1.412 mmol), and the mixture was stirred at rt for 1 h. After 1 h, sodium cyanoborohydride (74 mg, 1.177 mmol) was added and the mixture was heated at 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:acetonitrile (30:70); column: Xselect C18 (150 x 19)mm, 5 micron; mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile) to give 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol, formate (23 mg, 0.050 mmol, 4.25% yield, 99.5% purity) as an off-white solid.

[0480] 1 1H NMR (400 MHz, MeOD): 7.13 (s, 2H), 6.88 (d, J = 8.40 Hz, 1H), 6.54 (d, J = 2.40 Hz, 1H), 6.38 - 6.41 (m, 1H), 4.21 (s, 4H), 3.78 - 3.87 (m, 5H), 3.66 (d, J = 9.60 Hz, 2H), 2.44 (s, 6H), 2.02 - 2.06 (m, 1H), 1.49 (s, 3H), 0.89 - 0.94 (m, 2H), 0.56 - 0.60 (m, 2H). LCMS method 2; LCMS (ESI, m / z): 411.1 [M+H] +

[0481] Example S47. 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (47) [Chemical Structure] Synthesis of 4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde

Chem.

[0482] Synthesis of 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (47)

Chem.

[0483] 1 H NMR (400 MHz, DMSO-d6): δ 7.04 (s, 2H), 6.92 (d, J = 8.8 Hz, 2H) 2H), 6.41 (d, J = 8.4 Hz, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.83 (m, 1H), 3.69 (m, 3H), 2.36 (s, 6H), 1.82-1.78 (m, 1H), 1.34 (s, 3H), 0.86-0.81 (m, 2H), 0.54-0.51 (m, 2H). There are few protons overlapping with the solvent signal. LCMS method 1, LCMS (ESI, m / z): 377.2 [M+H] +

[0484] Example S48. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)-3-methylazetidin-3-ol (48) [Chemical formula] Synthesis of tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate

Chem.

[0485] Synthesis of methyl 4-(azetidin-3-yl)-2-fluoro-6-methylbenzoate; TFA salt

Chem.

[0486] Synthesis of Methyl 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzoate [Chemical formula] In anhydrous 1,4-dioxane (20 mL), cesium carbonate (3.4 g, 10.68 mmol) was added to a solution of 1-methyl 4-(azetidin-3-yl)-2-fluoro-6-methylbenzoate, TFA salt (1.2 g, 3.55 mmol) and 1,3-chloro-2-iodobenzene (1.2 g, 4.44 mmol). Next, the reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of RuPhos Pd G3 (149 mg, 0.17 mmol), and heated to 80 °C. After 16 hours, TLC analysis indicated that the conversion of the starting material was complete. Next, the reaction mixture was cooled to room temperature, filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel flash column chromatography (230 - 400 mesh) eluting with 0 - 50% ethyl acetate in petroleum ether to give methyl 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzoate (550 mg, 42% yield) as an orange-brown solid. LCMS method 1, LCMS (ESI, m / z): 369.8 [M+H] +

[0487] Synthesis of (4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylphenyl)methanol

Chem.

[0488] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzaldehyde

Chem.

[0489] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)-3-methylazetidin-3-ol (48) [Chemical Structure] To a stirred solution of 3-methylazetidin-3-ol, TFA salt (122 mg, 0.66 mmol) in MeOH (5 mL) was added sodium bicarbonate (75 mg, 0.88 mmol.), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to afford the free amine. To the free amine 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzaldehyde (150 mg, 0.44 mmol) in 5 mL of MeOH was added zinc chloride (60 mg, 0.44 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (42 mg, 0.66 mmol.) was added and the mixture was heated to 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:water:ACN (50:10:40); column: Luna C18 (250x21.2)mm, 10 micron mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile). The required fractions were lyophilized to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)-3-methylazetidin-3-ol (73 mg, 35.5%, 98.1% purity) as an off-white semi-solid.

[0490] 1 H NMR (400 MHz, MeOD): δ 7.17-7.23 (m, 4H), 6.74 (t, J = 8.00 Hz, 1H), 4.86-4.90 (m, 2H), 4.38-4.42 (m, 2H), 4.29 (s, 2H), 3.90 (d, J = 10.00 Hz, 2H), 3.72-3.79 (m, 3H), 2.48 (s, 3H), 1.51 (s, 3H); LCMS method 1, LCMS (ESI, m / z): 409.0 [M] +

[0491] Example S49. 1-(2-Chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol (49)

Chem.

Chem.

[0492] Synthesis of Methyl 4-(azetidin-3-yl)-2-chloro-6-methylbenzoate

Chem.

[0493] Synthesis of Methyl 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzoate

Chemical Structure

[0494] Synthesis of (2-Chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylphenyl)methanol

Chem.

[0495] Synthesis of 2-Chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde

Chem.

[0496] Synthesis of 1-(2-Chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol; formate (49) [Chemical formula] In MeOH (5 mL), sodium bicarbonate (71.1 mg, 0.846 mmol) was added to a stirred solution of 3-methylazetidin-3-ol and TFA (102 mg, 0.508 mmol), and then the mixture was stirred at rt for 1 h. The mixture was filtered through celite and concentrated to give the free amine. In 5 mL of MeOH, zinc chloride (86 mg, 0.634 mmol) was added to the free amine and 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde (150 mg, 0.423 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (26.6 mg, 0.423 mmol) was added and the mixture was heated to 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:water:ACN (50:10:40); column: Luna C18 (250x21.2)mm, 10 micron mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile). The required fractions were lyophilized to give 1-(2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol, formate (45 mg, 0.094 mmol, 22.21% yield, 98.5% purity) as an off-white semi-solid.

[0497] 1 H NMR (400 MHz, MeOD): δ 7.43 (s, 1H), 7.34 (s, 1H), 7.20 (d, J = 8.00 Hz, 2H), 6.74 (t, J = 8.00 Hz, 1H), 4.88 - 4.90 (m, 2H), 4.38 - 4.41 (m, 2H), 4.29 (s, 2H), 3.67 - 3.78 (m, 5H), 2.50 (s, 3H), 1.49 (s, 3H); LCMS method 1, LCMS (ESI, m / z): 427.0 [M+H] +

[0498] Example S50. 1-(2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (50)

Chem.

Chem.

[0499] Synthesis of Methyl 4-(azetidin-3-yl)-2-cyclopropylbenzoate

Chem.

[0500] Synthesis of Methyl 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzoate [Chemical formula] To a solution of methyl 4-(azetidin-3-yl)-2-cyclopropylbenzoate, TFA (1.2 g, 3.48 mmol) and 1,3-dichloro-2-iodobenzene (1.138 g, 4.17 mmol) in anhydrous 1,4-dioxane (20 mL) was added cesium carbonate (10.43 mmol). Next, the reaction mixture was degassed with nitrogen for 10 minutes, followed by the addition of Ruphos pd G3 (0.291 g, 0.348 mmol) and heating to 80 °C. After 16 hours, TLC analysis indicated that the conversion of the starting material was complete. The reaction mixture was then cooled to room temperature, filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by silica gel flash column chromatography (230 - 400 mesh) eluting with 0 - 50% ethyl acetate in petroleum ether to give methyl 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzoate (759 mg, 58.1% yield) as a yellow solid. LCMS method 1, LCMS (ESI, m / z): 376.2 [M+H] +

[0501] Synthesis of (2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)methanol

Chem.

[0502] Synthesis of 2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzaldehyde

Chem.

[0503] Synthesis of 1-(2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (50) [Chemical formula] In MeOH (5 mL), sodium bicarbonate (75 mg, 0.88 mmol) was added to a stirred solution of 3-methylazetidin-3-ol, TFA salt (87 mg, 0.433 mmol), and the mixture was then stirred at rt for 1 h. The mixture was filtered through celite and concentrated to give the free amine. In 5 mL of MeOH, zinc chloride (59.0 mg, 0.433 mmol) was added to the free amine and 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzaldehyde (150 mg, 0.433 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (40.8 mg, 0.65 mmol) was added and the mixture was heated to 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (eluent: THF:water:ACN (50:10:40); column: Luna C18 (250x21.2)mm, 10 micron mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile). The required fractions were lyophilized to give 1-(2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol, formate salt (39.0 mg, 0.082 mmol, 18.89% yield, 97.2% purity) as an off-white semi-solid.

[0504] 1 H NMR (400 MHz, MeOD): 7.32 - 7.37 (m, 1H), 7.15 - 7.21 (m, 3H), 6.74 (t, J = 8.00 Hz, 1H), 4.34 - 4.39 (m, 4H), 4.86 (s,3H), 3.84 - 3.86 (m, 2H), 3.66 - 3.75 (m, 3H), 2.06 - 2.12 (m, 1H), 1.53 (s, 3H), 1.03 - 1.08 (m, 2H), 0.73 - 0.76 (m, 2H); LCMS method 1, LCMS (ESI, m / z): 417.2 [M+H] +

[0505] Example S51. Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzyl)-3-methylazetidin-3-ol (51)

Chem.

Chem.

[0506] Synthesis of 4-(Azetidin-3-yl)-2-ethyl-6-methylbenzaldehyde

Chem.

[0507] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzaldehyde [Chemical formula] In anhydrous 1,4 - dioxane (20 mL), Cs2CO3 (3.59 g, 11.03 mmol) was added to a solution of 4-(azetidin - 3 - yl)-2 - ethyl - 6 - methylbenzaldehyde, TFA (1.0 g, 3.15 mmol), and 1,3 - dichloro - 2 - iodobenzene (1.032 g, 3.78 mmol). Next, the reaction mixture was degassed with nitrogen for 10 minutes, then RuPhos Pd G3 (0.264 g, 0.315 mmol) was added and heated to 80 °C. After 16 hours, TLC analysis indicated that the conversion of the starting material was complete. The reaction mixture was then cooled to room temperature, filtered through a Celite pad, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel flash column chromatography (230 - 400 mesh) eluting with 0 - 50% ethyl acetate in petroleum ether to give 4-(1-(2,6 - dichlorophenyl)azetidin - 3 - yl)-2 - ethyl - 6 - methylbenzaldehyde (1 g, 2.464 mmol, 78% yield) as a green solid. LCMS method 1; LCMS (ESI, m / z): 348.0 [M + H] +

[0508] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzyl)-3-methylazetidin-3-ol (51) [Chemical formula] A stirred solution of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzaldehyde (200 mg, 0.574 mmol) and 3-methylazetidin-3-ol (60.0 mg, 0.689 mmol) in 10 mL of MeOH was added zinc chloride (117 mg, 0.861 mmol), and the mixture was stirred at 25 °C for 1 h. After 1 h, sodium cyanoborohydride (54.1 mg, 0.861 mmol) was added and the mixture was heated at 65 °C for 12 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated ammonium chloride solution and water (20 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was ...

Claims

1. A compound of the following formula (I): 【Chemical Formula 1】 [wherein, L is -C≡C-, -HC=CH-, -CH ２ CH ２ -, -CH ２ O-, [Chemical Formula 2] is either or a bond; R １ is, independently of one another, halo, -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ -C ６ cycloalkyl; x is from 0 to 5; R ２ is H, halo, C １ -C ６ -alkyl, C ３ -C ６ -cycloalkyl, or C １ -C ６ -haloalkyl; R ３ａ and R ３ｂ is each H; Alternatively, R ２ and R ３ａ form a fused cyclopentyl together with the carbon atoms to which they are attached; Alternatively, R ２ and R ４ form a condensed phenyl together with the carbon atoms to which they are attached; R ４ is H, halo, -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ -C ６ cycloalkyl; X １ and X ２ each independently is N or CR ５ ; R ５ is, independently of one another, H, halo, -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or C ３ -C ６ cycloalkyl; R ６ is H; R ７ is C １ -C ６ alkyl-OH or; Alternatively, R ６ and R ７ form a 4- to 6-membered heterocyclyl substituted with n R ８ groups together with the nitrogen atom to which they are attached; n is from 1 to 5; R ８ is, independently of each other, halo, -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, or -OH, provided that However, at least one R ８ is —OH] or a pharmaceutically acceptable salt thereof.

2. L is -C≡C-, -CH ２ CH ２ -, -CH ２ O-, or a bond, The compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

3. L is [Chemical 3] The compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ is, independently of each other, halo, -CN, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, or C ３ -C ６ cycloalkyl, The compound according to any one of Claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. 【Fig. 4】 The compound according to any one of Claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R ２ is H, halo, C １ -C ３ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ３ haloalkyl; R ３ａ and R ３ｂ are each H, The compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R ２ and R ３ａ together with the carbon atoms to which they are attached form a fused cyclopentyl; R ３ｂ is H The compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. R ２ and R ４ together with the carbon atoms to which they are attached form a condensed phenyl ring The compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

9. R ４ is H, halo, -CN, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, or C ３ -C ６ cycloalkyl, The compound according to any one of Claims 1 to 7 or a pharmaceutically acceptable salt thereof.

10. R ５ is, independently of one another, H, halo, -CN, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, or C ３ -C ６ cycloalkyl, The compound according to any one of Claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 5】 The compound according to any one of Claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. R ６ is H; R ７ is C １ -C ６ alkyl-OH The compound according to any one of Claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. R ６ and R ７ together with the nitrogen atom to which they are attached 【Chemical Formula 6】 forms; R ８ is, independently of one another, halo, -CN, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, or -OH, The compound according to any one of Claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. 【Chemical Formula 7】 The compound according to any one of Claims 1 to 11 and 13 or a pharmaceutically acceptable salt thereof.

15. The following formula (II): 【Chemical 8】 A compound according to any one of Claims 1 to 5, 7, and 9 to 14 or a pharmaceutically acceptable salt thereof, represented by

16. The following formula (III): 【Chemical Formula 9】 A compound according to any one of Claims 1 to 6 and 8 to 14 or a pharmaceutically acceptable salt thereof, represented by

17. A compound selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A method for modulating S1P5, comprising contacting sphingosine 1-phosphate receptor 5 (S1P5) with an effective amount of the compound according to any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Claim 18.

20. A method for treating a neurological disorder in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, wherein optionally, the neurological disorder is Alzheimer's disease, multiple sclerosis, migraine, and amyotrophic lateral sclerosis.

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