Compounds for treatment of neurodegenerative diseases

Abstract

Provided herein are compounds and compositions thereof for modulating S1P5. In some embodiments, the compounds and compositions provided are useful in the treatment of neurological diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 390,069, filed on July 18, 2022, the disclosure of which is incorporated herein by reference in its entirety for any purpose. Technical Field

[0002] The present disclosure generally relates to compounds, compositions, and methods of making the same, as well as the use of the compounds and compositions for treating neurological diseases. Background Art

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadecen-4-enyl-1-phosphate) is a biologically active sphingomyelin that is synthesized through metabolic conversion of intracellular sphingomyelin and the extracellular action of secreted sphingosine kinase. S1P binds to and stimulates members of the endothelial differentiation gene family (EDG receptors), which are plasma membrane-localized G protein-coupled receptors. The five members of this receptor family are S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P mediates a wide variety of cellular responses, including proliferation, cytoskeletal organization and migration, adhesion and tight junction assembly, and morphogenesis.

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

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

[0006] In certain embodiments, the present application describes compounds and compositions thereof for modulating S1P5. In various embodiments, the compounds and compositions thereof can be used to treat neurodegenerative diseases.

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

[0008] Embodiment A1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is -C≡C-, -HC=CH-, -CH2CH2-, -CH2O-, or key; Each R 1 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; x is 0-5; R 2 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; R 3a and R 3b Each is H; or R 2 and R 3a Together with the carbon atoms to which they are attached, they form a fused cyclopentyl group; or R 2 and R 4 Together with the carbon atoms to which they are attached, they form fused phenyl groups; R 4 is H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X 1 and X 2 are independently N or CR 5 ; Each R 5 are independently H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 6 is H; R 7 is C1-C6 alkyl-OH; or R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 a 4- to 6-membered heterocyclic group substituted with a group; n is 1-5; and Each R 8 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -OH, The condition is that at least one R 8 It is -OH.

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

[0010] Embodiment A3. A compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein: L is

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

[0012] Embodiment A5. A compound according to any one of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein: for

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

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

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

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

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

[0018] Embodiment A11. A compound according to any one of Embodiments A1-A10, or a pharmaceutically acceptable salt thereof, wherein: for

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

[0020] Embodiment A13. A compound according to any one of Embodiments A1-A11, or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form as well as Each R 8 are independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or -OH.

[0021] Embodiment A14. A compound according to any one of Embodiments A1-A11 and A13, or a pharmaceutically acceptable salt thereof, wherein: for

[0022] Embodiment A15. A compound according to any one of Embodiments A1-A5, A7 and A9-A14, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II):

[0023] Embodiment A16. A compound according to any one of Embodiments A1-A6 and A8-A14, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (III):

[0024] Embodiment A17. A compound selected from the group consisting of the compounds of Table 1 and pharmaceutically acceptable salts thereof.

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

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

[0028] As used herein, the terms "include" and "comprising" are used interchangeably. The terms "include" and "comprising" should be interpreted as specifying the presence of the features or components, but not excluding the presence or addition of one or more features, components, or groups thereof. Additionally, the terms "include" and "comprising" are intended to encompass examples encompassed by the term "consisting of." Therefore, the term "consisting of" can be used in place of the terms "include" and "comprising" to provide more specific embodiments of the present invention.

[0029] The term "consisting of means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components of which it is composed. In another embodiment, the term "consisting of excludes any other features or components from the scope of any subsequent recitation, except those that are not essential for the technical effect to be achieved.

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

[0031] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer within the range, as well as fractions thereof (such as tenths and hundredths of integers) where appropriate. In addition, unless otherwise indicated, any numerical range described herein relating to any physical characteristic, such as polymer subunits, size, or thickness should be understood to include any integer within the range. As used herein, unless otherwise indicated, "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the referenced range, value, or structure.

[0032] An "alkyl" group is a group having 1 to 10 carbon atoms (C1-C 10In some embodiments, the alkyl group is a saturated, partially saturated, or unsaturated straight or branched non-cyclic hydrocarbon having 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 (C1-C6 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, the alkyl group is an unsaturated alkyl group, also defined as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH). Alkyl groups can be substituted or unsubstituted. When an alkyl group as described herein is referred to as "substituted," it may be substituted with any one or more of the substituents present in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy; oxo (=0); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocyclylalkylamino, cycloalkylalkylamino , arylalkylamino, heterocyclylalkylamino, heteroarylalkylamino, heterocyclylalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; arylalkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when an alkyl group described herein is referred to as "substituted," it may be substituted with any one or more of the substituents present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; sulfhydryl; thioether; imino; imido; amidino; guanidino; enamino; aminocarbonyl; acylamino; phosphonate; phosphino; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0033] "Alkyl-OH" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl group substituted with one or more -OH groups. An alkyl-OH group may contain multiple hydroxyl groups attached to the same carbon atom or multiple carbon atoms.

[0034] A "cycloalkyl" group is a 3 to 10 carbon atom (C3-C4) alkyl radical having a single ring or multiple fused or bridged rings which may be optionally substituted. 10 In some embodiments, the cycloalkyl group is a saturated cycloalkyl. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), but in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl) or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl. These saturated cycloalkyls include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl etc., or polycyclic structures 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 etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group may be substituted or unsubstituted. These substituted cycloalkyl groups include, for example, cyclohexanol, etc.

[0035] An "aryl" group is a 6-14 carbon atom (C6-C14) group having a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthracenyl). 14 In some embodiments, the aryl group contains 6-14 carbon atoms (C6-C 14aryl), and in other embodiments contains 6 to 12 (C6-C 12 aryl) or even 6 to 10 carbon atoms (C6-C 10 aryl). Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups may be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

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

[0037] "Haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halo substituents as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C1-C3 haloalkyl). The halo groups may be all the same or the halo groups may be different. Unless otherwise specifically stated, the haloalkyl group may be optionally substituted.

[0038] A "heteroaryl" group is an aromatic ring system having from 1 to 4 heteroatoms as ring atoms in the heteroaryl ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group contains from 3 to 6 ring atoms, and in other embodiments contains from 6 to 9 or even 6 to 10 heteroatoms 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, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridinyl (e.g., The heteroaryl groups include benzophenone, ...

[0039] "Heterocyclyl" is a non-aromatic cycloalkyl group 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 includes 3 to 10 ring members, while other such rings have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl group may also be bonded to other groups on any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). The heterocycloalkyl group may be substituted or unsubstituted. The heterocyclyl group encompasses saturated and partially saturated ring systems. In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, whether or not it is connected to the rest of the molecule. The phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents as listed below.

[0040] An "alkoxy" group is an -O-(alkyl) group wherein alkyl is as defined above.

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

[0042] When groups described herein (other than alkyl groups) are referred to as "substituted," they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imino; imido; amidino; guanidino; enamino; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo(═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, It may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or a heterocyclic group, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); monocyclic or fused or non-fused polycyclic or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0043]

[00146] Embodiments of the present disclosure are intended to encompass pharmaceutically acceptable salts, tautomers, isotopomers, and stereoisomers of the compounds provided herein, such as compounds of Formula (I).

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and inorganic bases and organic acids and organic bases. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-diphenylmethylethylenediamine, 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, aminobenzoic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic 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 and methanesulfonic acid. Therefore, the example of specific salt includes hydrochloride, formate and mesylate. Others are known in the art, referring to, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0045] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means 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 the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include 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, 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, 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, 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 occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0046] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, is encompassed within the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetric synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science&Business Media, 2007); 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 compounds may be isolated as E or Z isomers. In other embodiments, the compounds are mixtures of E and Z isomers.

[0048] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located and may differ, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

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

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

[0051] It will be understood that, independent of stereoisomer or isotopic composition, each compound disclosed herein can be provided in the form of any pharmaceutically acceptable salt discussed herein. Likewise, it will be understood that the isotopic composition can vary independently of the stereoisomer composition of each compound described herein. Furthermore, the isotopic composition, while limited to those elements present in the corresponding compound disclosed herein or a salt thereof, can also vary independently of the choice of a pharmaceutically acceptable salt of the corresponding compound.

[0052] It should be noted that if there is a discrepancy between a described structure and the name of the structure, the described structure takes precedence.

[0053] As used herein, "treating" means alleviating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition, in whole or in part, or slowing or stopping the further progression or worsening of these symptoms, or alleviating or eliminating one or more causes of the disorder, disease, or condition itself. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof as described herein.

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

[0055] The term "effective amount" in connection with 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 term "subject" or "patient" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, 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 who has or is 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, these features may also be provided separately or in any suitable combination. Conversely, although the invention may be described in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compound

[0058] In one aspect, provided herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is -C≡C-, -HC=CH-, -CH2CH2-, -CH2O-, or key; Each R 1 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; x is 0-5; R 2 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; R 3a and R 3b Each is H; or R 2 and R 3a Together with the carbon atoms to which they are attached, they form a fused cyclopentyl group; or R 2 and R 4 Together with the carbon atoms to which they are attached, they form fused phenyl groups; R 4 is H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X 1 and X 2 are independently N or CR 5 ; Each R 5 are independently H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 6 is H; R 7 is C1-C6 alkyl-OH; or R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 a 4- to 6-membered heterocyclic group substituted with a group; n is 1-5; and Each R 8 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -OH, The condition is that at least one R 8 It is -OH.

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

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

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

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

[0063] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is isopropyl.

[0064] In some embodiments, R 1 is a C1-C6 haloalkyl group. 1 is a haloalkyl group containing 1 to 13 halogen atoms. 1 is a C1-C3 haloalkyl group.1 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 1 In some embodiments, R 1 In some embodiments, R 1 is -CHF2.

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

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

[0067] In some embodiments, x is 0-5. 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, for:

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

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

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

[0072] In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is isopropyl.

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

[0074] In some embodiments, R 2 is a C1-C6 haloalkyl group. 2 is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 2 is a C1-C3 haloalkyl group. 2 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 2In some embodiments, R 2 In some embodiments, R 2 is -CHF2.

[0075] In some embodiments, R 2 and R 3a Together with the carbon atoms to which they are attached, they form a fused cyclopentyl. 3b For H.

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

[0077] In some embodiments, R 3a and R 3b Each is H.

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

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

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

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

[0082] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is isopropyl.

[0083] In some embodiments, R 4 is a C1-C6 haloalkyl group. 4 is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 4 is a C1-C3 haloalkyl group. 4 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 4 In some embodiments, R 4 In some embodiments, R 4 is -CHF2.

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

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

[0086] In some embodiments, X 1 and X 2 N or CR alone5 In some embodiments, X 1 and X 2 CR alone 5 In some embodiments, X 1 is N and X 2 CR 5 In some embodiments, X 1 CR 5 , and X 2 is N. In some embodiments, X 1 and X 2 Each is N.

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

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

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

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

[0091] In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 It is isopropyl.

[0092] In some embodiments, R 5 is a C1-C6 haloalkyl group. 5 is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 5 is a C1-C3 haloalkyl group. 5 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 5 In some embodiments, R 5 In some embodiments, R 5 is -CHF2.

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

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

[0095] In some embodiments, for:

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

[0097] In some embodiments, R 7 In some embodiments, R 7In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 It is -CH2C(OH)(CH3)2.

[0098] In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 In some embodiments, the heterocyclic group is azetidinyl, pyrrolidinyl or piperidinyl, each of which is substituted by n R 8 Group substitution.

[0099] In some embodiments, R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form

[0100] In some embodiments, n is 1-5. In some embodiments, n is 1-4. In some embodiments, n is 1-3. In some embodiments, n is 1-2. 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 R8 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -OH, provided that at least one R 8 In some embodiments, each R 8 R is independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or -OH. 8 is independently -CH3, -CH2CH3, -CFH2, -CF2H, -CF3 or -OH. In some embodiments, one R 8 It is -OH.

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

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

[0104] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is methyl, ethyl, n-propyl or isopropyl. In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is isopropyl.

[0105] In some embodiments, R 8 is a C1-C6 haloalkyl group. 8 is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 8 is a C1-C3 haloalkyl group. 8 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 8 In some embodiments, R8 In some embodiments, R 8 In some embodiments, R 8 It is -CF2H.

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

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

[0108] In some embodiments, there are two or more R 8 group and an R 8 In some embodiments, there are two R 8 group and an R 8 In some embodiments, there are three R 8 group and an R 8 The group is -OH.

[0109] In some embodiments, for:

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

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

[0112] In some embodiments, the compound of formula (I) is a compound of formula (II-A) or (II-B): where R 1 、R 4 、R 8 , L, X 1 、X 2 , n and x are as described in formula (I); and It is a 4- to 6-membered heterocyclic group.

[0113] In some embodiments, the compound of Formula (I) is a compound of Formula (IIA), (IIB), (IIC), (IID), (IIE), (IIF), or (IIG): where R 1 、R 4 、R 8 、X 1 、X 2 , x and n are as described in formula (I).

[0114] In some embodiments, the compound of formula (I) is a compound of formula (III): where R 1 、R 2 、R 4 、R 6 、R 7 , L, X 1 、X 2 and x are as described in formula (I).

[0115] In some embodiments, the compound of Formula (I) is a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg): where R 1 、R 2 、R 4 、R 6 、R 7 、X 1 、X 2 and x are as described in formula (I).

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

[0117] In some embodiments, the compound of formula (I) is a compound of formula (III-A) or (III-B): where R 1 、R 2 、R 4 、R 8 , L, X 1 、X 2 , n and x are as described in formula (I); and It is a 4- to 6-membered heterocyclic group.

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

[0119] In the description herein, it should be understood that each description, variation, embodiment or aspect of a section can be combined with each description, variation, embodiment or aspect of other sections, just as if each and every combination of descriptions were specifically and individually listed. For example, the descriptions provided herein for R of formula (I) 1 Each description, variation, embodiment or aspect may be combined with R 2 、R 3a 、R 3b 、R 4 、R 6 、R 7 、R 8 、X 1 、X 2Each description, variation, embodiment or combination of aspects of formula (I) is as if each and every combination were specifically and individually listed. It is also understood that, where applicable, all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to other formulas detailed herein and are similarly described as if each and every description, variation, embodiment or aspect of all formulas were separated and individually listed. For example, where applicable, all descriptions, variations, embodiments, or aspects of Formula (I) also apply to other formulae detailed herein, 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), and are likewise described as if each and every description, variation, embodiment, or aspect of all formulae were separated and listed individually.

[0120] In some embodiments, provided herein are compounds selected from Table 1, or pharmaceutically acceptable salts thereof. Although certain compounds described in the present disclosure, including those in Table 1, are represented as specific stereoisomers and / or are presented in non-stereochemical forms, it is understood that any and all stereochemical forms, including any enantiomeric or diastereomeric forms, as well as any tautomeric or other forms, of any compound of the present disclosure, including those in Table 1, are described herein. Table 1. or a pharmaceutically acceptable salt thereof.

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

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

[0123] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Scheme 1 or according to the examples listed herein. It should be noted that one skilled in the art will know how to modify the methods described in the illustrative schemes and examples to obtain the desired products. Solution 1. where R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 、R 7 、R 8 、X 1 、X 2 and x are as described in formula (I).

[0124] As outlined in Scheme 1, compounds of Formula A can be derived from bromo-substituted ring a via coupling with Boc-protected 3-iodo-azetidine to form intermediate b, which is then deprotected and reacted with aryl bromide c to produce intermediate d. Intermediate d then reacts with amine e via a subsequent Schiff's base reaction to produce compounds of Formula A.

[0125] As outlined in Scheme 1, compounds of Formula B can be prepared from bromo-substituted ring a via coupling with aryl alkyne f to form intermediate g, which undergoes a subsequent Schiff base reaction with amine e to form compounds of Formula B. Alternatively, bromo-substituted ring a and amine e first undergo a Schiff base reaction to form intermediate h, which is then coupled with aryl alkyne f to form Formula B. Further hydrogenation of the compound of Formula B can provide a compound of Formula C. The compound of Formula C can also be prepared by coupling trifluoroborate I to intermediate a, followed by a reductive amination reaction with amine e.

[0126] As outlined in Scheme 1, compounds of formula D can react with amines e via bromosubstituted ring a to form intermediates h, which, via subsequent coupling reaction with the amine of azetidine-aryl i, form compounds of formula D.

[0127] As outlined in Scheme 1, compounds of Formula E can be synthesized from intermediate h via two different routes. The first involves a two-step reaction, in which intermediate a is first coupled with a dioxaborolane compound to produce intermediate j, which is further coupled with an aryl bromide c to produce compound E. The other involves a direct coupling reaction between intermediate h and a dioxaborolane aryl group k to form compound E. Option 2. where R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 2 、R 6 、R 7 、R 8 、X 1 、X 2 and x are as described in formula (I).

[0128] Scheme 2 shows a synthetic route to compounds of formula F. Reaction of intermediate 1 with benzyl bromide m forms intermediate n, which is then coupled to amine o to form compounds of formula F. How to use

[0129] Embodiments of the present disclosure provide methods for modulating sphingosine-1-phosphate receptor 5 (S1P5) in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound of formula (I). Modulation (e.g., inhibition or activation) of S1P5 can be assessed and demonstrated by a variety of methods known in the art. Kits and commercially available assays can be used to determine whether and to what extent S1P5 is modulated (e.g., inhibited or activated).

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

[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 compounds of formula (I) modulate 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] On the other hand, there is provided herein a method for treating a neurological disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, there is provided herein a method for preventing a neurological disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) to the subject. Non-limiting examples of neurological diseases include Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), migraine, Bell's palsy (Bell's Palsy), ataxia, cerebral aneurysm, epilepsy, epileptic seizures, acute spinal cord injury, Guillain-Barre syndrome (Guillain-Barre syndrome), meningitis, Niemann Pick disease (Niemann Pickdisease) and Parkinson's disease. In some embodiments, the neurological disease is Alzheimer's disease or multiple sclerosis. In some embodiments, the neurological disease is Alzheimer's disease. In some embodiments, the neurological disease is multiple sclerosis.

[0133] In some embodiments, administering a compound of formula (I) to a subject susceptible to a neurological disease prevents the subject from developing any symptoms of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject who has not yet exhibited symptoms of a neurological disease prevents the subject from developing any symptoms of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need reduces the extent of the subject's neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need stabilizes the neurological disease (prevents or delays the worsening of the neurological disease). In some embodiments, administering a compound of formula (I) to a subject in need delays the appearance or recurrence of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need slows down the progression of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need provides partial relief of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need provides complete relief of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need reduces the dosage of one or more other drugs required to treat the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need enhances the effect of another drug for treating the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need slows the progression of the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need improves the quality of life of a subject suffering from the neurological disease. In some embodiments, administering a compound of formula (I) to a subject in need prolongs the survival of a subject suffering from the neurological disease.

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

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

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

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

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

[0139] Also provided herein is a method for delaying the progression of a neurological disease in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the method improves the quality of life of a subject suffering from a neurological disease. In some embodiments, the method prolongs the survival of a subject suffering from a neurological disease.

[0140] On the other hand, there is provided herein a method for treating a neurological symptom caused by a disease of a subject in need thereof, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, there is provided herein a method for preventing a neurological symptom caused by a disease of a subject in need thereof, comprising administering an effective amount of a compound of formula (I) to the subject. In some embodiments, administering a compound of formula (I) to a subject susceptible to a disease causing neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject who has not yet shown neurological symptoms of a disease causing neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need thereof reduces the extent of the neurological symptoms caused by the disease in the subject. In some embodiments, administering a compound of formula (I) to a subject in need thereof stabilizes the neurological symptoms of the disease (preventing or delaying the worsening of the neurological symptoms). In some embodiments, administering a compound of formula (I) to a subject in need thereof delays the appearance or recurrence of neurological symptoms caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need thereof slows down the progression of neurological symptoms caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need provides partial relief of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need provides complete relief of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need reduces the dosage of one or more other drugs required for treating a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need enhances the effect of another drug for treating the neurological symptoms of the disease. In some embodiments, administering a compound of formula (I) to a subject in need delays the progression of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need improves the quality of life of a subject suffering from a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need prolongs the survival of a subject suffering from a disease that causes neurological symptoms. In some embodiments, the disease is Niemann-Pick disease.

[0141] In some embodiments, the compounds of Formula (I) are used to treat a disease selected from the group consisting of Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis and septic arthritis, spondyloarthropathies, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, 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's disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, and the like. granulomatosis), Henoch-Schoenlein purpurea, renal microvasculitis, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancy, heart failure, myocardial infarction, Addison's disease, sporadic polyglandular deficiency type I and type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease disease), psoriatic arthropathy, ulcerative colitis arthropathy, enteropathic synovitis, arthropathy associated with chlamydia, Yersinia, and Salmonella, atherosclerotic disease / arteriosclerosis, atopic allergies, autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Royal Free diseaseDisease), chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency syndrome, acquired immunodeficiency-related diseases, hepatitis B, hepatitis C, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, infertility, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial Lung disease, fibrosis, interstitial pneumonia, interstitial lung disease associated with connective tissue disease, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, lung disease associated with Sjögren's disease, lung disease associated with ankylosing spondylitis, diffuse vasculitic lung disease, lung disease associated with hemosiderosis, drug-induced interstitial lung disease disease, radiation-induced fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrate lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classic autoimmune or lupus-like hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune diseases associated with organ transplantation, chronic hepatitis associated with organ transplantation Immunological disorders, osteoarthritis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, renal disease (NOS), glomerulonephritis, renal microvasculitis, Lyme disease, discoid lupus erythematosus, idiopathic or NOS male infertility, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome syndrome), pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease, Hashimoto'sdisease), atrophic autoimmune hypothyroidism, primary myxedema, phakogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver disease, alcoholic cirrhosis, alcoholic liver injury, cholestasis, idiopathic liver disease, drug-induced hepatitis, nonalcoholic steatohepatitis, allergies and asthma, group B Streptococcus (GBS) infection, psychiatric disorders (e.g., depression and schizophrenia), Th2- and Th1-mediated diseases, acute and chronic pain (different forms of pain), and Cancers such as lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer and rectal cancer as well as hematopoietic malignancies (leukemia and lymphoma), abetalipoprotemia, acrocyanosis, acute and chronic parasitic or infectious diseases, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infections, acute pancreatitis, acute renal failure, adenocarcinoma, atrial ectopic beats, ectopic beats), AIDS dementia complex, alcoholic hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, antireceptor hypersensitivity, aortic and peripheral artery aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (persistent or paroxysmal), atrial flutter, atrioventricular block, B-cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, atrioventricular bundle branch block, Burkitt's lymphoma lymphoma), burns, arrhythmias, cardiac coma syndrome, cardiac tumors, cardiomyopathy, inflammatory response to extracorporeal circulation, cartilage transplant rejection, cerebellar cortical degeneration, cerebellar dysfunction, confusion or multifocal atrial tachycardia, chemotherapy-related conditions, chronic myeloid leukemia (CML), chronic alcoholism, chronic inflammatory pathology, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate poisoning, colorectal cancer, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture-negative sepsis, cystic fibrosis, cytokine therapy-related conditions, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus), diabetic arteriosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglia disorder, middle-aged Down's syndromeSyndrome), drug-induced movement disorders induced by drugs that block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, fetal thymic implant rejection, Friedreich's ataxia, functional peripheral arterial disorder, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, transplant rejection of any organ or tissue, gram-negative sepsis, gram-positive sepsis, granulomas caused by intracellular microorganisms, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis thyroiditis), hay fever, cardiac transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, bleeding, hepatitis A, His bundle arrythmias, HIV infection / HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, weakness, infantile spinal muscular atrophy, aortic inflammation, influenza A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma sarcoma), renal transplant rejection, Legionella, leishmaniasis, leprosy, corticospinal system disease, lipedema, liver transplant rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic, migraine, mitochondrial multisystem disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multisystem degeneration (Mencel Dejerine-Thomas)Shi-Drager and Machado-Joseph), myasthenia gravis, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorder, nasopharyngeal carcinoma, chronic lung disease of the newborn, nephritis, kidney disease, neurodegenerative disease, neurogenic amyotrophy, neutropenic fever, non-Hodgkin lymphoma, abdominal aorta and its branches occlusion, occlusive artery disease, OKT3 therapy, orchitis / epididymitis, orchitis / vasectomy reversal surgery, organomegaly, osteoporosis, pancreatic transplant rejection, pancreatic cancer , carcinoid syndrome / malignant hypercalcemia, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disease, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), postperfusion syndrome, post-pump syndrome, post-myocardial infarction cardiotomy syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease phenomenon and disease), Raynaud's disease, Refsum's disease, conventional narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, choreoathetosis, Alzheimer's disease with Lewy bodies, seronegative arthropathy, shock, sickle cell anemia, skin allograft rejection, skin change syndrome, small bowel transplant rejection, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degeneration, streptococcal myositis, structural cerebellar lesions, subacute sclerosing panencephalitis, syncope, cardiovascular syphilis, anaphylaxis, systemic inflammatory response syndrome, systemic juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxicity, transplant, trauma / bleeding, type III hypersensitivity, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis / aseptic meningitis, viral-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndromesyndrome), Wilson's disease, xenograft rejection of any organ or tissue, acute pain, age-associated memory impairment (AAMI), attention deficit disorder with anxiety, general attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, central neuropathic pain syndrome, central post-stroke pain, chemotherapy-induced neuropathy, cognitive deficits and functional impairment in psychiatric disorders, cognitive deficits associated with aging and neurodegeneration, cognitive deficits associated with diabetes, cognitive deficits in schizophrenia, and complex regional pain syndrome, cognitive decline in Alzheimer's disease and related dementias, attention deficit, dementia, dementia associated with Down syndrome, dementia associated with Lewy bodies, depression in Cushing's syndrome, CNS dysfunction associated with traumatic brain injury, memory impairment, dizziness, substance abuse, epilepsy, HIV sensory neuropathy, Huntington's disease, hyperalgesia (including neuropathic pain, inflammation and inflammatory diseases, inflammatory hyperalgesia), inflammatory pain, insulin resistance syndrome, jet lag, poor circulation, learning, major depressive disorder, medullary thyroid cancer, Meniere's disease disease), metabolic syndrome, mild cognitive impairment, mood changes, motion sickness, multiple sclerosis pain, narcolepsy, the need for new blood vessel growth associated with lack of vascularization and blood circulation in skin grafts, the need for new blood vessel growth associated with wound healing, neuropathic pain, neuropathy, neuropathy secondary to tumor infiltration, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, Parkinson's disease pain, pathological hypersomnia, phantom limb pain, Pick's disease, polycystic ovary syndrome, post-traumatic stress disorder, postherpetic neuralgia, post-mastectomy pain, postoperative pain, psychotic depression, schizoaffective disorder, seizures, Alzheimer's disease, sepsis syndrome, sleep disorders, smoking cessation, pain after spinal cord injury, steroid-induced acute psychosis, subtypes of neuropathic pain (including peripheral neuropathic pain syndromes), substance abuse (including alcohol abuse), syndrome X, Tourette's syndrome, treatment-resistant depression, trigeminal neuralgia, type 2 diabetes mellitus, vertigo, and vestibular disorders. Pharmaceutical compositions and routes of administration

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

[0143] The compounds disclosed herein can be administered orally, topically or parenterally to a subject in the form of conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by commonly used methods using conventional organic or inorganic additives such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), Lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring (e.g., citric acid, menthol, glycine or orange powder), preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizer (e.g., citric acid, sodium citrate or acetic acid), suspending agent (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersant (e.g., hydroxypropyl methylcellulose), diluent (e.g., water) and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition can be at a level that will produce the desired effect; for example, a unit dose of about 0.005 mg / kg subject body weight to about 10 mg / kg subject body weight for both oral and parenteral administration.

[0144] The dosage of the compound of formula (I) applied to the subject varies greatly and can be judged by health care practitioners. Generally speaking, compounds disclosed herein can be applied 1 to 4 times a day with a dosage of about 0.001mg / kg subject weight to about 10mg / kg subject weight, but the above dosage can be appropriately changed according to the age, weight and medical condition of the subject and the type of application. In one embodiment, the dosage is about 0.001mg / kg subject weight to about 5mg / kg subject weight, about 0.01mg / kg subject weight to about 5mg / kg subject weight, about 0.05mg / kg subject weight to about 1mg / kg subject weight, about 0.1mg / kg subject weight to about 0.75mg / kg subject weight or about 0.25mg / kg subject weight to about 0.5mg / kg subject weight. In one embodiment, a dosage is given every day. In any given case, the amount of the compound of formula (I) applied will depend on factors such as the solubility of the active ingredient, the preparation used and the route of administration.

[0145] In some embodiments, the compound of Formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0146] In another embodiment, provided herein are unit dose formulations comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (I).

[0147] In a specific embodiment, provided herein are unit dosage formulations comprising about 0.1 mg or 100 mg of a compound of Formula (I).

[0148] In another embodiment, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a compound of Formula (I).

[0149] The compound of formula (I) can be administered once, twice, three times, four times or more daily. In a specific embodiment, a dose of 100 mg or less is administered as a once daily dose, and a dose exceeding 100 mg is administered twice daily in an amount equal to half the total daily dose.

[0150] For reasons of convenience, the compound of formula (I) can be administered orally. In one embodiment, when administered orally, the compound of formula (I) is administered with a meal and water. In another embodiment, the compound of formula (I) is dispersed in water or fruit 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, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the health care practitioner and may depend, in part, on the location of the medical condition.

[0152] In one embodiment, provided herein are capsules containing a compound of Formula (I) without additional carriers, excipients, or vehicles.

[0153] In another embodiment, the compositions provided herein include an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0154] The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions. The composition can be formulated as a convenient portion containing a daily dose or a daily dose in a dosage unit, which can be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared by a water-soluble salt such as hydrochloride. Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the compound of formula (I) with a suitable carrier or diluent, and filling an appropriate amount of the mixture in a capsule. Common carriers and diluents include but are not limited to inert powdered substances such as many different types of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), cereal flour and similar edible powders.

[0155] Tablets can be prepared by direct compression, wet granulation or dry granulation. Its preparation usually incorporates diluents, binders, lubricants and disintegrants as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride) and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders are substances such as starch, gelatin and sugars (such as lactose, fructose, glucose, etc.). Natural gums and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, polyvinyl pyrrolidone, etc. Polyethylene glycol, ethyl cellulose and wax can also be used as binders.

[0156] Lubricants may be necessary in tablet formulations to prevent tablets and punches from sticking to the die. Lubricants can be selected from smooth solids such as talc, magnesium stearate and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are a type of material that expands when wet and breaks up tablets and releases compounds. They include starch, clay, cellulose, algin and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, lignocellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavoring and sealant, or coated with a film-forming protective agent to change the dissolution characteristics of the tablet. Compositions can also be formulated as chewable tablets, for example, by using a material such as mannitol in the formulation.

[0157] When it is desired to administer the compound of formula (I) as a suppository, typical bases may be used. Cocoa butter is a traditional suppository base, modified by the addition of waxes to slightly increase its melting point. Water-miscible suppository bases (particularly including polyethylene glycols of various molecular weights) are widely used.

[0158] The effect of the compound of formula (I) can be delayed or prolonged by appropriate formulations. For example, slowly dissolving microspheres of the compound of formula (I) can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. The technology also includes preparing pellets with several different dissolution rates and filling capsules with a mixture of these pellets. Tablets or capsules can be film-coated to resist dissolution over a predictable period of time. Parenteral formulations can even be made long-lasting by dissolving or suspending the compound of formula (I) in an oily or emulsifying vehicle that slowly disperses it in serum. Exemplary embodiments

[0159] The present disclosure is further described by the following embodiments. Where appropriate and practical, the features of each embodiment may be combined with any features of the other embodiments.

[0160] Embodiment 1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is -C≡C-, -HC=CH-, -CH2CH2-, -CH2O-, or key; Each R 1 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; x is 0-5; R 2 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; R 3a and R 3b Each is H; or R 2 and R 3a Together with the carbon atoms to which they are attached, they form a fused cyclopentyl group; or R 2 and R 4 Together with the carbon atoms to which they are attached, they form fused phenyl groups; R 4 is H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X 1 and X2 are independently N or CR 5 ; Each R 5 are independently H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; R 6 is H; R 7 is C1-C6 alkyl-OH; or R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 a 4- to 6-membered heterocyclic group substituted with a group; n is 1-5; and Each R 8 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -OH, The condition is that at least one R 8 It is -OH.

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

[0162] Embodiment 3. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein: L is

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

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

[0165] Embodiment 6. The compound according to embodiment 5 or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently F, Cl or cyclopropyl.

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

[0167] Embodiment 8. The compound according to any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein: for

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

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

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

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

[0172] Embodiment 13. The compound according to any one of Embodiments 1-8 and 12, or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 4 Together with the carbon atoms to which they are attached, they form a fused phenyl group.

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

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

[0175] Embodiment 16. The compound according to any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Independently for CR 5 .

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

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

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

[0179] Embodiment 20. The compound of embodiment 19 or a pharmaceutically acceptable salt thereof, wherein: Each R 5 are independently H, F, -CH3, -CH2CH3 or -CH(CH3)2.

[0180] Embodiment 21. The compound according to any one of Embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein: for

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

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

[0183] Embodiment 24. The compound according to any one of Embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form

[0184] Embodiment 25. The compound according to any one of Embodiment 24, or a pharmaceutically acceptable salt thereof, wherein: Each R 8 are independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or -OH.

[0185] Embodiment 26. The compound of embodiment 25 or a pharmaceutically acceptable salt thereof, wherein: Each R 8 are independently -CH3, -CH2CH3, -CFH2, -CF2H, -CF3 or -OH.

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

[0187] Embodiment 28. The compound according to embodiment 27 or a pharmaceutically acceptable salt thereof, wherein one R 8 It is -OH.

[0188] Embodiment 29. The compound according to any one of Embodiments 1-21 and 24-28, or a pharmaceutically acceptable salt thereof, wherein: for

[0189] Embodiment 30. A compound according to any one of Embodiments 1-8, 11 and 14-29, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II):

[0190] Embodiment 31. The compound according to Embodiment 30, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II-A) or (II-B): and It is a 4- to 6-membered heterocyclic group.

[0191] Embodiment 32. A compound according to any one of Embodiments 1-10 and 12-29, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (III):

[0192] Embodiment 33. The compound according to Embodiment 32, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II-A) or (II-B): and It is a 4- to 6-membered heterocyclic group.

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

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

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

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

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

[0198] The following examples are intended to illustrate rather than limit the present invention. The naming of the compounds was performed using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rule for stereochemistry. One skilled in the art can modify the procedures shown in the illustrative examples to obtain the desired products.

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

[0200] In certain chemical structures provided in the following examples, designation of a particular atom by "or 1" indicates that the absolute stereochemistry of the indicated atom has not been determined.

[0201] The following abbreviations may be used in connection with this application. abbreviation Synthesis Example Example S1. 1-(5-((2-Fluoro-phenyl)ethynyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (1a and 1b)

[0202] Synthesis of 1-(5-bromoindan-1-yl)-3-methyl-azetidin-3-ol A solution of NaCNBH3 (4.76 g, 75.8 mmol, 4 equivalents) and ZnCl2 (4 M in 4Me-THF, 28.5 mL, 113.8 mmol, 6 equivalents) in methanol (50 mL) was stirred for 30 min at room temperature. 5-Bromoindan-1-one (4.0 g, 18.9 mmol, 1 equivalent) and 3-methylazetidine-3-ol (3.3 g, 37.9 mmol, 2 equivalents) were then added in portions. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by water (100 mL) and extracted with DCM (3 x 30 mL). The resulting organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 1:1) to give 1-(5-bromoindan-1-yl)-3-methyl-azetidin-3-ol (5 g, 93%) as a yellow oil. LCMS (ESI, m / z): 282 [M+H] + .

[0203] Chiral Separation of 1-(5-bromoindan-1-yl)-3-methyl-azetidin-3-ol 5 g of the racemic product was separated by SFC (column: Lux Cellulose-4, 3*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.2% DEA); flow rate: 100 mL / min; gradient: 30% B; 220 nm) to obtain a first elution peak (2.2 g, RT: 3.28 min) and a second elution peak (2.1 g, RT: 4.07 min), both as light yellow oils.

[0204] Synthesis of 1-[5-[2-(2-fluorophenyl)ethynyl]indan-1-yl]-3-methyl-azetidin-3-ol (1a) To a stirred solution of 1-(5-bromoindan-1-yl)-3-methyl-azetidine-3-ol (100 mg, 0.35 mmol, 1 eq) in DMF (2 mL) was added 1-ethynyl-2-fluoro-benzene (213 mg, 1.77 mmol, 5 eq), Pd(PPh ) Cl (25 mg, 0.04 mmol, 0.1 eq), CuI (14 mg, 0.07 mmol, 0.2 eq) and K CO (143 mg, 1.06 mmol, 3 eq). The resulting mixture was stirred overnight at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was passed through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18OBD 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-methyl-azetidin-3-ol (25.6 mg, 22%) as a white solid.

[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] 1H NMR (400MHz, DMSO-d6) δ7.64-7.60(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=6.4Hz,1H),2.91(t,J=8.0Hz,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]indan-1-yl]-3-methyl-azetidin-3-ol (1b) To a stirred solution of 1-(5-bromoindan-1-yl)-3-methyl-azetidine-3-ol (100 mg, 0.35 mmol, 1 eq) in DMF (2 mL) was added 1-ethynyl-2-fluoro-benzene (213 mg, 1.77 mmol, 5 eq), Pd(PPh ) Cl (25 mg, 0.04 mmol, 0.1 eq), CuI (14 mg, 0.07 mmol, 0.2 eq) and K CO (143 mg, 1.06 mmol, 3 eq). The resulting mixture was stirred overnight at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was passed through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative 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-methyl-azetidin-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: 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.

[0209] 1 H NMR (400MHz, DMSO-d6) δ7.64-7.60(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=6.8Hz,1H),2.91(t,J=8.0Hz,1H), 2.79-2.72(m,1H),2.09-2.00(m,1H),1.87-1.79(m,1H),1.32(s,3H). Example S2. 1-[5-[2-(3-Fluorophenyl)ethynyl]-indan-1-yl]-3-methyl-azetidin-3-ol (2a and 2b)

[0210] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]indan-1-yl]-3-methyl-azetidin-3-ol (2a) To a stirred solution of 1-(5-bromoindan-1-yl)-3-methyl-azetidine-3-ol (100 mg, 0.35 mmol, 1 eq) in DMF (2 mL) was added 1-ethynyl-3-fluoro-benzene (213 mg, 1.77 mmol, 5 eq), Pd(PPh ) Cl (25 mg, 0.04 mmol, 0.1 eq), CuI (14 mg, 0.07 mmol, 0.2 eq) and K CO (143 mg, 1.06 mmol, 3 eq). The resulting mixture was stirred overnight at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was passed through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm, 30*250 mm; 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; 210 / 254 nm; RT: 6.42 min) to give 1-[5-[2-(3-fluorophenyl)ethynyl]indan-1-yl]-3-methyl-azetidin-3-ol (94 mg, 82%) as a white solid.

[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] 1 H NMR(400MHz,DMSO-d6)δ7.50-7.44(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=6.8Hz,1H),2.91(t,J=8.0Hz,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]indan-1-yl]-3-methyl-azetidin-3-ol (2b) To a stirred solution of 1-(5-bromoindan-1-yl)-3-methyl-azetidine-3-ol (100 mg, 0.35 mmol, 1 eq) in DMF (2 mL) was added 1-ethynyl-3-fluoro-benzene (213 mg, 1.77 mmol, 5 eq), Pd(PPh ) Cl (25 mg, 0.04 mmol, 0.1 eq), CuI (14 mg, 0.07 mmol, 0.2 eq) and K CO (143 mg, 1.06 mmol, 3 eq). The resulting mixture was stirred overnight at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was passed through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 30*250 mm, 5 μm; mobile phase A: water (10 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-methyl-azetidin-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: 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: 1.292 min.

[0215] 1H NMR(400MHz,DMSO-d6)δ7.50-7.44(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=6.4Hz,1H),2.91(t,J=8.0Hz,1H) ,2.79-2.72(m,1H),2.09-2.00(m,1H),1.87-1.79(m,1H),1.32(s,3H). Example S3. 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3a and 3b)

[0216] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]indan-1-one To a stirred solution of 5-hydroxyindan-1-one (2.0 g, 13.5 mmol, 1 eq) in toluene (15 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (6.5 g, 27.0 mmol, 2 eq) and AgCO (11.2 g, 40.5 mmol, 3 eq). The resulting mixture was stirred at 110 ° C overnight. LCMS showed that the reaction was complete. The reaction mixture was passed through celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 1: 1) to give 5-[(2,6-dichlorophenyl)methoxy]indan-1-one (775 mg, 19%) as a yellow oil. LCMS (ESI, m / z): 307 [M + H] + .

[0217] Synthesis of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol A solution of NaCNBH3 (82 mg, 1.30 mmol, 4 equiv) and ZnCl2 (4 M in 4Me-THF, 0.17 mL, 0.65 mmol, 2 equiv) in methanol (2 mL) was stirred at room temperature for 30 min. 3-Methylazetidine-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 then added. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by adding 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 preparative 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 Separation of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3a) 100 mg of the racemic product was separated by chiral HPLC (column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 17 min; 220 / 254 nm) to obtain the first eluting peak (43.3 mg, RT: 9.736 min) as a white solid.

[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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 0.916 min.

[0220] 1 H NMR (400MHz, DMSO-d6) δ7.57-7.55(m,2H),7.49-7.45(m,1H),7.17(d,J=8.0 Hz,1H),6.93(d,J=2.4Hz,1H),6.80(dd,J=8.0,2.4Hz,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 Separation of 1-(5-((2,6-dichlorobenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (3b) 100 mg of the racemic product was separated by chiral HPLC (column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 10% B to 10% B in 17 min; 220 / 254 nm) to obtain the first eluting peak (45.8 mg, RT: 12.940 min) as a white solid.

[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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 0.911 min.

[0223] 1 H NMR (400MHz, DMSO-d6) δ7.58-7.55(m,2H),7.49-7.45(m,1H),7.17(d,J=8.0 Hz,1H),6.93(d,J=2.4Hz,1H),6.80(dd,J=8.0,2.4Hz,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). Example S4. 1-(5-(4-cyclopropyl-3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (4a and 4b)

[0224] Synthesis of 5-(3-fluoro-4-cyclopropyl-phenyl)indan-1-one Under nitrogen atmosphere, a mixture of 5-bromoindan-1-one (500 mg, 2.37 mmol, 1 eq), 2-(3-fluoro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (681 mg, 2.60 mmol, 1.1 eq), NaCO (750 mg, 7.11 mmol, 3 eq) and Pd(PPh) (274 mg, 0.24 mmol, 0.1 eq) in 1,2-dimethoxyethane (8 mL) and water (1.5 mL) was stirred for 3 h at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH, 19:1) to give 5-(3-fluoro-4-cyclopropyl-phenyl)indan-1-one (200 mg, 32%) as a yellow oil. LCMS (ESI, m / z): 267 [M+H] + .

[0225] Synthesis of 1-[5-(3-chloro-4-fluoropropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol A mixture of NaCNBH3 (133 mg, 2.12 mmol, 4 equivalents) and ZnCl2 (2M in 4Me-THF, 0.53 mL, 1.06 mmol, 2 equivalents) in methanol (3 mL) was stirred for 30 min at room temperature. 3-Methylazetidine-3-ol (92 mg, 1.06 mmol, 2 equivalents) and 5-(3-fluoro-4-cyclopropyl-phenyl)indan-1-one (140 mg, 0.53 mmol, 1 equivalent) were then added. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by 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 preparative HPLC (column: YMC-Actus Triart C18, 30*250, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 54% B to 84% B in 7 min; 254 / 210 nm; RT1: 6.42 min) to give 1-[5-(3-chloro-4-fluoropropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (100 mg, 56%) as a white solid. LCMS (ESI, m / z): 338 [M+H] + .

[0226] Chiral Separation of 1-[5-(3-chloro-4-fluoropropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (4a) The racemate was separated by chiral HPLC (column: CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 45 mL / min; gradient: 5% B to 5% B in 24 min; wavelength: 220 / 254 nmn) to obtain the first eluting peak (47.2 mg, Rt: 15.160 min) as a white solid.

[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: 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: 1.690 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 Separation of 1-[5-(3-chloro-4-fluoropropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (4b) The racemate was separated by chiral HPLC (column: CHIRALPAK IG, 3*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH 3 -MeOH)--HPLC, mobile phase B: IPA--HPLC; flow rate: 45 mL / min; gradient: 5% B to 5% B in 24 min; wavelength: 220 / 254 nm) to obtain the first eluting peak (47.2 mg, Rt: 21.712 min) as a white solid.

[0230] 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: 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: 1.687 min.

[0231] 1H 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). Example S5. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (5a and 5b)

[0232] Synthesis of 5-(3-chloro-4-cyclopropyl-phenyl)indan-1-one Under nitrogen atmosphere, a mixture of 5-bromoindan-1-one (500 mg, 2.37 mmol, 1 eq), 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (727 mg, 2.60 mmol, 1.1 eq), NaCO (750 mg, 7.11 mmol, 3 eq) and Pd(PPh) (274 mg, 0.24 mmol, 0.1 eq) in 1,2-dimethoxyethane (8 mL) and water (1.5 mL) was stirred for 3 h at 80 ° C. LCMS showed that the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH, 20:1) to give 5-(3-chloro-4-cyclopropyl-phenyl)indan-1-one (350 mg, 52%) as a yellow oil. LCMS (ESI, m / z): 283 [M+H] + .

[0233] Synthesis of 1-[5-(3-chloro-4-cyclopropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol A mixture of NaCNBH3 (133 mg, 2.12 mmol, 4 equivalents) and ZnCl2 (2M in 4Me-THF, 0.53 mL, 1.06 mmol, 2 equivalents) in methanol (3 mL) was stirred at room temperature for 30 min. 3-Methylazetidine-3-ol (92 mg, 1.06 mmol, 2 equivalents) and 5-(3-chloro-4-cyclopropyl-phenyl)indan-1-one (150 mg, 0.53 mmol, 1 equivalent) were then added. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by 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 preparative HPLC (column: SunFirePrep 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-cyclopropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (120 mg, 64%) as a yellow solid. LCMS (ESI, m / z): 354 [M+H] + .

[0234] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (5a) The racemate was separated by SFC (column: Lux 5 μm Cellulose-4, 3*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2 M NH 3 -MeOH); flow rate: 60 mL / min; gradient: 50% B; 220 nm) to obtain the first eluting peak (29.0 mg, Rt: 5.59 min) as a yellow solid.

[0235] LCMS (ESI, m / z): 354 [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: 1.645 min.

[0236] 1 H NMR (300MHz, methanol-d4) δ7.64-7.61(m,3H),7.57-7.53(m,1H),7.48(dd,J=8.1,1 .8Hz,1H),7.07(d,J=8.1Hz,1H),4.96(dd,J=7.8,1.8Hz,1H),4.31-4.16(m,3 H),4.08(d,J=10.5Hz,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 Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)indan-1-yl]-3-methyl-azetidin-3-ol (5b) The racemate was separated by SFC (column: Lux 5μm Cellulose-4, 3*25cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 60mL / min; gradient: 50% B; 220nm) to obtain the second eluting peak (33.8mg, Rt: 8.34min) as a yellow solid.

[0238] LCMS (ESI, m / z): 354 [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: 1.652 min.

[0239] 1H NMR (300MHz, methanol-d4) δ7.64-7.61(m,3H),7.57-7.54(m,1H),7.48(dd,J=8.1,1 .8Hz,1H),7.08(d,J=8.1Hz,1H),4.96(dd,J=7.8,3.0Hz,1H),4.31-4.16(m,3 H),4.08(d,J=10.5Hz,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). Example S6. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (6) A mixture of NaCNBH3 (90 mg, 1.40 mmol, 4 equivalents) and ZnCl2 (4 M in 4Me-THF, 0.18 mL, 0.71 mmol, 2 equivalents) in methanol (5 mL) was stirred at room temperature for 30 min. 4-Methylpiperidin-4-ol (41 mg, 0.35 mmol, 1 equivalent) was then added in portions. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by 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 preparative HPLC (column: Xselect CSH OBD column 30*150mm 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 21% B to 45% B in 7min; 254 / 220nm; RT: 5.95min) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (12.4mg, 9%) as a white solid.

[0240] 1H NMR (400MHz, chloroform-d) δ7.60-7.59(m,1H),7.45-7.38(m,4H),6.99(d,J=8.0Hz,1H),4.38-4.35(m,1H),3.15-3.07(m,2H),2.93-2.5 7(m,4H),2.52-2.43(m,1H),2.28-2.14(m,3H),1.98-1.85(m,3H),1.37(d,J=6.0Hz,3H),1.09-1.00(m,2H),0.77-0.742(m,2H).

[0241] 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: 1.50 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: 0.998 min. Example S7. 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (7) A mixture of NaCNBH3 (91 mg, 1.41 mmol, 4 eq) and ZnCl2 (2 M in 4Me-THF, 0.36 mL, 0.71 mmol, 2 eq) in methanol (5 mL) was stirred at room temperature for 30 min. 5-(3-chloro-4-cyclopropyl-phenyl)indan-1-one (100 mg, 0.35 mmol, 1 eq) and 3-methylpyrrolidin-3-ol (34 mg, 0.35 mmol, 1 eq) were then added in portions. The resulting mixture was stirred overnight at 60 ° C. LCMS showed that the reaction was complete. The reaction was quenched by water (20 mL) and extracted with DCM (3x10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sun Fire Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 42% B in 8 min, hold at 42% B for 1 min; 254 / 210 nm; RT: 8.32 min) to give 1-(5-(3-chloro-4-cyclopropylphenyl)-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (23.4 mg, 18%) as a yellow oil.

[0242] 1 H 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).

[0243] LCMS (ESI, m / z): 368 [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: 1.50 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. Example S8. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-methyl-piperidin-4-ol (8)

[0244] Synthesis of tert-butyl 3-(1-oxoindane-5-yl)azetidine-1-carboxylate To a stirred solution of tert-butyl 3-iodoazetidine-1-formate (60 g, 211 mmol, 4.00 equivalents) in DMF (900 mL) was added zinc powder (22.5 g, 344 mmol, 7.00 equivalents). The mixture solution was stirred at 80 ° C for 2 h. 5-bromoindan-1-one (10.5 g, 49.8 mmol, 1.00 equivalents), Pd2(dba)3 (4.5 g, 4.97 mmol, 0.10 equivalents) and tri-tolylphosphine (3.0 g, 9.95 mmol, 0.20 equivalents) were then added. The resulting mixture was stirred overnight at 80 ° C under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction was filtered. The organic layer was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with dichloromethane / methanol, 20 / 1) to give tert-butyl 3-(1-oxoindane-5-yl)azetidine-1-carboxylate (4.5 g, 31%) as an off-white solid. LCMS (ESI, m / z): 288 [M+H] + .

[0245] Synthesis of 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one To a solution of tert-butyl 3-(1-oxo-2,3-dihydro-1H-inden-5-yl)azetidine-1- tert-butyl ester (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 showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column on C18 (eluting with water / ACN, 5 / 95) to give 5-(azetidine-3-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 77%) as a white solid. LCMS (ESI, m / z): 188 [M+H] + .

[0246] Synthesis of 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one A solution of 5-(azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.60 mmol, 1.00 equiv), 2-bromo-1,3-dichlorophenyl (358 mg, 1.60 mmol, 1.00 equiv), Pd(dba)CHCl (166 mg, 0.160 mmol, 0.10 equiv), t-BuONa (470 mg, 4.80 mmol, 3.00 equiv), and XPhos (152 mg, 3.200 mmol, 0.20 equiv) in toluene (10 mL) was stirred at 90° C. under N atmosphere for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by flash column on silica gel (eluted with PE / EA, 1 / 1) to give 5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-one (150 mg, 28%) as a yellow oil. LCMS (ESI, m / z): 332 [M+H] + .

[0247] Synthesis of 1-[5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-yl]-4-methyl-piperidin-4-ol (8) To a stirred solution of 5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-one (50 mg, 0.15 mmol, 1.00 equiv) and 4-methylpiperidin-4-ol (34 mg, 0.30 mmol, 2.00 equiv) in methanol (2 mL) was added NaBH3CN (28 mg, 0.45 mmol, 3.00 equiv) and ZnCl2 (2 M in THF, 0.15 mL, 0.30 mmol, 2.00 equiv). The mixture solution was stirred at 80 ° C overnight. LCMS showed that the reaction was complete. The reaction was quenched with water (10 mL) and extracted with dichloromethane (2x10 mL). The organic layer was concentrated under vacuum. 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: 62% B to 75% B in 8 min; wavelength: 254 / 220 nm; RT: 6.97 min) to give 1-[5-[1-(2,6-dichlorophenyl)azetidin-3-yl]indan-1-yl]-4-methyl-piperidin-4-ol (26.9 mg, 40%) as an off-white solid.

[0248] LCMS (ESI, m / z): 431 [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: 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.

[0249] 1 H NMR (300MHz, DMSO-d6) δ7.27-7.21(m,5H),6.74(t,J=8.1Hz,1H),4.82(t,J=8.1Hz,2H),4.40-4.32(m,2H),4.24(t,J=7.2Hz,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). Example S9. 1-(5-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (9) 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) in methanol (2.0 mL) was added NaBHCN (34 mg, 0.54 mmol, 3.00 equiv) and ZnCl (2 M in THF, 0.18 mL, 0.36 mmol, 2.00 equiv). The mixture solution was stirred at 80 ° C overnight. LCMS showed that the reaction was complete. The organic layer was concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge C18 OBD preparative 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-methyl-pyrrolidin-3-ol (66.1 mg, 86%) as a light orange semisolid.

[0250] 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: 5% B to 65% B in 1.7 min, 65% B to 100% B in 0.3 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.10 min; 254 nm; RT: 1.495 min.

[0251] 1 H NMR (400MHz, DMSO-d6) δ7.29-7.18(m,5H),6.75(t,J=8.0Hz,1H),4.82(t,J=8.0Hz,2H),4.46-4.44(m,1H),4.34(t,J=7.6Hz,2H),4.10(t,J=6.0Hz,1 H),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). Example S10. 1-(5-(3-chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (10a and 10b)

[0252] Synthesis of 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-one To a stirred solution of 5-bromo-7-methyl-indan-1-one (500 mg, 2.22 mmol, 1.00 equiv) and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (804 mg, 2.89 mmol, 1.30 equiv) in 1,4-dioxane (10 mL) and water (1.0 mL) was added Pd(dppf)Cl2 (162 mg, 0.22 mmol, 0.10 equiv) and Cs2CO3 (2.2 g, 6.66 mmol, 3.00 equiv). The resulting mixture was stirred at 80 ° C for 4 h. LCMS showed that the reaction was complete. The reaction was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with dichloromethane / methanol, 10 / 1) to give 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-one (400 mg, 60%) as an off-white solid. LCMS (ESI, m / z): 297 [M+H] + .

[0253] Synthesis of 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-ol To a stirred solution of 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-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 showed that the reaction was complete. The reaction was quenched by water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography on C18 silica gel (eluting with water / acetonitrile, 2 / 3) to give 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-ol (350 mg, 69%) as a light yellow oil. LCMS (ESI, m / z): 299 [M+H] + .

[0254] Synthesis of 1-chloro-5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indane To a stirred solution of 5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-ol (250 mg, 0.84 mmol, 1.00 equiv) in DCM (5 mL) was added SOCl2 (0.3 mL, 4.180 mmol, 5.00 equiv). The mixture was stirred at 0 ° C for 1 h. TLC showed that the reaction was complete. The reaction was concentrated under vacuum to give 1-chloro-5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan as a crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): 317 [M + H] + .

[0255] Synthesis of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol To a stirred solution of 1-chloro-5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indane (250 mg, 0.79 mmol, 1.00 equiv) and 3-methylazetidine-3-ol (102 mg, 1.18 mmol, 1.50 equiv) in DMSO (5 mL) was added KCO (326 mg, 2.360 mmol, 3.00 equiv). The resulting solution was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography on C18 silica gel (eluting with water / acetonitrile, 1 / 3) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (80 mg, 27%) as an off-white solid. LCMS (ESI, m / z): 368 [M+H] + .

[0256] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (10a) The racemate was purified by preparative chiral HPLC (column: Lux 5um Cellulose-2, 2.12*25cm, 5μm; mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 2% B to 2% B in 25min; 220 / 254nm; RT1: 15.924min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (29.9mg, 35%) as an off-white solid.

[0257] 1 H NMR(300MHz,DMSO-d6)δ7.65(d,J=2.1Hz,1H),7.50(dd,J=8.1,2.1Hz,1H),7.31 (s,1H),7.23(s,1H),7.07(d,J=8.1Hz,1H),5.11(s,1H),4.08-4.04(m,1H),3.1 2(d,J=6.0Hz,1H),3.06-2.91(m,4H),2.80-2.71(m,1H),2.42(s,3H),2.22-2.1 0(m,2H),1.96-1.84(m,1H),1.32(s,3H),1.07-1.00(m,2H),0.77-0.72(m,2H).

[0258] LCMS (ESI, m / z): 368 [M+H] + Analytical conditions: Column: L-column 3C18 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.

[0259] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (10b) The racemate was purified by preparative chiral HPLC (column: Lux 5um Cellulose-2, 2.12*25cm, 5μm; mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 2% B to 2% B in 25min; 220 / 254nm; RT2: 22.478min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (33.4mg, 41%) as an off-white solid.

[0260] 1 H NMR(300MHz,DMSO-d6)δ7.66(d,J=2.1Hz,1H),7.50(dd,J=8.1,2.1Hz,1H),7.31 (s,1H),7.24(s,1H),7.07(d,J=8.1Hz,1H),5.11(s,1H),4.06(d,J=6.6Hz,1H),3 .12(d,J=6.0Hz,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).

[0261] 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: 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: 1.157 min. Example S11. 1-(5-(3-chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-4-methylpiperidin-4-ol (11) To a solution of 1-chloro-5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indane (150 mg, 0.47 mmol, 1.00 equiv) in MeCN (5 mL) was added 4-methylpiperidin-4-ol (82 mg, 0.71 mmol, 1.50 equiv) and KCO (196 mg, 1.42 mmol, 3.00 equiv). The resulting mixture was stirred at 60 ° C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 43% B in 10 min; 254 / 210 nm; RT: 9.65 min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-4-methyl-piperidin-4-ol (83.7 mg, 43%) as an off-white solid.

[0262] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=2.0Hz,1H),7.58(dd,J=8.0,2.0Hz,1H),7.54(m,1H),7. 47(m,1H),7.11(d,J=8.0Hz,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).

[0263] 19 F NMR(282MHz,DMSO-d6)δ-74.202.

[0264] 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: 80% B to 95% B in 1.80 min, hold at 95% for 0.80 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.289 min. Example S12. 1-(5-(3-chloro-4-cyclopropylphenyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylpyrrolidin-3-ol (12) To a solution of 1-chloro-5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indane (150 mg, 0.47 mmol, 1.00 equiv) in MeCN (5 mL) was added 3-methylpyrrolidin-3-ol (58 mg, 0.58 mmol, 1.2 equiv) and KCO (196 mg, 1.42 mmol, 3.00 equiv). The resulting mixture was stirred at 60 ° C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 43% B in 10 min; 254 / 210 nm; RT: 9.65 min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-7-methyl-indan-1-yl]-3-methyl-pyrrolidin-3-ol (54.1 mg, 29%) as an off-white solid.

[0265] 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=2.0Hz,1H),7.57(dd,J=8.0,2.0Hz,1H),7.52(m,1H), 7.45(m,1H),7.10(d,J=8.0Hz,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).

[0266] 19 F NMR(282MHz,DMSO-d6)δ-74.011.

[0267] 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: 80% B to 95% B in 1.80 min, hold at 95% for 0.80 min, 95% B to 10% B in 0.15 min; 254 nm; RT: 1.079 min. Example S13. 1-(5-((3-Fluorophenyl)ethynyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (13a and 13b)

[0268] Synthesis of 5-[2-(3-fluorophenyl)ethynyl]-7-methyl-indan-1-one A solution of 1-ethynyl-3-fluoro-benzene (533 mg, 4.44 mmol, 2.00 equiv), 5-bromo-7-methyl-indan-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) in DMF (10.0 mL) was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 3 / 1) to give 5-[2-(3-fluorophenyl)ethynyl]-7-methyl-indan-1-one (500 mg, 85%) as an off-white solid. LCMS (ESI, m / z): 265 [M+H] + .

[0269] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[2-(3-fluorophenyl)ethynyl]-7-methyl-indan-1-one (500 mg, 1.89 mmol, 1.00 equiv), 3-methylazetidin-3-ol (164 mg, 1.89 mmol, 1.00 equiv), ZnCl2 (2M in THF, 1.9 mL, 3.78 mmol, 2.00 equiv) and NaBH3CN (363 mg, 5.68 mmol, 3.00 equiv) in methanol (10 mL) was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. 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 flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 1:1) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (80 mg, 12%) as an off-white solid. LCMS (ESI, m / z): 336 [M+H] + .

[0270] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (13a) The racemate (80 mg) was purified by preparative chiral HPLC (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-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (first eluting peak, 17.7 mg, 21%).

[0271] 1H NMR (300MHz, DMSO-d6) δ7.52-7.45(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=6.6Hz,1H),3.11(d, J=6.3Hz,1H),3.02(d,J=6.3Hz,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).

[0272] 19 F NMR(376MHz,DMSO-d6)δ-112.515.

[0273] LCMS (ESI, m / z): 336 [M+H] + Analytical conditions: Column: L-column 3C18 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: 1.701 min.

[0274] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (13b) The racemate (80 mg) was purified by preparative chiral HPLC (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-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (second eluting peak, 21.9 mg, 27%).

[0275] 1H NMR (300MHz, DMSO-d6) δ7.52-7.45(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=6.6Hz,1H),3.10(d, J=6.0Hz,1H),3.02(d,J=6.0Hz,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).

[0276] 19 F NMR(376MHz,DMSO-d6)δ-112.173.

[0277] LCMS (ESI, m / z): 336 [M+H] + Analytical conditions: Column: L-column 3C18 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. Example S14. 1-(5-(2,6-dichlorophenethyl)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (14a and 14b)

[0278] Synthesis of 5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-one A solution of 5-bromo-7-methyl-indan-1-one (500 mg, 2.22 mmol, 1.00 equiv), potassium 2-(2,6-dichlorophenyl)ethyl-trifluoro-borate (811 mg, 2.89 mmol, 1.30 equiv), Pd(dppf)Cl2 (162 mg, 0.22 mmol, 0.10 equiv) and Cs2CO3 (2.1 mg, 6.66 mmol, 3.00 equiv) in toluene (10 mL) was stirred at 80 ° C for 2 h. LCMS showed that the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 3: 1) to give 5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-one (500 mg, 70% yield) as an off-white solid. LCMS (ESI, m / z): 319 [M+H] + .

[0279] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-one (500 mg, 1.57 mmol, 1.00 equiv), 3-methylazetidin-3-ol (136 mg, 1.57 mmol, 1.00 equiv), ZnCl2 (2M in THF, 1.5 mL, 3.13 mmol, 2.00 equiv) and NaBH3CN (300 mg, 4.70 mmol, 3.00 equiv) in methanol (10 mL) was stirred at 80 ° C for 16 h. LCMS showed 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 flash column chromatography on silica gel (eluting with water / acetonitrile, 1:2) to give 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (100 mg, 16%) as an off-white solid. LCMS (ESI, m / z): 390 [M+H] + .

[0280] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (14a) The racemate (100 mg) was purified by preparative chiral HPLC (column: Lux 5μm Cellulose-2, 2.12*25 cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 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-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (first eluting peak, 27.7 mg, 27%).

[0281] 1 H NMR (300MHz, DMSO-d6) δ7.50-7.47(m,2H),7.33-7.27(m,1H),6.94(s,1H),6.84(s,1H),5.10(s,1H),4.02(d,J=6.6Hz,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).

[0282] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.994 min.

[0283] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (14b) The racemate (100 mg) was purified by preparative chiral HPLC (column: Lux 5μm Cellulose-2, 2.12*25 cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 15 min; 220 / 254 nm; RT2: 11.608 min) to give the desired isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (second eluting peak, 27.5 mg, 27%).

[0284] 1 H NMR (300MHz, DMSO-d6) δ7.51-7.47(m,2H),7.33-7.27(m,1H),6.94(s,1H),6.84(s,1H),5.09(s,1H),4.01(d,J=6.6Hz,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).

[0285] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.994 min. Example S15. 1-(5-((2,6-dichlorobenzyl)oxy)-7-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (15a and 15b)

[0286] Synthesis of 5-Hydroxy-7-methyl-indan-1-one A solution of 5-bromo-7-methyl-indan-1-one (800 mg, 3.55 mmol, 1.00 equiv) and KOH (597 mg, 10.660 mmol, 3.00 equiv), Pd(dba)CHCl (367 mg, 0.36 mmol, 0.10 equiv), and t-BuBrettphos (344 mg, 0.71 mmol, 0.20 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80°C for 16 h. LCMS showed the reaction was complete. The reaction was acidified to pH 4-5 with 1 M HCl. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 2:3) to give 5-hydroxy-7-methyl-indan-1-one (480 mg, 83%) as an off-white solid. LCMS (ESI, m / z): 163 [M+H] + .

[0287] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-one A solution of 5-hydroxy-7-methyl-indan-1-one (450 mg, 2.77 mmol, 1.00 equiv), 2-(bromomethyl)-1,3-dichloro-benzene (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 showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:6) to give 5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-one (600 mg, 67% yield) as an off-white solid. LCMS (ESI, m / z): 321 [M+H] + .

[0288] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol 5-[(2,6-Dichlorophenyl)methoxy]-7-methyl-indan-1-one (600 mg, 1.87 mmol, 1.00 equiv), 3-methylazetidin-3-ol (162 mg, 1.87 mmol, 1.00 equiv), ZnCl2 (2M in THF, 1.8 mL, 3.74 mmol, 2.00 equiv) and NaBH3CN (358 mg, 5.60 mmol, 3.00 equiv) were stirred in methanol (15 mL) at 80 ° C for 16 h. LCMS showed 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 flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:2) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (150 mg, 20%) as an off-white solid. LCMS (ESI, m / z): 392 [M+H] + .

[0289] Chiral Separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (15a) The racemate (120 mg) was purified by SFC (column: Lux 5μm Celluloes-3, 3*25 cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 80 mL / min; gradient: 30% B; 220 nm; RT1: 4.21 min) to give the desired isomer 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (first eluting peak, 33.1 mg, 27%).

[0290] 1 H NMR (300MHz, DMSO-d6) δ7.59-7.56(m,2H),7.47(dd,J=9.0,6.6Hz,1H),6.75(d,J=2.4Hz,1H),6.63(d,J=2.4Hz,1H),5.17(s,2H),5.10(s,1H),3. 99(d,J=6.3Hz,1H),3.09(d,J=6.0Hz,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).

[0291] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.923 min.

[0292] Chiral Separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (15b) The racemate (120 mg) was purified by SFC (column: Lux 5μm Celluloes-3, 3*25 cm, 5μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-MeOH); flow rate: 80 mL / min; gradient: 30% B; 220 nm; RT2: 4.98 min) to give the desired isomer 1-[5-[(2,6-dichlorophenyl)methoxy]-7-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as an off-white solid (second eluting peak, 21.6 mg, 17%).

[0293] 1 H NMR(300MHz, DMSO-d6)δδ7.59-7.56(m,2H),7.47(dd,J=9.3,6.3Hz,1H),6.75(d,J=2.4Hz,1H),6.63(d,J=2.4Hz,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).

[0294] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.931 min. Example S16. 1-(5-(3-chloro-4-cyclopropylphenyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (16a and 16b)

[0295] Synthesis of 5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-one To a solution of 5-bromo-4-methyl-indan-1-one (600 mg, 2.67 mmol, 1.00 equiv) in 1,4-dioxane (8 mL) and water (0.8 mL) was added 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.48 g, 5.33 mmol, 2.00 equiv), t-BuONa (767 mg, 8.00 mmol, 3.00 equiv) and Pd(dppf)Cl2 (217 mg, 0.27 mmol, 0.10 equiv). The reaction was stirred at 90 ° C for 12 h. LCMS showed that the reaction was complete. The reaction was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with dichloromethane / methanol, 17 / 1) to give 5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-one (432 mg, 54%) as a yellow solid. LCMS (ESI, m / z): 297 [M+H] + .

[0296] Synthesis of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A mixture of 5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-one (250 mg, 0.84 mmol, 1.00 equiv), 3-methylazetidine-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) in methanol (8 mL) was stirred at 60 ° C for 12 h. LCMS showed that the reaction was complete. The reaction was quenched by 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 flash column chromatography on C18 silica gel (eluted with water / acetonitrile, 1 / 3) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (165 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 368 [M+H] + .

[0297] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (16a) The racemate was purified by preparative chiral HPLC (column: Lux 5μm Cellulose-2, 12*25cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 2% B to 2% B in 21min; 254 / 220nm; RT1: 16.824min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (9.9mg, 12%) as an off-white solid.

[0298] LCMS (ESI, m / z): 368 [M+H] + Analytical conditions: Column: L-column 3C18 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: 1.771 min.

[0299] 1 H NMR (400MHz, DMSO-d6) δ7.31 (d, J = 2.0 Hz, 1H), 7.18-7.13 (m, 2H), 7.07 (d, J = 8. 0Hz,1H),6.99(d,J=7.6Hz,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),2.09-2.0 4(m,1H),1.91-1.84(m,1H),1.32(s,3H),1.06-1.01(m,2H),0.77-0.73(m,2H).

[0300] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (16b) The racemate was purified by preparative chiral HPLC (column: Lux 5μm Cellulose-2, 12*25cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20mL / min; gradient: 2% B to 2% B in 21min; 254 / 220nm; RT1: 19.055min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (31 mg, 36%) as an off-white solid.

[0301] LCMS (ESI, m / z): 368 [M+H] + Analytical conditions: Column: L-column 3C18 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: 30% B to 80% B in 6.00 min, 80% B to 95% B in 2.00 min, 95% B to 10% B in 2.00 min; 254 nm; RT: 6.295 min.

[0302] 1H NMR (400MHz, DMSO-d6) δ7.31(d,J=1.6Hz,1H),7.17(dd,J=8.0,1.6Hz,1H),7.12(d,J=8.0Hz,1H) ,7.07(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,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=6.4Hz,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). Example S17. 1-(5-((3-Fluorophenyl)ethynyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (17a and 17b)

[0303] Synthesis of 5-[2-(3-fluorophenyl)ethynyl]-4-methyl-indan-1-one A solution of 5-bromo-4-methyl-indan-1-one (300 mg, 1.33 mmol, 1.00 equiv), 1-ethynyl-3-fluoro-benzene (480 mg, 4.00 mmol, 3.00 equiv), KCO (368 mg, 2.67 mmol, 2.00 equiv), Pd(PPh)Cl (93 mg, 0.13 mmol, 0.10 equiv) and CuI (51 mg, 0.27 mmol, 0.20 equiv) in DMF (3 mL) was stirred at 60 ° C for 2 days under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 1 / 1) to give 5-[2-(3-fluorophenyl)ethynyl]-4-methyl-indan-1-one (300 mg, 85%) as a yellow solid. LCMS (ESI, m / z): 265 [M+H] + .

[0304] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[2-(3-fluorophenyl)ethynyl]-4-methyl-indan-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) in methanol (10 mL) was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. 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 flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 2:3) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (350 mg, 92%) as a yellow solid. LCMS (ESI, m / z): 356 [M+H] + .

[0305] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (17a) 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 preparative 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, maintained at 35% B for 2 min; wavelength: 254 / 220 nm; RT: 10.38 min) to give the desired isomer 1-[5-[2-(3-fluoropropyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (71.7 mg, 20.3%) as a white solid.

[0306] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H,H FA),7.51-7.45(m,1H),7.43-7.39(m,2H),7.34(d,J=8.0Hz,1H),7.30-7.25( m,1H),7.13(d,J=8.0Hz,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=6.4Hz,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).

[0307] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 0.921 min.

[0308] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (17b) The racemate (350 mg) was separated by chiral HPLC (column: Lux 5μm Cellulose-2, 3*15 cm, 5μm; 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 desired isomer 1-[5-[2-(3-fluoropropyl)ethynyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as a white solid (second eluting peak, 118.6 mg, 33.6%).

[0309] 1H NMR (400MHz, DMSO-d6) δ7.51-7.45(m,1H),7.43-7.39(m,2H),7.34(d,J=7.6Hz, 1H),7.30-7.25(m,1H),7.13(d,J=7.6Hz,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=6.8Hz,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).

[0310] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 0.922 min. Example S18. 1-(5-(2,6-dichlorophenethyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (18a and 18b)

[0311] Synthesis of 5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-one A solution of 5-bromo-4-methyl-indan-1-one (300 mg, 1.33 mmol, 1.00 equiv), potassium 2-(2,6-dichlorophenyl)ethyl-trifluoro-borate (1.1 g, 4.00 mmol, 3.00 equiv), CsCO (1.3 g, 4.00 mmol, 3.00 equiv), and Pd(dppf)Cl (98 mg, 0.13 mmol, 0.10 equiv) in toluene (5 mL) and water (0.5 mL) was stirred at 90° C. for 3 h under a nitrogen atmosphere. LCMS showed the reaction was complete. The residue was purified by flash column chromatography on silica gel (eluting with PE / EtOAc, 1:1) to give 5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-one (400 mg, 94%) as a yellow solid. LCMS (ESI, m / z): 319 [M+H] + .

[0312] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-one (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) in methanol (5 mL) was stirred at 80 ° C for 3 h. LCMS showed 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 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-indan-1-yl]-3-methyl-azetidin-3-ol (390 mg, 80%) as a white solid. LCMS (ESI, m / z): 390 [M+H] + .

[0313] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (18a) The racemate (390 mg) was purified by chiral HPLC (column: Lux 5μm Cellulose-4, 2.12*25 cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 11.46; RT2 (min): 14.04) to obtain the desired isomer (first eluting peak, 66 mg, 16.3%) as a white solid.

[0314] 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=8.0Hz,2H),7.30(t,J=8.0Hz,1H),7.03(d,J=7.6Hz,1H),6.99(d,J=7.6Hz,1H),5.13(s,1H),3.78-3.75(m,1 H),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).

[0315] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 1.003 min.

[0316] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (18b) The racemate (390 mg) was purified by chiral HPLC (column: Lux 5μm Cellulose-4, 2.12*25 cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 16 min; wavelength: 220 / 254 nm; RT1 (min): 11.46; RT2 (min): 14.04) to obtain the desired isomer as a white solid (second eluting peak, 65.9 mg, 16.7%).

[0317] 1 H NMR (400MHz, DMSO-d6) δ7.48(d,J=8.0Hz,2H),7.29(t,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),5.19(s,1H),3.77-3.74(m,1 H),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).

[0318] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 0.990 min. Example S19. 1-(5-((2,6-Dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (19a and 19b)

[0319] Synthesis of 5-Hydroxy-4-methyl-indan-1-one A solution of 5-bromo-4-methyl-indan-1-one (500 mg, 2.22 mmol, 1.00 equiv), KOH (373 mg, 6.66 mmol, 3.00 equiv), Pd2(dba)3 (203 mg, 0.22 mmol, 0.10 equiv), and t-BuBrettPhos (215 mg, 0.44 mmol, 0.20 equiv) in 1,4-dioxane (4 mL) and water (0.4 mL) was stirred at 80°C under a nitrogen atmosphere for 12 h. LCMS showed the reaction was complete. The reaction was acidified to pH 4-5 with 1 M HCl. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 2:3) to give 5-hydroxy-4-methyl-indan-1-one (284 mg, 78%) as a yellow solid. LCMS (ESI, m / z): 163 [M+H] + .

[0320] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-one To a solution of 5-hydroxy-4-methyl-indan-1-one (284 mg, 1.75 mmol, 1.00 equiv) in MeCN (5 mL) was added 2-(bromomethyl)-1,3-dichloro-benzene (630 mg, 2.63 mmol, 1.50 equiv) and K2CO3 (724 mg, 5.25 mmol, 3.00 equiv). The reaction was stirred at 60 ° C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:3) to give 5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-one (300 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 321 [M+H] + .

[0321] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-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, 2 M in 4Me-THF, 2.33 mmol, 2.50 equiv) and NaBH3CN (239 mg, 3.74 mmol, 4.00 equiv) in methanol (5 mL) was stirred at 60 ° C for 12 h. LCMS showed 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 flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:1) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (300 mg, 81%) as a yellow solid. LCMS (ESI, m / z): 392 [M+H] + .

[0322] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (19a) The racemate (150 mg) was purified by preparative 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-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (37.7 mg, 24%) as an off-white solid.

[0323] 1H NMR(300MHz,DMSO-d6)δ7.60-7.57(m,2H),7.48(dd,J=9.0,6.9Hz,1H),7.08(d, J=8.1Hz,1H),6.98(d,J=8.1Hz,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).

[0324] LCMS (ESI, m / z): 392 [M+H] + Analytical conditions: Column: L-column 3C18 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.

[0325] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (19b) The racemate (150 mg) was purified by preparative 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: 13.499 min) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (36.1 mg, 23%) as an off-white solid.

[0326] 1H NMR(300MHz,DMSO-d6)δ7.60-7.55(m,2H),7.46(dd,J=9.0,6.9Hz,1H),7.08 (d,J=8.1Hz,1H),6.97(d,J=8.1Hz,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).

[0327] LCMS (ESI, m / z): 392 [M+H] + Analytical conditions: Column: L-column 3C18 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: 1.462 min. Example S20. 1-((5-((2,6-Dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20a and 20b)

[0328] Synthesis of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol A solution of 5-[(2,6-dichlorophenyl)methoxy]-4-methyl-indan-1-one (120 mg, 0.37 mmol, 1.00 equiv), 1-amino-2-methyl-propan-2-ol (66 mg, 0.75 mmol, 2.00 equiv), NaHBCN (94 mg, 1.49 mmol, 4.00 equiv), and ZnCl (2 M in 4Me-THF, 0.37 mL, 0.75 mmol, 2.00 equiv) in methanol (5 mL) was stirred at 80 ° C for 15 h. LCMS showed that the reaction was complete. The reaction 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 flash chromatography on C18 silica gel (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-methylpropan-2-ol (120 mg, 81%) as a yellow oil. LCMS (ESI, m / z): 394 [M+H] + .

[0329] Chiral Separation of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20a) The racemate (120 mg) was purified 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: 48% B to 73% B, 73% B in 9 min; wavelength: 254 / 220 nm; RT: 8.85 min) to give the desired isomer 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol as a yellow oil (first eluting peak, 31.1 mg, 25%, 100% ee).

[0330] 1H NMR (400MHz, methanol-d4) δ7.48(d,J=8.8Hz,1H),7.47(d,J=7.6Hz,1H),7.37(dd,J= 8.8,7.6Hz,1H),7.22(d,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),5.30(s,2H),4.2 9(t,J=6.4Hz,1H),3.02-2.95(m,1H),2.80-2.72(m,1H),2.64(d,J=2.8Hz,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).

[0331] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 0.962 min.

[0332] Chiral Separation of 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol (20b) The racemate (120 mg) was purified 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: 48% B to 73% B, 73% B in 9 min; wavelength: 254 / 220 nm; RT: 8.85 min) to give the desired isomer 1-((5-((2,6-dichlorobenzyl)oxy)-4-methyl-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpropan-2-ol as a yellow oil (second eluting peak, 25.4 mg, 20%, 99% ee).

[0333] 1H NMR (400MHz, methanol-d4) δ7.48(d,J=8.8Hz,1H),7.47(d,J=7.6Hz,1H),7.37(dd,J= 8.8,7.6Hz,1H),7.22(d,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),5.29(s,2H),4.2 8(t,J=6.4Hz,1H),3.02-2.94(m,1H),2.79-2.71(m,1H),2.64(d,J=2.0Hz,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).

[0334] 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: 5% B to 100% B in 1.19 min, hold at 100% for 0.6 min, 100% B to 5% B in 0.03 min; 210 nm; RT: 0.964 min. Example S21. 1-(5-(3-chloro-4-cyclopropylphenyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (21a and 21b)

[0335] Synthesis of 5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-one To a stirred solution of 5-bromo-6-methyl-indan-1-one (300 mg, 1.33 mmol, 1.00 equiv) and 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (557 mg, 2.00 mmol, 1.50 equiv) in 1,4-dioxane (2.5 mL) and water (0.25 mL) was added Pd(dppf)Cl2 (109 mg, 0.13 mmol, 0.10 equiv) and Cs2CO3 (1303 mg, 4.00 mmol, 3.00 equiv). The resulting mixture was stirred at 90 ° C overnight. LCMS showed that the reaction was complete. The reaction was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with PE:EtOAc=5:1) to give 5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-one (305 mg, 77.1%) as an orange oil. LCMS (ESI, m / z): 297 [M+H] + .

[0336] Synthesis of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol To a stirred solution of 5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-one (300 mg, 1.01 mmol, 1.00 equiv) and 3-methylazetidine-3-ol (176 mg, 2.02 mmol, 2.00 equiv) in methanol (3 mL) was added ZnCl (2.0 M in THF, 1 mL, 2.02 mmol, 2.00 equiv) and NaBHCN (259 mg, 4.04 mmol, 4.00 equiv). The resulting mixture was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. The reaction was quenched with water (30 mL) and extracted with EtOAc (2x15 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30*250, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 . The product was purified by HPLC (5% HCl, 5% HCl, 1% HCl, 4% HCl, 0.1% HCl, 0.2% HCl, 0.5% HCl, 0.6% HCl, 0.8% HCl, 0.9% HCl, 0.7% HCl, 0.9% HCl, 0.8 ... + .

[0337] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (21a) The 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% 2M 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 give the desired isomer (66.3 mg, 37.5%, 98.4% ee) as a white solid.

[0338] 1 H NMR(400MHz,DMSO-d6)δ7.32(d,J=1.6Hz,1H),7.18(dd,J=8.0,1.6Hz,1H),7.15(s,1H),7.06 (d,J=8.0Hz,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).

[0339] 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: 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.

[0340] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (21b) The 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% 2M 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 give the desired isomer (58.3 mg, 32.9%, 99.1% ee) as a white solid.

[0341] 1 H NMR(400MHz,DMSO-d6)δ7.32(d,J=1.6Hz,1H),7.18(dd,J=8.0,1.6Hz,1H),7.15(s,1H),7.06 (d,J=8.0Hz,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).

[0342] 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: 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: 1.070 min. Example S22. 1-(5-((3-Fluorophenyl)ethynyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (22a and 22b)

[0343] Synthesis of 5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-one A solution of 5-bromo-6-methyl-indan-1-one (400 mg, 1.78 mmol, 1.00 equiv), 1-ethynyl-3-fluoro-benzene (427 mg, 3.55 mmol, 2.00 equiv), Pd(Ph3P)2Cl2 (125 mg, 0.18 mmol, 0.10 equiv) and triethylamine (0.5 mL, 3.55 mmol, 2.00 equiv) in THF (5 mL) was stirred at 60 ° C overnight under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 10 / 1) to give 5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-one (460 mg, 98%) as a light yellow solid. LCMS (ESI, m / z): 265 [M+H] + .

[0344] Synthesis of 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of 5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-one (460 mg, 1.74 mmol, 1.00 equiv), 3-methylazetidin-3-ol (303 mg, 3.48 mmol, 2.00 equiv), ZnCl2 (2.0 M in THF, 1.7 mL, 3.48 mmol, 2.00 equiv) and NaBH3CN (446 mg, 6.96 mmol, 4.00 equiv) in methanol (5 mL) was stirred at 80 ° C overnight. LCMS showed that the reaction was complete. 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 preparative HPLC (column: YMC-Actus Triart C18 ExRS, 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 45% B in 7 min, 45% B to 75% B in 11 min; 254 / 220 nm; RT: 7.53 min) to give 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (380 mg, 65.1%) as a yellow oil. LCMS (ESI, m / z): 336 [M+H] + .

[0345] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (22a) 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: 3% B to 3% B in 21 min; wavelength: 220 / 254 nm; RT1: 13.944 min; RT2: 16.488 min) to give the desired isomer 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as a white solid (first eluting peak, 108.5 mg, 28%, 100% ee).

[0346] 1 H NMR (400MHz, methanol-d4) δ7.44-7.38(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=8.0Hz,1H),3.22(d,J=8.0Hz,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).

[0347] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 0.927 min.

[0348] Chiral Separation of 1-[5-[2-(3-Fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (22b) 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: 3% B to 3% B in 21 min; wavelength: 220 / 254 nm; RT1: 13.944 min; RT2: 16.488 min) to give the desired isomer 1-[5-[2-(3-fluorophenyl)ethynyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as a white solid (second eluting peak, 94.7 mg, 24.6%, 99.7% ee).

[0349] 1 H NMR (400MHz, methanol-d4) δ7.44-7.38(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=8.0Hz,1H),3.23(d,J=8.0Hz,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).

[0350] LCMS (ESI, m / z): 336 [M+H] + .Analytical conditions: Column: L-column 3C18 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: 40% B to 80% B in 2.00 min, 80% B to 95% B in 0.25 min, maintained at 95% for 0.55 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 1.318 min. Example S23. 1-(5-(2,6-dichlorophenethyl)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (23a and 23b)

[0351] Synthesis of 5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-one A mixture of 5-bromo-6-methyl-indan-1-one (300 mg, 1.33 mmol, 1.00 equiv), 2-(2,6-dichlorophenyl)ethyl-trifluoro-potassium bromide (749 mg, 2.67 mmol, 2.00 equiv), CsCO (1.3 g, 4 mmol, 3.00 equiv) and Pd(dppf)Cl (98 mg, 0.13 mmol, 0.10 equiv) in toluene (5 mL) and water (1 mL) was stirred at 90 ° C overnight. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with PE / EtOAc, 10:1) to give 5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-one (400 mg, 94.0%) as an off-white solid. LCMS (ESI, m / z): 319 [M+H] + .

[0352] Synthesis of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol A solution of ZnCl2 (2M in 4Me-THF, 1.26 mL, 2.51 mmol, 2.00 equiv), NaBH3CN (320.8 mg, 5.01 mmol, 4.00 equiv), 5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-one (400 mg, 1.25 mmol, 1.00 equiv) and 3-methylazetidin-3-ol (218 mg, 2.51 mmol, 2.00 equiv) in methanol (3 mL) was stirred at 80 ° C overnight. LCMS showed that the reaction was complete. The 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 OBD C18 column, 30×150 mm 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 · H 2 O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 53% B to 73% B in 7 min; 254 / 210 nm; RT: 6.3 min) to give 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (192 mg, 39.3%) as a white solid. LCMS (ESI, m / z): 390 [M+H] + .

[0353] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (23a) 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: 95% B to 95% B in 13 min; 220 / 254 nm; RT1: 8.824 min; RT2: 11.342 min) to give the desired isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (25 mg, 12.9%, 99.7% ee) as a white solid.

[0354] 1 H NMR (400MHz, methanol-d4) δ7.39(d,J=8.0Hz,2H),7.21(t,J=8.0Hz,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=7.6H z,1H),3.16-3.11(m,2H),3.06-2.99(m,1H),2.87-2.83(m,2H),2.81-1.7 3(m,1H),2.41(s,3H),2.25-2.16(m,1H),1.93-1.85(m,1H),1.48(s,3H).

[0355] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 1.000 min.

[0356] Chiral Separation of 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (23b) 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: 95% B to 95% B in 13 min; 220 / 254 nm; RT1: 8.824 min; RT2: 11.342 min) to give the desired isomer 1-[5-[2-(2,6-dichlorophenyl)ethyl]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (31.3 mg, 16.3%, 98.9% ee) as a white solid.

[0357] 1 H NMR (400MHz, methanol-d4) δ7.39(d,J=8.0Hz,2H),7.21(t,J=8.0Hz,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=8.0H z,1H),3.16-3.12(m,2H),3.06-2.99(m,1H),2.87-2.82(m,2H),2.80-1.7 5(m,1H),2.41(s,3H),2.27-2.18(m,1H),1.95-1.87(m,1H),1.48(s,3H).

[0358] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 0.995 min. Example S24. 1-(5-((2,6-Dichlorobenzyl)oxy)-6-methyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (24a and 24b)

[0359] Synthesis of 5-Hydroxy-6-methyl-indan-1-one A solution of 5-bromo-6-methyl-indan-1-one (300 mg, 1.33 mmol, 1.00 equiv), KOH (224 mg, 4 mmol, 3.00 equiv), t-BuBrettPhos (129 mg, 0.27 mmol, 0.20 equiv) and Pd2(dba)3 (122.1 mg, 0.13 mmol, 0.10 equiv) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80 °C overnight. LCMS showed the reaction was complete. The reaction was acidified to pH 4-5 with 1 M HCl. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 2:3) to give 5-hydroxy-6-methyl-indan-1-one (175 mg, 81%) as a white solid. LCMS (ESI, m / z): 163 [M+H] + .

[0360] Synthesis of 5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-one A mixture of 5-hydroxy-6-methyl-indan-1-one (175 mg, 1.08 mmol, 1.00 equiv), 2-(bromomethyl)-1,3-dichloro-benzene (388 mg, 1.62 mmol, 1.50 equiv) and K2CO3 (447 mg, 3.24 mmol, 3.00 equiv) in MeCN (4 mL) was stirred at 60 ° C overnight. LCMS showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:3) to give 5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-one (234 mg, 67.5%) as a white solid. LCMS (ESI, m / z): 321 [M+H] + .

[0361] Synthesis of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol 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-methyl-indan-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 showed 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 flash chromatography on C18 silica gel (eluting with water / acetonitrile, 1:1) to give 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (110 mg, 42.9%) as a light yellow oil. LCMS (ESI, m / z): 336 [M+H] + .

[0362] Chiral Separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (24a) 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: 2% B to 2B% in 19 min; 220 / 254 nm; RT1: 10.127 min; RT2: 11.859 min) to give the desired isomer 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as a white solid (first eluting peak, 37.3 mg, 32.9%, 97.9% ee).

[0363] 1H NMR (400MHz, methanol-d4) δ7.49-7.46 (m, 2H), 7.37 (dd, J = 9.2, 7.6Hz, 1H), 7.1 2(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=8.0Hz,1H),3.29(d,J=8.0Hz,1H),3.12-3.06(m,1H),2.88-2.8 1(m,1H),2.30-2.21(m,1H),2.13(s,3H),1.97-1.90(m,1H),1.48(s,3H).

[0364] 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: 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; 220 nm; RT: 0.955 min.

[0365] Chiral Separation of 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol (24b) 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: 2% B to 2B% in 19 min; 220 / 254 nm; RT1: 10.127 min; RT2: 11.859 min) to give the desired isomer 1-[5-[(2,6-dichlorophenyl)methoxy]-6-methyl-indan-1-yl]-3-methyl-azetidin-3-ol as a white solid (second eluting peak, 21.7 mg, 19.5%, 97.6% ee).

[0366] 1H NMR (400MHz, methanol-d4) δ7.49-7.46 (m, 2H), 7.37 (dd, J = 9.2, 7.6Hz, 1H), 7.1 2(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=8.0Hz,1H),3.25(d,J=8.0Hz,1H),3.13-3.06(m,1H),2.87-2.8 0(m,1H),2.29-2.20(m,1H),2.13(s,3H),1.96-1.89(m,1H),1.48(s,3H).

[0367] 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: 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; 210 nm; RT: 0.950 min. Example S25. 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25a and 25b)

[0368] Synthesis of 1-(4-bromo-3,5-dimethyl-phenyl)-3-chloro-propan-1-one To a stirred solution of 3-chloropropionyl 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-dimethyl-benzene (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 obtain a mixture of isomers comprising 1- (4-bromo-3,5-dimethyl-phenyl) -3-chloro-propane-1-one as a crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): 275 [M+H] + .

[0369] Synthesis of 5-bromo-4,6-dimethyl-indan-1-one A solution of the isomeric mixture (including 1-(4-bromo-3,5-dimethyl-phenyl)-3-chloro-propan-1-one) (1.3 g, 4.72 mmol, 1.00 equiv) in concentrated H2SO4 (5 mL) was stirred at 90 ° C for 1 h. The reaction mixture was then 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 flash column chromatography on silica gel (eluted with PE:EtOAc=12:1) to give a mixture of isomers of 5-bromo-4,6-dimethyl-indan-1-one (800 mg, 70%) as a white solid, which was separated by achiral SFC (column: Green SepNaphthyl, 3*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2M NH 3 -MeOH); flow rate: 80 mL / min; gradient: isocratic 30% B; wavelength: 254 nm; RT1 (min): 3.63; RT2 (min): 4.18) to give the desired isomer 5-bromo-4,6-dimethyl-indan-1-one (400 mg, 50%, 99% ee) as a white solid. LCMS (ESI, m / z): 239 [M+H] + .

[0370] Synthesis of 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol A solution of 5-bromo-4,6-dimethyl-indan-1-one (400 mg, 1.67 mmol, 1.00 equiv), 3-methylazetidine-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) in methanol (10 mL) was placed in a 25 ml round-bottom flask. The resulting solution was stirred at 60 ° C for 15 h. LCMS showed that the reaction was complete. The reaction was quenched by 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 flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 2:3) to give 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (200 mg, 39%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H]+ .

[0371] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol A solution of 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (190 mg, 0.61 mmol, 1.00 equiv), 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetrahydro-1,3,2-dioxaborolane (170 mg, 0.61 mmol. 1.00 equiv), CsCO (598 mg, 1.84 mmol, 3.00 equiv) and Pd(dppf)Cl (44 mg, 0.060 mmol, 0.10 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90 ° C. under N2 atmosphere for 4 h. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted 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] + .

[0372] Chiral Separation of 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25a) The racemate (200 mg) was separated by chiral HPLC (column: Lux 5μm Cellulose-2, 2.12*25cm, 5μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 25 min; 220 / 254 nm; RT1: 15.662 min; RT2: 21.512 min) to give the desired isomer (first eluting peak, 12.3 mg, 6%, 100% ee) as a white solid.

[0373] 1H 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).

[0374] 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: 5% B to 70% B in 1.70 min, 70% B to 95% B in 0.30 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.10 min; 220 nm; RT: 1.545 min.

[0375] Chiral Separation of 1-(5-(3-chloro-4-cyclopropylphenyl)-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (25b) The racemate (200 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: 98% B to 98% B in 25 min; 220 / 254 nm; RT1: 15.662 min; RT2: 21.512 min) to give the desired isomer as a white solid (second eluting peak, 14 mg, 7%, 99% ee).

[0376] 1H NMR (400MHz, methanol-d4) δ7.10-7.05(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=2.0Hz,3H),1.09-1.04(m,2H),0.78-0.74(m,2H).

[0377] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 220 nm; RT: 1.033 min. Example S26. 1-(5-(3-chloro-4-cyclopropylphenyl)-4,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (26a and 26b)

[0378] Synthesis of 1-(4-bromo-2,5-dimethylphenyl)-3-chloropropane-1-one To AlCl3 (2.2 g, 16.2 mmol, 1.5 equiv) and 3-chloropropionyl chloride (1.7 g, 13.0 mmol, 1.2 equiv) in DCM (20 mL) was added dropwise at 0 ° C. A solution of 2-bromo-1,4-dimethyl-benzene (2 g, 10.8 mmol, 1 equiv) in DCM (20 mL) was then added. 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 ethyl acetate (3*50 mL). The combined organic layers were concentrated under vacuum to give 1-(4-bromo-2,5-dimethylphenyl)-3-chloropropane-1-one as a crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): 275 [M+H] + .

[0379] Synthesis of 5-bromo-4,7-dimethyl-indan-1-one A solution of 1-(4-bromo-2,5-dimethylphenyl)-3-chloropropane-1-one (2.8 g, 10.8 mmol, 1 equivalent) in concentrated H2SO4 (8 mL) was stirred at 90 ° C for 1 h. The reaction mixture was then 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 flash column chromatography on silica gel (eluted with PE:EtOAc=12:1) to give 5-bromo-4,7-dimethyl-indan-1-one (2 g, 76.7%) as a brown solid. LCMS (ESI, m / z): 239 [M+H] + .

[0380] Synthesis of 1-(5-bromo-4,7-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol A solution of NaCNBH3 (1.27 g, 33.46 mmol, 4 equivalents) and ZnCl2 (4.2 mL, 2 M in 4Me-THF, 8.36 mmol, 1 equivalent) in methanol (20 mL) was stirred at room temperature for 0.5 h. 5-bromo-4,7-dimethyl-indan-1-one (2 g, 8.36 mmol, 1 equivalent) and 3-methylazetidine-3-ol (1.46 g, 16.7 mmol, 2 equivalents) were then added. The resulting mixture was stirred at 60 ° C for 12 h. LCMS showed that the reaction was complete. The reaction was quenched by 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 flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 1:1) to give 1-(5-bromo-4,7-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (500 mg, 19.2%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H] + .

[0381] Synthesis of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol A mixture of 1-(5-bromo-4,7-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (500 mg, 1.61 mmol, 1 eq), 2-(3-chloro-4-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (898 mg, 3.22 mmol, 2 eq), Pd(dppf)Cl (118 mg, 0.16 mmol, 0.1 eq) and CsCO (1.57 g, 4.84 mmol, 3 eq) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 90 ° C overnight. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 1:1) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol (300 mg, 48.7%) as a yellow oil. LCMS (ESI, m / z): 382 [M+H] + .

[0382] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol (26a) The racemate (300 mg) was purified by chiral HPLC (column: Lux 5μm Celluloes-3, 2.12*25cm, 5μm; 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 20 min; 220 / 254 nm; RT1: 6.271 min; RT2: 13.587 min) to give the enantiomers. The first eluting peak enantiomer was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150mm 5μm; mobile phase A: water (10mM NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 65% B to 95% B in 7min; 254 / 210nm; RT1: 5.68min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol (67.6mg, 22.3%) as a white solid.

[0383] 1H NMR (300MHz, methanol-d4) δ7.24(d,J=1.5Hz,1H),7.10(dd,J=7.8,1.5Hz,1H),7.03(d,J=7 .8Hz,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=7.2Hz,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).

[0384] LCMS (ESI, m / z): 382 [M+H] + Analytical conditions: Column: YMC MeteoricCore C18 BIO, 2.1*30 mm, 2.7 μm; Mobile phase A: Water (5 mM NH4HCO3), Mobile phase B: Acetonitrile; Flow rate: 1.20 mL / min; Gradient: 10% B to 95% B in 1.20 min, hold at 95% for 0.58 min, 95% B to 10% B in 0.05 min; 254 nm; RT: 1.186 min.

[0385] Chiral Separation of 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol (26b) The racemate (300 mg) was purified by chiral HPLC (column: Lux 5μm Celluloes-3, 2.12*25cm, 5μm; 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 20 min; 220 / 254 nm; RT1: 6.271 min; RT2: 13.587 min) to give the enantiomers. The second eluting peak enantiomer was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150mm 5μm; mobile phase A: water (10mM NH4HCO3), mobile phase B: ACN; flow rate: 60mL / min; gradient: 65% B to 95% B in 7min; 254 / 210nm; RT1: 8.32min) to give 1-[5-(3-chloro-4-cyclopropyl-phenyl)-4,7-dimethyl-indan-1-yl]-3-methyl-azetidin-3-ol (63.4mg, 21.0%) as a white solid.

[0386] 1 H NMR (300MHz, methanol-d4) δ7.24(d,J=1.5Hz,1H),7.10(dd,J=7.8,1.5Hz,1H),7.03(d,J=7 .8Hz,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=6.9Hz,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).

[0387] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.045 min. Example S27. 1-(5-(3-chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27a and 27b)

[0388] Synthesis of 1-(4-bromo-2,3-dimethyl-phenyl)-3-chloro-propan-1-one To a stirred solution of 3-chloropropionyl chloride (3.4 g, 27.0 mmol, 1.00 equiv) and AlCl3 (5.1 g, 37.9 mmol, 1.50 equiv) in DCM (80 mL) was added dropwise a solution of 1-bromo-2,3-dimethyl-benzene (5 g, 27.0 mmol, 1.00 equiv) in DCM (8 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 obtain a mixture of isomers comprising 1-(4-bromo-2,3-dimethyl-phenyl)-3-chloro-propane-1-one as a crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): 275[M+H] + .

[0389] Synthesis of 5-bromo-6,7-dimethyl-2,3-dihydro-1H-inden-1-one A solution of the isomeric mixture (containing 1-(4-bromo-2,3-dimethyl-phenyl)-3-chloro-propan-1-one) (2.6 g, 9.44 mmol, 1.00 equiv) in concentrated H2SO4 (10 mL) was stirred at 90 ° C for 1 h. The reaction mixture was then 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 flash column chromatography on silica gel (eluted with PE:EtOAc=12:1) to give a mixture of isomers as a white solid (1.2 g, 55%), which was separated by achiral SFC (column: Green Sep Naphthyl, 3*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2M NH 3 -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 give the desired isomer 5-bromo-6,7-dimethyl-2,3-dihydro-1H-inden-1-one (530 mg, 44%, 99% ee) as a white solid. LCMS (ESI, m / z): 239 [M+H] + .

[0390] Synthesis of 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol A solution of 5-bromo-6,7-dimethyl-2,3-dihydro-1H-indene-1-one (530 mg, 1.71 mmol, 1.00 equiv), 3-methylazetidine-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) in methanol (10 mL) was stirred at 60 ° C for 15 h. LCMS showed that the reaction was complete. The reaction was quenched by 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 flash chromatography on silica gel (eluted with ethyl acetate / petroleum ether, 2:3) to give 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (120 mg, 17%) as a yellow oil. LCMS (ESI, m / z): 310 [M+H] + .

[0391] Synthesis of 1-(5-(3-chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol Under N2 atmosphere, a solution of 1-(5-bromo-4,6-dimethyl-indan-1-yl)-3-methyl-azetidin-3-ol (120 mg, 0.39 mmol, 1.00 equiv), 2-(3-chloro-4-cyclopropyl-phenyl)-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) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90 ° C for 4 h. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted 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] + .

[0392] Chiral Separation of 1-(5-(3-chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27a) The racemate (60 mg) was separated by chiral HPLC (column: CHIRALPAK IG-3.4.6*50 cm, 3 μm; mobile phase A: Hex (0.1% DEA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 25 min; 220 / 254 nm; RT1: 15.662 min; RT2: 21.512 min) to give the desired isomer (first eluting peak, 10.0 mg, 16%, 99% ee) as a white solid.

[0393] 1H NMR (400MHz, methanol-d4) δ7.23(d,J=1.6Hz,1H),7.09(dd,J=8.0,1.6Hz,1H),7.04(d,J=8.0Hz, 1H), 6.92 (s, 1H), 4.22 (d, J = 6.4Hz, 1H), 3.30-3.27 (m, 2H), 3.24-3.23 (m, 1H), 3.19 (d, J = 7. 6Hz,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).

[0394] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.027 min.

[0395] Chiral Separation of 1-(5-(3-chloro-4-cyclopropylphenyl)-6,7-dimethyl-2,3-dihydro-1H-inden-1-yl)-3-methylazetidin-3-ol (27b) The racemate (60 mg) was separated by chiral HPLC (column: CHIRALPAK IG-3.4.6*50 cm, 3 μm; mobile phase A: Hex (0.1% DEA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 98% B to 98% B in 25 min; 220 / 254 nm; RT1: 15.662 min; RT2: 21.512 min) to give the desired isomer as a white solid (second eluting peak, 8.1 mg, 13%, 99% ee).

[0396] 1H NMR (400MHz, methanol-d4) δ7.23(d,J=1.6Hz,1H),7.09(dd,J=8.0,1.6Hz,1H),7.03(d,J=8.0Hz, 1H),6.92(s,1H),4.22(d,J=6.4Hz,1H),3.32-3.30(m,2H),3.25-3.23(m,1H),3.19(d,J=7. 6Hz,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).

[0397] 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 1.024 min. Example S28. 1-(4-((2,6-Difluoro-phenyl)ethynyl)benzyl)-3-methylazetidin-3-ol (28)

[0398] Synthesis of 1-[(4-bromophenyl)methyl]-3-methyl-azetidin-3-ol To a stirred solution of 1-bromo-4-(chloromethyl)benzene (1.0 g, 4.87 mmol, 1.00 equiv) in MeCN (10 mL) was added 3-methylazetidine-3-ol (847 mg, 9.73 mmol, 2.00 equiv), K2CO3 (2.1 g, 14.6 mmol, 3.00 equiv). The reaction was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluting with water / acetonitrile, 1 / 2) to give 1-[(4-bromophenyl)methyl]-3-methyl-azetidine-3-ol (1.0 g, 80%) as an off-white solid. LCMS (ESI, m / z): 256 / 258 [M+H] + .

[0399] Synthesis of 1-[[4-[2-(2,6-difluorophenyl)ethynyl]phenyl]methyl]-3-methyl-azetidin-3-ol (28) To a stirred solution of 1-[(4-bromophenyl)methyl]-3-methyl-azetidin-3-ol (100 mg, 0.39 mmol, 1.00 equiv) in DMF (6 mL) was added 2-ethynyl-1,3-difluoro-benzene (108 mg, 0.78 mmol, 2.00 equiv), Pd(PPh3)2Cl2 (29 mg, 0.04 mmol, 0.10 equiv), K2CO3 (162 mg, 1.17 mmol, 3.00 equiv) and CuI (4 mg, 0.02 mmol, 0.05 equiv). The reaction was stirred at 60 ° C for 3 h. LCMS showed that the reaction was complete. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min; 254 / 210 nm) to give 1-[[4-[2-(2,6-difluorophenyl)ethynyl]phenyl]methyl]-3-methyl-azetidin-3-ol (50.8 mg, 41%) as an off-white solid.

[0400] LCMS (ESI, m / z): 314 [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: 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.

[0401] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),7.70-7.53(m,5H),7.28(t,J=8.4Hz,2H),6.10(s,1H),4.46-4.40(m,2H),4.02-3.89(m,4H),1.43(s,3H).

[0402] Synthesis of 1-[[4-[2-(3-fluorophenyl)ethynyl]phenyl]methyl]-3-methyl-azetidin-3-ol (29) To a stirred solution of 1-[(4-bromophenyl)methyl]-3-methyl-azetidin-3-ol (100 mg, 0.39 mmol, 1.00 equiv) in DMF (5 mL) was added 1-ethynyl-3-fluoro-benzene (94 mg, 0.78 mmol, 2.00 equiv), Pd(PPh3)2Cl2 (29 mg, 0.04 mmol, 0.10 equiv), K2CO3 (162 mg, 1.17 mmol, 3.00 equiv) and CuI (4 mg, 0.02 mmol, 0.05 equiv). The resulting mixture was stirred at 60 ° C for 3 h. LCMS showed that the reaction was complete. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep C18 OBD column, 19*150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min; 254 / 210 nm) to give 1-[[4-[2-(3-fluorophenyl)ethynyl]phenyl]methyl]-3-methyl-azetidin-3-ol (48.1 mg, 41%) as an off-white solid.

[0403] LCMS (ESI, m / z): 296 [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: 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: 1.673 min.

[0404] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),7.65(d,J=8.0Hz,2H),7.54(d,J=8.0Hz,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). Example S30. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-4-methylpiperidin-4-ol (30)

[0405] Synthesis of [1-[[4-(azetidin-3-yl)phenyl]methyl]-4-methyl-4-piperidinyl]acetate A solution of tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidinyl)methyl]phenyl]azetidine-1-carboxylate (1.2 g, 2.98 mmol, 1.00 equiv) and TBSOTf (2 mL, 11.29 mmol, 3.79 equiv) in methanol (3 mL) was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% TFA) / MeCN, 2 / 1) to give [1-[[4-(azetidine-3-yl)phenyl]methyl]-4-methyl-4-piperidinyl]acetate (800 mg, 88.7%) as a yellow oil. LCMS (ESI, m / z): 303 [M+H] + .

[0406] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-4-piperidinyl]acetate A mixture of [1-[[4-(azetidin-3-yl)phenyl]methyl]-4-methyl-4-piperidinyl]acetate (750 mg, 2.48 mmol, 1.00 equiv), 2-bromo-1,3-dichloro-benzene (1.1 g, 4.96 mmol, 2.00 equiv), BrettPhos Pd G3 (225 mg, 0.25 mmol, 0.1 equiv), and K2CO3 (1.0 g, 7.44 mmol, 3.00 equiv) in tert-butanol (5 mL) was stirred at 80° C. overnight under a nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluting with water (0.05% TFA) / MeCN, 1 / 3) to give [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-4-piperidinyl]acetate (450 mg, 40.6%) as a yellow oil. LCMS (ESI, m / z): 447 [M+H] + .

[0407] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-piperidin-4-ol (30) To a stirred solution of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-4-piperidinyl]acetate (450 mg, 1.01 mmol, 1.00 equiv) in methanol (2 mL) was added MeONa (2 mL, 10.5 mmol, 30% w in MeOH) dropwise. The resulting reaction was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. 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: 56% B to 67% B in 10 min; wavelength: 254 / 220 nm; RT (min): 9) to give 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-4-methyl-piperidin-4-ol (95.0 mg, 23.2%) as an orange oil.

[0408] 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.

[0409] 1 H NMR (400MHz, methanol-d4) δ7.42(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),6.72(t,J=8.0Hz,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). Example S31. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (31)

[0410] Synthesis of tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-1-yl)methyl]phenyl]azetidine-1-carboxylate A solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.1 g, 4.02 mmol, 4.00 equiv) and Zn (460 mg, 7.04 mmol, 7.00 equiv) in DMF (15 mL) was stirred at 80 ° C for 2 h. Then [1-[(4-bromophenyl)methyl]-3-methyl-azetidin-3-yl]acetate (300 mg, 1.01 mmol, 1.00 equiv), Pd2(dba)3 (92 mg, 0.10 mmol, 0.10 equiv) and tri-m-tolylphosphine (61 mg, 0.20 mmol, 0.20 equiv) were added. The resulting mixture was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was filtered through celite; the filter cake was washed with MeCN (3*10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 6) to give tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-1-yl)methyl]phenyl]azetidine-1-carboxylate (200 mg, 53%) as an off-white solid. LCMS (ESI, m / z): 375 [M+H] + .

[0411] Synthesis of [1-[[4-(azetidin-3-yl)phenyl]methyl]-3-methyl-azetidin-3-yl]acetate To a stirred solution of tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-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 was stirred at room temperature for 30 min. LCMS showed that the reaction was complete and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% FA) / MeCN, 7 / 3) to give [1-[[4-(azetidin-3-yl)phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (140 mg, 95% yield) as an off-white solid. LCMS (ESI, m / z): 275[M+H] + .

[0412] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methylazetidin-3-yl]acetate A solution of [1-[[4-(azetidin-3-yl)phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (120 mg, 0.44 mmol, 1.00 equiv), 2-bromo-1,3-dichloro-benzene (148 mg, 0.66 mmol, 1.50 equiv), BrettPhosPd G3 (39 mg, 0.04 mmol, 0.10 equiv) and K2CO3 (181 mg, 1.31 mmol, 3.00 equiv) in tert-butanol (5 mL) was stirred at 80° C. for 2 h. LCMS showed the reaction was complete and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% FA) / MeCN, 3 / 7) to give [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (60 mg, 32% yield) as an off-white oil. LCMS (ESI, m / z): 419 [M+H] + .

[0413] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methyl-azetidin-3-ol (31) To a stirred solution of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (60 mg, 0.14 mmol, 1.00 equiv) in methanol (2 mL) was added MeONa (30% in MeOH, 1.0 mL, 0.28 mmol, 2.00 equiv). The mixture solution was stirred at 25 °C for 16 h. LCMS showed 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: 15% B to 45% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.12) to give 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]phenyl]methyl]-3-methyl-azetidin-3-ol (33.4 mg, 61%) as an off-white solid.

[0414] 1 H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H, H FA ),7.55(d,J=7.6Hz,2H),7.45(d,J=7.6Hz,2H),7.20(d,J=8.0Hz,2H),6.73(t,J=8.0Hz,1H),4.91(t, J=8.0Hz,2H),4.44-4.41(m,2H),4.26(s,2H),3.95(d,J=10.4Hz,2H),3.84-3.75(m,3H),1.52(s,3H).

[0415] LCMS (ESI, m / z): 377 [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: 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. Example S32. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)-4-methylpiperidin-4-ol (32)

[0416] Synthesis of 1-[(4-bromophenyl)methyl]-4-methyl-piperidin-4-ol To a stirred solution of [1-[(4-bromophenyl)methyl]-4-methyl-4-piperidinyl]acetate (600 mg, 1.84 mmol, 1.00 equiv) in methanol (5 mL) was added CH3ONa (2 M in MeOH, 0.9 mL, 1.84 mmol, 1.00 equiv). The mixture solution was stirred at 25 ° C for 16 h. LCMS showed 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 under vacuum. The residue was purified by flash column chromatography on C18 silica gel (eluting with water (5 mM NH4HCO3) / MeCN, 1 / 3) to give 1-[(4-bromophenyl)methyl]-4-methyl-piperidin-4-ol (300 mg, 57% yield) as an off-white solid. LCMS (ESI, m / z): 284 [M+H] + .

[0417] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-4-methyl-piperidin-4-ol (32) To a stirred solution of 1-[(4-bromophenyl)methyl]-4-methyl-piperidin-4-ol (200 mg, 0.70 mmol, 1.00 equiv) and 3-(2,6-dichlorophenyl)azetidine (142 mg, 0.70 mmol, 1.00 equiv) in tert-butanol (4 mL) 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 showed 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-methyl-piperidin-4-ol (14.6 mg, 5%) as an off-white solid.

[0418] 1 H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H, H FA),7.39(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),7.23(t,J=8.4Hz,1H),6.62(d,J=8.4Hz,2H),4.78-4.69(m,1H) ,4.50(t,J=8.0Hz,2H),4.24(t,J=8.0Hz,2H),4.17(s,2H),3.24-3.18(m,4H),1.82-1.78(m,4H),1.29(s,3H).

[0419] LCMS (ESI, m / z): 405 [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: 5% B to 60% B in 1.80 min, 60% B to 100% B in 0.15 min, hold at 100% for 0.70 min, 100% B to 5% B in 0.15 min; 254 nm; RT: 1.540 min. Example S33. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)benzyl)-3-methylazetidin-3-ol (33)

[0420] Synthesis of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methyl-azetidin-3-yl]acetate To a stirred solution of 3-(2,6-dichlorophenyl)azetidine (150 mg, 0.74 mmol, 1.00 equiv) in tert-butanol (5 mL) was added [1-[(4-bromophenyl)methyl]-3-methyl-azetidin-3-yl]acetate (443 mg, 1.48 mmol, 2.00 equiv), BrettPhos Pd G3 (67 mg, 0.07 mmol, 0.10 equiv) and K2CO3 (512 mg, 3.710 mmol, 5.00 equiv). The reaction was stirred at 90 ° C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 3) to give [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (50 mg, 16%) as an off-white solid. LCMS (ESI, m / z): 419 [M+H] + .

[0421] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methyl-azetidin-3-ol (33) To a stirred solution of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (50 mg, 0.12 mmol, 1.00 equiv) in methanol (3 mL) was added MeONa (2 M in MeOH, 0.12 mL, 0.24 mmol, 2.00 equiv). The reaction was stirred at room temperature for 16 h. LCMS showed 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 under vacuum. The residue was purified by (column: XBridge Prep C18 OBD column, 19×150 mm 5 μm; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 47% B to 67% B in 7 min; 254 / 210 nm) to give 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]phenyl]methyl]-3-methyl-azetidin-3-ol (29.8 mg, 66%) as an off-white solid.

[0422] 1H NMR (300MHz, DMSO-d6) δ8.25(s,1H),7.47(d,J=7.8Hz,2H),7.30(t,J=7.8Hz,1H),7.09(d,J=7.8Hz,2H),6.47(d,J=7.8Hz,2H),4.5 9-4.54(m,1H),4.43(t,J=7.8Hz,2H),3.99(t,J=7.8Hz,2H),3.49(s,2H),3.16(d,J=6.6Hz,2H),2.90(d,J=6.6Hz,2H),1.34(s,3H).

[0423] LCMS (ESI, m / z): 377 [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: 1.50 mL / min; Gradient: 5% B to 60% B in 1.80 min, 60% B to 100% B in 0.15 min, hold at 100% for 0.40 min, 100% B to 5% B in 0.70 min; 254 nm; RT: 1.505 min. Example S34. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-4-methylpiperidin-4-ol (34)

[0424] Synthesis of tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidinyl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate 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. Then, [1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-4-methyl-4-piperidinyl] acetate (600 mg, 1.69 mmol, 1.00 equiv), Pd2(dba)3 (155 mg, 0.17 mmol, 0.10 equiv) and tri-m-tolylphosphine (102 mg, 0.34 mmol, 0.20 equiv) were added. The resulting mixture was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was filtered through celite; the filter cake was washed with MeCN (3*10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 6) to give tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidinyl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate (700 mg, 95%) as an off-white solid. LCMS (ESI, m / z): 431 [M+H] + .

[0425] Synthesis of [1-[[4-(azetidin-3-yl)-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate To a stirred solution of tert-butyl 3-[4-[(4-acetoxy-4-methyl-1-piperidinyl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate (700 mg, 1.63 mmol, 1.00 equiv) in DCM (10 mL) was added TBSOTf (0.8 mL, 4.880 mmol, 3.00 equiv). The mixture solution was stirred at 0 ° C for 2 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% FA) / MeCN, 9 / 1) to give [1-[[4-(azetidine-3-yl)-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (500 mg, 93% yield) as an off-white solid. LCMS (ESI, m / z): 331 [M+H] + .

[0426] Synthesis of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate To a stirred solution of [1-[[4-(azetidin-3-yl)-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (300 mg, 0.91 mmol, 1.00 equiv) and 2-bromo-1,3-dichloro-benzene (307 mg, 1.36 mmol, 1.50 equiv) in tert-butanol (5 mL) was added BrettPhos Pd G3 (82 mg, 0.09 mmol, 0.10 equiv) and K2CO3 (375 mg, 2.72 mmol, 3.00 equiv). The mixture solution was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% FA) / MeCN, 3 / 7) to give [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (120 mg, 27% yield) as an off-white solid. LCMS (ESI, m / z): 475 [M+H] + .

[0427] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-piperidin-4-ol (34) To a stirred solution of [1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (120 mg, 0.25 mmol, 1.00 equiv) in methanol (1 mL) was added CH3ONa (1 M in MeOH, 0.3 mL, 0.25 mmol, 1.00 equiv). The mixture solution was stirred at 25 ° C for 16 h. LCMS showed 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 under vacuum. 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-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-piperidin-4-ol (38.2 mg, 34%) as an off-white solid.

[0428] 1 H NMR (400MHz, DMSO-d6) δ7.23(d,J=8.0Hz,2H),7.02(s,2H),6.74(t,J=8.0Hz,1H),4.80(t,J=8.0Hz,2H),4.33(t,J=7.2Hz,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).

[0429] LCMS (ESI, m / z): 433 [M+H] + Analytical 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: 5% B to 100% B in 1.20 min, hold at 100% for 0.60 min, 100% B to 5% B in 0.03 min; 254 nm; RT: 0.917 min. Example S35. 1-(4-((2,6-Dichlorophenyl)ethynyl)benzyl)-3-methylazetidin-3-ol (35)

[0430] Synthesis of 3-Methylazetidin-3-ol To a stirred solution of tert-butyl 3-hydroxy-3-methylazetidine-1-formate (3.00 g, 16.0 mmol, 1.00 equiv) in DCM (10 mL) was added TBSOTf (4.24 g, 16.0 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The resulting mixture was concentrated under reduced pressure. The crude product, 3-methylazetidine-3-ol (1.2 g), was used directly in the next step without further purification.

[0431] Synthesis of 1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-ol To a stirred solution of 3-methylazetidine-3-ol (1.00 g, 11.5 mmol, 1.00 equiv) and 4-bromo-2,6-dimethylbenzaldehyde (2.45 g, 11.5 mmol, 1.00 equiv) in MeOH (10 mL) was added NaBH3CN (0.72 g, 11.5 mmol, 1.00 equiv) and ZnCl2 (5.8 mL, 2.0 M in 2Me-THF, 11.5 mmol, 1.00 equiv) in portions at room temperature. The resulting mixture solution was stirred at 60 ° C overnight under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered through celite; the filter cake was washed with MeOH (3*10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 3 / 7) to give 1-[(4-bromo-2,6-dimethylphenyl)methyl]-3-methylazetidin-3-ol (1.8 g, 55.2%) as a pale yellow oil. LCMS (ESI, m / z): 284 [M+H] + .

[0432] Synthesis of [1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-methyl-azetidin-3-yl]acetate To a stirred solution of 1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-methyl-azetidine-3-ol (820 mg, 2.89 mmol, 1.00 equiv) in DCM (10 mL) was added TEA (1.0 mL, 5.77 mmol, 2.00 equiv), AcO (1.1 mL, 11.54 mmol, 4.00 equiv) and DMAP (35 mg, 0.29 mmol, 0.10 equiv). The reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 9) to give [1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-methyl-azetidin-3-yl]acetate (830 mg, 88.0%) as an off-white solid. LCMS (ESI, m / z): 326 [M+H] + .

[0433] Synthesis of tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-1-yl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate A mixture of [1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-methyl-azetidin-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. Pd2(dba)3 (121 mg, 0.13 mmol, 0.10 equiv) and tri-o-tolylphosphine (39 mg, 0.13 mmol, 0.10 equiv) were then added at room temperature. The resulting mixture was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was filtered through celite; the filter cake was washed with MeCN (3*10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 6) to give tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-1-yl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate (210 mg, 39%) as an off-white solid. LCMS (ESI, m / z): 403 [M+H] + .

[0434] Synthesis of [1-[[4-(azetidin-3-yl)-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-yl]acetate To a stirred solution of tert-butyl 3-[4-[(3-acetoxy-3-methyl-azetidin-1-yl)methyl]-3,5-dimethyl-phenyl]azetidine-1-carboxylate (210 mg, 0.52 mmol, 1.00 equiv) in DCM (2 mL) was added TBSOTf (137 mg, 0.52 mmol, 1.00 equiv). The reaction was stirred at room temperature for 30 min. LCMS showed that the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (0.05% FA) / MeCN, 6 / 1) to give [1-[[4-(azetidin-3-yl)-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (150 mg, 95%) as a light yellow oil. LCMS (ESI, m / z): 303 [M+H] + .

[0435] Synthesis of 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-ol (35) To a stirred solution of [1-[[4-(azetidin-3-yl)-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-yl]acetate (150 mg, 0.50 mmol, 1.00 equiv) in tert-butanol (3 mL) was added BrettPhosPd G3 (45 mg, 0.05 mmol, 0.10 equiv) and K2CO3 (342 mg, 2.48 mmol, 5.00 equiv). The reaction was then stirred at 60 ° C for 3 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative 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: 68% B to 85% B in 9 min; wavelength: 254 / 220 nm; RT: 8.22 min) to give 1-[[4-[1-(2,6-dichlorophenyl)azetidin-3-yl]-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-ol (16.9 mg, 8%) as an off-white solid.

[0436] 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.

[0437] 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=8.0Hz,2H),7.01(s,2H),6.74(t,J=8.0Hz,1H),5.11(s,1H),4.80(t,J=8.0Hz,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). Example S36. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)-4-methylpiperidin-4-ol (36)

[0438] Synthesis of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethylphenyl]methyl]-4-methyl-4-piperidinyl]acetate To a stirred solution of [1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-4-methyl-4-piperidinyl]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) was added BrettPhos Pd G3 (35 mg, 0.04 mmol, 0.10 equiv) and K2CO3 (163 mg, 1.19 mmol, 3.00 equiv). The mixture was stirred at 80 ° C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica gel (eluted with water (5 mM NH4HCO3) / MeCN, 1 / 3) to give [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (60 mg, 31%) as an off-white solid. LCMS (ESI, m / z): 475 [M+H] + .

[0439] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-piperidin-4-ol (36) To a stirred solution of [1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethyl-phenyl]methyl]-4-methyl-4-piperidinyl]acetate (60 mg, 0.13 mmol, 1.00 equiv) in methanol (2 mL) was added CH3ONa (2 M in MeOH, 0.5 mL, 1.04 mmol, 8.00 equiv). The mixture solution was stirred at 25 ° C for 16 h. LCMS showed 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 under vacuum. 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-dimethyl-phenyl]methyl]-4-methyl-piperidin-4-ol (6.4 mg, 11%) as an off-white solid.

[0440] 1 H NMR (300MHz, methanol-d4) δ7.38(d,J=8.1Hz,2H),7.21(d,J=8.1Hz,1H),6.26(s,2H),4.60-4.52(m,1H),4.46(t,J=7 .5Hz,2H),4.05(t,J=7.5Hz,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).

[0441] LCMS (ESI, m / z): 433 [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: 1.2000 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; 254 nm; RT: 0.902 min. Example S37. 1-(4-(3-(2,6-dichlorophenyl)azetidin-1-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (37)

[0442] Synthesis of 1-(4-bromo-2,6-dimethylbenzyl)-3-methylazetidin-3-ol To a solution of ZnCl2 (2M in THF, 7.75 mL, 15.5 mmol, 2.00 equiv) in methanol (5.0 mL) was added NaBH3CN (1.95 g, 31.0 mmol, 4.00 equiv). The solution was stirred at room temperature for 10 min. 3-Methylazetidin-3-yl acetate (1.0 g, 7.75 mmol, 1.00 equiv) and 4-bromo-2,6-dimethylbenzaldehyde (1.7 g, 7.75 mmol, 1.00 equiv) were then added to the above solution. The reaction was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. The resulting solution was diluted with 10 ml of water and extracted with ethyl acetate (3*30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(4-bromo-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (500 mg, 23%) as a yellow oil. LCMS (ESI, m / z): 284 [M+H] + .

[0443] Synthesis of 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-ol (37) To a solution of compound 1-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-methyl-azetidin-3-ol (127 mg, 0.45 mmol, 1.00 equiv) in tert-butanol (2.0 mL) was added 3-(2,6-dichlorophenyl)azetidine (60 mg, 0.30 mmol, 0.67 equiv), K2CO3 (123 mg, 0.89 mmol, 2.00 equiv) and BrettPhos Pd G3 (27 mg, 0.03 mmol, 0.067 equiv) under a nitrogen atmosphere. The reaction was stirred at 80°C for 12 h. LCMS showed the desired product was formed. 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: 49% B to 74% B in 10 min; wavelength: 254 / 220 nm) to give 1-[[4-[3-(2,6-dichlorophenyl)azetidin-1-yl]-2,6-dimethyl-phenyl]methyl]-3-methyl-azetidin-3-ol (16.6 mg, 13.5%) as an off-white solid.

[0444] 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: 50% B to 95% B in 2.0 min, hold at 95% B for 0.7 min, 95% B to 15% B in 0.15 min; 254 nm; RT: 1.164 min.

[0445] 1 H NMR (400MHz, DMSO-d6) δ7.45(d,J=8.0Hz,2H),7.29(t,J=8.0Hz,1H),6.15(s,2H),5.07(s,1H),4.51(q,J=8.0Hz,1H),4.39( t,J=7.6Hz,2H),3.95(t,J=7.6Hz,2H),3.46(s,2H),3.03(d,J=6.0Hz,2H),2.88(d,J=6.0Hz,2H),2.28(s,6H),1.29(s,3H).

[0446] LC-MS methods used in the following examples

[0447] Method 1: Method information: Column: Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm; Mobile phase: A: 5 mm ammonium formate pH 3.3: ACN (98:02); Mobile phase: B: ACN: buffer (98:02; Flow rate: 1.0 mL / min.

[0448] Method 2: Method information: Column: XBridge C8 (50x4.6mm) 5μm; Mobile phase: A: 0.1% TFA / H2O; Mobile phase: B: 0.1% TFA / ACN; Flow rate: 1.5mL / min.

[0449] Method 3: Column: Aquity Uplc BEH C18 (50 x 3.0) mm, 1.7 μm; Mobile phase: A: 0.1% FA / water; Mobile phase: B: 0.1% TFA / ACN; Flow rate: 1.0 mL / min. Example S38. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzyl)-3-ethylazetidin-3-ol (38)

[0450] Synthesis of tert-Butyl 3-(4-Formyl-3,5-dimethylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (15.34 g, 235 mmol) in anhydrous DMF (200 mL) was added 1,2-dibromoethane (1.01 mL, 11.73 mmol) and heated to 75 ° C. After 15 min, the reaction was cooled to room temperature, trimethylsilyl chloride (1.5 mL, 11.73 mmol) was added and stirred at ambient temperature for an additional 30 min. Then a solution of tert-butyl 3-iodine azetidine-1-formate (19.93 g, 70.4 mmol) in 50 mL of anhydrous DMF was added to the reaction mixture and stirred at room temperature for another 30 min, followed by addition of 4-bromo-2,6-dimethylbenzaldehyde (5 g, 23.47 mmol) and XPhos Pd G4 (4.04 g, 4.69 mmol) in 50 mL of DMF. The reaction mixture was stirred at 80 ° C for 2 h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (250 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) eluting with 0-20% ethyl acetate in petroleum ether to afford tert-butyl 3-(4-formyl-3,5-dimethylphenyl)azetidine-1-carboxylate (4.3 g, 63% yield). LCMS Method 1; LCMS (ESI, m / z): 190.2 [M-100] + .

[0451] Synthesis of 4-(azetidin-3-yl)-2,6-dimethylbenzaldehyde To a stirred solution of tert-butyl 3-(4-formyl-3,5-dimethylphenyl)azetidine-1-carboxylate (2 g, 6.91 mmol) in anhydrous dichloromethane (40 mL) was added trifluoroacetic acid (5.32 mL, 69.1 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction process was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 4-(azetidine-3-yl)-2,6-dimethylbenzaldehyde (1.96 g, 98% yield) as a brown semisolid. LCMS method 1; LCMS (ESI, m / z): 190.0 [M + H] + .

[0452] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (1.8 g, 5.94 mmol) and 1,3- dichloro -2- iodobenzene (2.02 g, 7.42 mmol) in anhydrous 1,4- dioxane (30 mL) was added cesium carbonate (5.8 g, 17.8 mmol). The reaction mixture was degassed with nitrogen for 10 min and RuPhos Pd G3 (248 mg, 0.297 mmol) was added. The reaction mixture was stirred at 80 ° C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to afford 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (600 mg, 30% yield) as a white solid. LCMS Method 1; LCMS (ESI, m / z): 334.0 [M+H] + .

[0453] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-ethylazetidin-3-ol (38) To the stirring solution of 3-ethylazetidine-3-ol TFA salt (142mg, 0.718mmol) in MeOH (20mL) is added sodium bicarbonate (240mg, 2.8mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. To the free amine 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2,6- dimethylbenzaldehyde (200mg, 0.598mmol) in MeOH (8mL) is added zinc chloride (82mg, 0.598mmol) and stirred at 25 ° C for 1h. After 1h, sodium cyanoborohydride (57mg, 0.898mmol) is added and heated to 65 ° C for 12h. After the completion of the reaction, the reaction mixture is diluted with dichloromethane (60mL) and washed with saturated ammonium chloride solution and water (60mL). The organic phase is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The crude material was purified by preparative HPLC (Method Information: Diluent: THF: Water: ACN (50:20:30); Column: Zorbax C18 (50 x 21.5) mm, 5 micron; Mobile Phase A: 0.1% formic acid / water; Mobile Phase B: acetonitrile). The desired fractions were concentrated and lyophilized to afford the title compound, 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-ethylazetidin-3-ol formate, as a white solid (108.5 mg, 0.226 mmol, 37.8% yield, 97% purity).

[0454] 1 H NMR(400MHz,MeOD):7.19-7.23(m,4H),6.73(t,J=8.00Hz,1H),4.86-4.90(m,2H),4.38-4.42(m,4H),4.00-4.02(m,2H),3.7 7-3.80(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] + . Example S39. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(fluoromethyl)azetidin-3-ol (39)

[0455] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(fluoro-methyl)azetidin-3-ol (39) To the stirring solution of 3- (fluoromethyl) azetidine -3- alcohol HCl (79mg, 0.561mmol) in MeOH (8mL) is added sodium bicarbonate (94mg, 1.122mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. To the free amine 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2,6- dimethylbenzaldehyde (150mg, 0.449mmol) (synthesis see Example 1) in MeOH (6mL) is added zinc chloride (73.4mg, 0.539mmol) and stirred at 25 DEG C for 1h. After 1h, sodium cyanoborohydride (28.2mg, 0.449mmol) is added and heated to 65 DEG C for 12h. After the completion of the reaction, the reaction mixture is diluted with dichloromethane (60mL) and washed with saturated ammonium chloride solution and water (60mL). The organic phase was dried over NaSO, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by preparative HPLC (Method Information: Diluent: THF:acetonitrile (30:70), Column: Xbridge C8 (250 x 19) mm, 5 micron, Mobile Phase A: 0.1% formic acid / water, Mobile Phase B: acetonitrile). The desired fractions were concentrated and lyophilized to afford 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.

[0456] 1 H NMR (400MHz, MeOD): δ7.19(d,J=8.00Hz,2H),7.09(s,2H),6.71(t,J=8.40Hz,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] + . Example S40. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol (40)

[0457] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol (40) To the stirring solution of 3- (difluoromethyl) azetidine -3- alcohol HCl (100mg, 0.627mmol) in MeOH (10mL) was added sodium bicarbonate (106mg, 1.257mmol), then stirred at room temperature for 1h. The mixture was filtered through diatomaceous earth and concentrated to produce free amine. To the free amine 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2,6- dimethylbenzaldehyde (168mg, 0.503mmol) (synthesis see Example 1) in MeOH (6mL) was added zinc chloride (68.5mg, 0.503mmol) and stirred at 25 ° C for 1h. After 1h, sodium cyanoborohydride (106mg, 1.257mmol) was added and heated to 65 ° C for 12h. After the completion of the reaction, the reaction mixture was diluted with dichloromethane (60mL) and washed with saturated ammonium chloride solution and water (60mL). The organic phase was dried over NaSO, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by preparative HPLC (Method Information: Diluent: THF:water:ACN (50:20:30), Column: Zorbax C18 (50 x 21.5) mm, 5 micron, Mobile Phase A: 0.1% formic acid / water, Mobile Phase B: acetonitrile). The desired fractions were concentrated and lyophilized to afford the title compound, 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(difluoromethyl)azetidin-3-ol formate, as a white solid (30 mg, 0.061 mmol, 12.17% yield).

[0458] 1 H 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 peaks were combined with the solvent peak. LCMS method 1; LCMS (ESI, m / z): 443.0 [M+H] + . Example S41. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(trifluoromethyl)azetidin-3-ol (41)

[0459] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-(trifluoromethyl)azetidin-3-ol (41) To a stirred solution of 3-(trifluoromethyl)azetidine-3-ol (158 mg, 1.122 mmol) and 4-(1-(2,6-dichlorophenyl)azetidine-3-yl)-2,6-dimethylbenzaldehyde (250 mg, 0.748 mmol) (synthesis see Example) in MeOH (6 mL) was added zinc chloride (122 mg, 0.898 mmol) and stirred at 25 ° C for 1 h. After 1 h, sodium cyanoborohydride (70.5 mg, 1.122 mmol) was added and heated to 65 ° C for 12 h. 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 material was purified by flash column chromatography using 100-200 mesh silica gel and 5-25% EtOAc / petroleum ether. The desired fractions were evaporated to afford 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.

[0460] 1 H NMR (400MHz, DMSO-d6): δ7.23(d,J=8.0Hz,2H),7.02(s,2H),6.85(s,1H),6.74(t,J=8.0Hz,1H),4.80(t,J=8.4Hz,2H),4.32(t,J =7.2Hz,2H),3.67-3.64(m,3H),3.46(d,J=9.2Hz,2H),3.19(d,J=8.4Hz,2H),2.35(s,6H).LCMS method 1; LCMS(ESI,m / z):461.0[M+H] + . Example S42. 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (42)

[0461] Synthesis of 4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (300 mg, 0.98 mmol) and 1,3- difluoro -2- iodobenzene (356 mg, 1.48 mmol) in anhydrous 1,4- dioxane (8 mL) is added cesium carbonate (0.96 g, 2.97 mmol). The reaction mixture is then degassed with nitrogen for 10 min, then RuPhos Pd G3 (83 mg, 0.09 mmol) is added and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) (eluted with 0-20% ethyl acetate / petroleum ether) to give 4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (100 mg, 31% yield) as a yellow semisolid. LCMS (ESI, m / z): 302.0 [M+H] + .

[0462] Synthesis of 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (42) To the stirring solution of 3-methylazetidine-3-ol TFA salt (200mg, 0.9mmol) in MeOH (5mL) was added sodium bicarbonate (167mg, 1.99mmol), then stirred at room temperature for 1h. The mixture was filtered through diatomaceous earth and concentrated to obtain free amine. Zinc chloride (90mg, 0.664mmol) was added to the free amine 4- (1- (2,6- difluorophenyl) azetidine -3- bases) -2,6- dimethylbenzaldehyde (200mg, 0.664mmol) in 5ml MeOH and stirred for 1h at 25 ° C. After 1h, sodium cyanoborohydride (62mg, 0.9mmol) was added and heated to 65 ° C for 12h. The reaction mixture was diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:acetonitrile (50:50); column: Sunfire C18 (150 x 19) mm, 5 microns; mobile phase A: 0.1% formic acid / water; mobile phase B: acetonitrile). 1-(4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol formate was obtained as a white solid (38 mg, 14% yield, 99.8% purity).

[0463] 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] + . Example S43. Synthesis of 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol (43)

[0464] Synthesis of 2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (1g, 3.68mmol) and iodobenzene (750mg, 3.68mmol) in anhydrous 1,4- dioxane (10mL) is added cesium carbonate (3.5g, 11.03mmol). The reaction mixture is then degassed with nitrogen for 10min, then RuPhos Pd G3 (307mg, 0.368mmol) is added and heated to 80°C. After 16h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) (eluting with 0-20% ethyl acetate / 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] + .

[0465] Synthesis of 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol (43) To a stirred solution of 3-methylazetidine-3-ol (157 mg, 1.80 mmol) in MeOH (10 mL) was added 2,6-dimethyl-4-(1-phenylazetidine-3-yl)benzaldehyde (400 mg, 1.507 mmol) and zinc chloride (247 mg, 1.507 mmol) and stirred at room temperature for 1 h. After 1 h, sodium cyanoborohydride (95 mg, 1.507 mmol) was added and 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 layers were dried over Na SO , filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:acetonitrile (30:70); Gemini NX C18 (50 x 21.2) mm, 10 micron, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile) to give 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol formate (51 mg, 0.131 mmol, 8.70% yield, 98.4% purity) as a white solid. 1H-NMR (400MHz, MeOD): δ7.19-7.23(m,2H),7.12(s,2H),6.75(t,J=7.60Hz,1H),6.54-6.56(m,2H),4.24(t,J=7.60Hz,2H) ,4.19(s,2H),3.76-3.89(m,5H),3.62(d,J=9.60Hz,2H),2.44(s,6H),1.48(s,3H).LCMS method 2; LCMS(ESI,m / z):337.2[M+H] + . Example S44. 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (44) To a stirred solution of 3-methylazetidine-3-ol (157 mg, 1.80 mmol) in MeOH (10 mL) was added 2,6-dimethyl-4-(1-phenylazetidine-3-yl)benzaldehyde (400 mg, 1.507 mmol), zinc chloride (247 mg, 1.507 mmol) and the mixture was stirred at room temperature. After 1 h, sodium cyanoborohydride (95 mg, 1.507 mmol) was added and 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 layers were dried over Na SO , filtered, and the solvent was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (diluent: THF:acetonitrile (30:70); Gemini NX C18 (50 x 21.2) mm, 10 micron, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile) to give 1-(2,6-dimethyl-4-(1-phenylazetidin-3-yl)benzyl)-3-methylazetidin-3-ol as a white solid as a formate salt (51 mg, 0.131 mmol, 8.70% yield, 98.4% purity). 1 H-NMR (400MHz, MeOD): δ7.19-7.23(m,2H),7.12(s,2H),6.75(t,J=7.60Hz,1H),6.54-6.56(m,2H),4.24(t,J=7.60Hz,2H) ,4.19(s,2H),3.76-3.89(m,5H),3.62(d,J=9.60Hz,2H),2.44(s,6H),1.48(s,3H).LCMS method 2; LCMS(ESI,m / z):337.2[M+H] + .

[0466] Synthesis of 4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (300 mg, .98 mmol) and 1- fluoro-2- iodobenzene (329 mg, 1.48 mmol) in anhydrous 1,4- dioxane (8 mL) is added cesium carbonate (0.96 g, 2.97 mmol). The reaction mixture is then degassed with nitrogen for 10 min, then RuPhos Pd G3 (83 mg, 0.09 mmol) is added and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to afford 4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (175 mg, 62.8% yield) as a light yellow semisolid. LCMS Method 1, LCMS (ESI, m / z): 284.0 [M+H] + .

[0467] Synthesis of 1-(4-(1-(2-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (44) To the stirring solution of 3-methylazetidine-3-ol TFA (213mg, 1.059mmol) in MeOH (5mL) was added sodium bicarbonate (178mg, 2.118mmol) and then stirred at room temperature for 1h. The mixture was filtered through diatomaceous earth and concentrated to produce free amine. To the free amine 4-(1-(2-fluorophenyl)azetidine-3-yl)-2,6-dimethylbenzaldehyde (200mg, 0.706mmol) in 5mL MeOH was added zinc chloride (96mg, 0.706mmol) and stirred at room temperature for 1h. After 1h, sodium cyanoborohydride (66.5mg, 1.059mmol) was added and heated to 65°C for 12h. The reaction mixture was diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (Method Information: Diluent: THF:Acetonitrile (30:70); Column: Xbridge C18 (150 x 19) mm, 5 micron; Mobile Phase A: 5 mM ammonium formate / water; Mobile Phase B: Acetonitrile) to afford 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.

[0468] 1 H NMR (400MHz, MeOD): δ7.19(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=11.20Hz,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] + . Example S45. 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (45)

[0469] Synthesis of tert-butyl 3-(4-((3-hydroxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate To a stirred solution of 3-methylazetidine-3-ol (2.5 g, 8.64 mmol) in MeOH (10 mL) was added tert-butyl 3-(4-formyl-3,5-dimethylphenyl)azetidine-1-carboxylate (2.5 g, 8.64 mmol) (synthesis see Example 1) and zinc chloride (1.766 g, 12.96 mmol) and stirred at room temperature for 1 h. After 1 h, sodium borohydride (0.814 g, 12.96 mmol) was added and 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 material was purified by reverse phase column chromatography (method: diluent: THF:acetonitrile (30:70) column: Symmetry C8 (300x19) mm, 7 micron, mobile phase A: 5 mM ammonium formate / water, mobile phase B: acetonitrile) to give tert-butyl 3-(4-((3-hydroxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate (1.5 g, 3.92 mmol, 45.4% yield) as a colorless semisolid. LCMS method 1; LCMS (ESI, m / z): 361.2 [M+H] + .

[0470] Synthesis of tert-butyl 3-(4-((3-acetoxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate To a stirred solution of tert-butyl 3-(4-((3-hydroxy-3-methylazetidine-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate (1.5 g, 4.16 mmol) in DCM (20 mL) was added DMAP (0.508 g, 4.16 mmol) and Py (0.6 mL) and the reaction mixture was stirred at room temperature for 10 minutes. Acetic anhydride (1.178 mL, 12.48 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with a saturated solution of ammonium chloride and extracted with DCM. The combined organic layers were dried over sodium sulfate, concentrated under vacuum, and purified by flash column chromatography on 230-400 mesh silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to give tert-butyl 3-(4-((3-acetoxy-3-methylazetidin-1-yl)methyl)-3,5-dimethylphenyl)azetidine-1-carboxylate (800 mg, 1.987 mmol, 47.8% yield) as a clear oil. LCMS Method 1; LCMS (ESI, m / z): 403.2 [M+H] + .

[0471] Synthesis of 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate 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) in anhydrous dichloromethane (40 mL) was added trifluoroacetic acid (2.7 mL, 69.1 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 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to give a quantitative amount of 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate TFA as a brown semisolid. LCMS method 1; LCMS (ESI, m / z): 303.0 [M+H] + .

[0472] Synthesis of 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate To a solution of 1- (4- (azetidin-3-yl) -2,6- dimethylbenzyl) -3- methylazetidin-3-yl acetate TFA salt (300 mg, .98 mmol) and 1- fluoro-3- iodobenzene (356 mg, 1.48 mmol) in anhydrous 1,4- dioxane (8 mL) was added cesium carbonate (0.96 g, 2.97 mmol). The reaction mixture was degassed with nitrogen for 10 min, then RuPhos Pd G3 (83 mg, 0.09 mmol) was added to the reaction mixture and heated to 80 ° C. After 16 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a pad of celite, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to afford 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-yl acetate (60 mg, 16% yield) as a yellow semisolid. LCMS Method 1; LCMS (ESI, m / z): 397.4 [M+H] + .

[0473] Synthesis of 1-(4-(1-(3-fluorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (45) 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 h. The reaction mixture was diluted with a saturated solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude material was purified using preparative HPLC (Method Information: Diluent: THF:Water:ACN (50:10:40); Column: Symmetry C8 (300 x 19) mm, 7 micron; Mobile Phase A: 0.1% formic acid / water; Mobile Phase B: acetonitrile) to afford 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.

[0474] 1 H 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] + . Example S46. 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (46)

[0475] Synthesis of 4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (770 mg, 2.69 mmol) (synthesis see Example 1) and 2- chloro- 1- cyclopropyl -4- iodobenzene (750 mg, 2.69 mmol) in anhydrous 1,4- dioxane (10 mL) is added cesium carbonate (2.6 g, 8.08 mmol). The reaction mixture is then degassed with nitrogen for 10 min, then RuPhos PdG3 (225 mg, 0.269 mmol) is added and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to afford 4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (255 mg, 27.9% yield) as a yellow solid. LCMS Method 1, LCMS (ESI, m / z): 340.1 [M+H] + .

[0476] Synthesis of 1-(4-(1-(3-chloro-4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (46) To a stirred solution of 3-methylazetidin-3-ol (123 mg, 1.34 mmol) in MeOH (10 mL) 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 stirred at room temperature for 1 h. After 1 h, sodium cyanoborohydride (74 mg, 1.177 mmol) was added and 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 layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:acetonitrile (30:70); column: Xselect C18 (150 x 19) mm, 5 micron; mobile phase A: 0.1% formic acid / 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 salt (23 mg, 0.050 mmol, 4.25% yield, 99.5% purity) as an off-white solid.

[0477] 1 H NMR (400MHz, MeOD): 7.13 (s, 2H), 6.88 (d, J = 8.40Hz, 1H), 6.54 (d, J = 2.40Hz, 1H), 6.38-6.41 (m, 1H), 4.21 (s, 4H), 3.78-3.87 (m, 5H), 3.66 ( d,J=9.60Hz,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] + . Example S47. 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (47)

[0478] Synthesis of 4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- dimethylbenzaldehyde TFA salt (750mg, 2.473mmol) (synthesis see Example 1) and 1- bromo -4- cyclopropylbenzene (585mg, 2.97mmol) in anhydrous 1,4- dioxane (10mL) is added cesium carbonate (2.4g, 7.42mmol). The reaction mixture is then degassed with nitrogen for 10min, then RuPhos Pd G3 (207mg, 0.247mmol) is added and heated to 80°C. After 16h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 4-(1-(2,6-difluorophenyl)azetidin-3-yl)-2,6-dimethylbenzaldehyde (297 mg, 39% yield) as an off-white solid; LCMS Method 1; LCMS (ESI, m / z): 306.3 [M+H] + .

[0479] Synthesis of 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol (47) To a stirred solution of 3-methylazetidine-3-ol (171 mg, 1.965 mmol) in MeOH (10 mL) was added 4-(1-(4-cyclopropylphenyl)azetidine-3-yl)-2,6-dimethylbenzaldehyde (400 mg, 1.310 mmol) and zinc chloride (214 mg, 1.572 mmol) and stirred at room temperature for 1 h. After 1 h, sodium cyanoborohydride (123 mg, 1.965 mmol) was added and 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 material was purified by preparative HPLC (diluent: THF:acetonitrile (30:70); column: Xselect C18 (150 x 19) mm, 5 micron; mobile phase A: 0.1% formic acid / water; mobile phase B: acetonitrile) to give 1-(4-(1-(4-cyclopropylphenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-3-methylazetidin-3-ol formate (210 mg, 0.493 mmol, 37.6% yield, 99.1% purity) as a light brown solid.

[0480] 1 H NMR (400 MHz, DMSO-d6): δ 7.04 (s, 2H), 6.92 (d, J = 8.8 Hz, 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). Minor protons merged with the solvent signal. LCMS method 1, LCMS (ESI, m / z): 377.2 [M+H] + . Example S48. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)-3-methylazetidin-3-ol (48)

[0481] Synthesis of tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (5.3 g, 81 mmol) in anhydrous DMF (40 mL) was added 1,2-dibromoethane (0.34 mL, 4.05 mmol) and heated to 75 ° C. After 15 min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.285 mL, 2.229 mmol) was added and stirred at ambient temperature for another 30 min. A solution of tert-butyl 3-iodine azetidine-1-formate (6.8 g, 24.29 mmol) in 20 mL of anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30 min. Methyl 4-bromo-2-fluoro-6-methylbenzoate (2 g, 8.10 mmol) and XPhos Pd G4 (1 g, 1.214 mmol) were then added to 20 mL of DMF. The reaction mixture was stirred at 80 ° C for 2 h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate (2.2 g, 87% purity, 73% yield); LCMS method 1, LCMS (ESI, m / z): 224.2 [M-100] + .

[0482] Synthesis of methyl 4-(azetidin-3-yl)-2-fluoro-6-methylbenzoate TFA salt To a stirred solution of tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate (2.2 g, 6.80 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (5.24 mL, 68 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction progress was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to give methyl 4-(azetidine-3-yl)-2-fluoro-6-methylbenzoate TFA salt (2.2 g, 96% yield) as a brown semi-solid; LCMS method 1, LCMS (ESI, m / z): 224.2 [M+H] + .

[0483] Synthesis of methyl 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzoate To a solution of 4-(azetidine-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) in anhydrous 1,4-dioxane (20 mL) was added cesium carbonate (3.4 g, 10.68 mmol). The reaction mixture was then degassed with nitrogen for 10 min, followed by the addition of RuPhos Pd G3 (149 mg, 0.17 mmol) and heated to 80 ° C. After 16 h, TLC analysis indicated the complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (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] + .

[0484] Synthesis of (4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylphenyl)methanol To a stirred solution of methyl 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzoate (550 mg, 1.494 mmol) in DCM (20 mL) was added DIBAL-H (2.99 mL, 2.99 mmol) in THF at -78 ° C and stirred for 4 h at -78 ° C. The reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with DCM (60 mL) and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate / petroleum ether 0-30% to give the title compound 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylphenyl)methanol (530 mg, 1.496 mmol, 100% yield) as a yellow liquid; LCMS method 1, LCMS (ESI, m / z): 341.8 [M+H] + .

[0485] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzaldehyde To a stirred solution of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylphenyl)methanol (530 mg, 1.558 mmol) in DCM (10 mL) was added dess-martin periodinane (793 mg, 1.869 mmol) at 0° C. under a nitrogen atmosphere. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-20% ethyl acetate in petroleum ether to give 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzaldehyde (371 mg, 70%) as a yellow semisolid; LCMS Method 1, LCMS (ESI, m / z): 338.0 [M+H] + .

[0486] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-fluoro-6-methylbenzyl)-3-methylazetidin-3-ol (48) To the stirring solution of 3-methylazetidine-3-ol TFA salt (122mg, 0.66mmol) in MeOH (5mL) is added sodium bicarbonate (75mg, 0.88mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. Zinc chloride (60mg, 0.44mmol) is added to the free amine 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2- fluoro- 6- methylbenzaldehyde (150mg, 0.44mmol) in 5mL MeOH and stirred for 1h at 25 DEG C. After 1h, sodium cyanoborohydride (42mg, 0.66mmol) is added and heated to 65 DEG C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250x21.2) mm, 10 micron mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile). The desired 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 semisolid.

[0487] 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] + . Example S49. 1-(2-Chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol (49)

[0488] Synthesis of tert-butyl 3-(3-chloro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (4.96g, 76mmol) in anhydrous DMF (20mL) was added 1,2-dibromoethane (0.065mL, 0.759mmol) and heated to 75°C. After 15min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.097mL, 0.759mmol) was added and stirred at ambient temperature for another 30min. A solution of tert-butyl 3-iodine azetidine-1-formate (8.59g, 30.4mmol) in 10mL anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30min, followed by addition of methyl 4-bromo-2-chloro-6-methylbenzoate (2.0g, 7.59mmol) and XPhos Pd G4 (0.653g, 0.759mmol) in 10mL DMF. The reaction mixture was allowed to stir at 80°C for 2h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) (eluted with 0-50% ethyl acetate / petroleum ether) to afford tert-butyl 3-(3-chloro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate (1.58 g, 61.3% yield) as a colorless semisolid; LCMS method 1, LCMS (ESI, m / z): 240.0 [M-100] + .

[0489] Synthesis of methyl 4-(azetidin-3-yl)-2-chloro-6-methylbenzoate To a stirred solution of tert-butyl 3-(3-chloro-4-(methoxycarbonyl)-5-methylphenyl)azetidine-1-carboxylate (1.75 g, 5.15 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (1.190 mL, 15.45 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction progress was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with ether to obtain methyl 4-(azetidine-3-yl)-2-chloro-6-methylbenzoate TFA (1.74 g, 96% yield) as a yellow semisolid; LCMS method 3, LCMS (ESI, m / z): 240.0 [M+H] + .

[0490] Synthesis of methyl 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzoate To a solution of 4- (azetidine -3- bases) -2- chloro- 6- methylbenzoate TFA (1.296 g, 3.66 mmol) and 1,3- dichloro- 2- iodobenzene (1 g, 3.66 mmol) in anhydrous 1,4- dioxane (10 mL) is added cesium carbonate (3.58 g, 10.99 mmol). The reaction mixture is then degassed with nitrogen for 10 min, then RuPhos Pd G3 (0.306 g, 0.366 mmol) is added and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give methyl 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzoate (574 mg, 41.2% yield) as a yellow solid; LCMS Method 2, LCMS (ESI, m / z): 385.8 [M+H] + .

[0491] Synthesis of (2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylphenyl)methanol To a stirred solution of methyl 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzoate (700 mg, 1.820 mmol) in DCM (10 mL) was added DIBAL-H (3.03 mL, 3.64 mmol) at -78 ° C and stirred for 4 h at -78 ° C. The reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with DCM (30 mL) and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate / petroleum ether 0-50% to give the title compound (2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylphenyl)methanol (565 mg, 87% yield) as a white semisolid; LCMS Method 3, LCMS (ESI, m / z): 357.8 [M+H] + .

[0492] Synthesis of 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde To a stirred solution of (2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylphenyl)methanol (580 mg, 1.626 mmol) in DCM (10 mL) was added Dess-Martin periodinane (828 mg, 1.951 mmol) at 0° C. under a nitrogen atmosphere. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) (eluted with 0-20% ethyl acetate in petroleum ether) to afford 2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde (467 mg, 81%) as a yellow solid; LCMS method 3, LCMS (ESI, m / z): 356.0 [M+H] + .

[0493] Synthesis of 1-(2-chloro-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol formate (49) To the stirring solution of 3-methylazetidine-3-ol TFA (102mg, 0.508mmol) in MeOH (5mL) is added sodium bicarbonate (71.1mg, 0.846mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth to produce free amine. Zinc chloride (86mg, 0.634mmol) is added to the free amine and 2-chloro-4-(1-(2,6-dichlorophenyl)azetidine-3-yl)-6-methylbenzaldehyde (150mg, 0.423mmol) in 5mL MeOH and stirred for 1h at 25°C. After 1h, sodium cyanoborohydride (26.6mg, 0.423mmol) is added and heated to 65°C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250×21.2) mm, 10 micron). Mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile). The desired 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 semisolid.

[0494] 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] + . Example S50. 1-(2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (50)

[0495] Synthesis of tert-butyl 3-(3-cyclopropyl-4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate To a suspension of activated zinc (6.41g, 98mmol) in anhydrous DMF (30mL) was added 1,2-dibromoethane (0.422ml, 4.90mmol) and heated to 75°C. After 15min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.285ml, 2.229mmol) was added and stirred at ambient temperature for another 30min. A solution of tert-butyl 3-iodine azetidine-1-formate (8.32g, 29.4mmol) in 10mL anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30min, followed by addition of methyl 4-bromo-2-cyclopropylbenzoate (2.5g, 9.80mmol) and XPhos Pd G4 (1.265g, 1.470mmol) in 10mL DMF. The reaction mixture was stirred at 80°C for 2h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was passed through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) (eluted with 0-50% ethyl acetate / petroleum ether) to afford tert-butyl 3-(3-cyclopropyl-4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (1.72 g, 53.2% yield) as a yellow semisolid; LCMS method 1, LCMS (ESI, m / z): 232.0 [M-100] + .

[0496] Synthesis of methyl 4-(azetidin-3-yl)-2-cyclopropylbenzoate To a stirred solution of tert-butyl 3-(3-cyclopropyl-4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (1.9 g, 5.73 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (4.0 mL, 51.9 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction progress was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to give methyl 4-(azetidine-3-yl)-2-cyclopropylbenzoate TFA (0.97 g, 53.9% yield) as a brown semisolid; LCMS method 1, LCMS (ESI, m / z): 232.2 [M+H] + .

[0497] Synthesis of Methyl 2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzoate To a solution of 4- (azetidine -3- bases) -2- cyclopropylbenzoic acid methyl esters 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) is added cesium carbonate (10.43 mmol). The reaction mixture is then degassed with nitrogen for 10 min, then Ruphos pd G3 (0.291 g, 0.348 mmol) is added and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (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] + .

[0498] Synthesis of (2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)methanol To a stirred solution of methyl 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzoate (700 mg, 1.860 mmol) in DCM (20 mL) was added DIBAL-H (3.72 mL, 3.72 mmol) in THF at -78 ° C and stirred for 4 h at -78 ° C. The reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with DCM (30 mL) and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate / petroleum ether 0-30% to give the title compound (2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)methanol (462 mg, 71.4% yield) as a yellow solid; LCMS Method 1, LCMS (ESI, m / z): 350.2 [M+2H] + .

[0499] Synthesis of 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzaldehyde To a stirred solution of (2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)phenyl)methanol (420 mg, 1.206 mmol) in DCM (10 mL) was added Dess-Martin periodinane (614 mg, 1.447 mmol) at 0 ° C under a nitrogen atmosphere. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) (eluted with 0-20% ethyl acetate / petroleum ether) to give 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzaldehyde (326 mg, 78% yield) as a yellow semisolid; LCMS method 2; LCMS (ESI, m / z): 348.1 [M+2H] + .

[0500] Synthesis of 1-(2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol (50) To the stirring solution of 3-methylazetidine-3-ol TFA salt (87mg, 0.433mmol) in MeOH (5mL), sodium cyanoborohydride (75mg, 0.88mmol) is added, and then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. Zinc chloride (59.0mg, 0.433mmol) is added to the free amine and 2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidine-3-yl) benzaldehyde (150mg, 0.433mmol) in 5mL MeOH and stirred for 1h at 25°C. After 1h, sodium cyanoborohydride (40.8mg, 0.65mmol) is added and heated to 65°C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic layer is dried over Na2SO4, filtered and the solvent is evaporated under reduced pressure. The residue was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250 x 21.2) mm, 10 micron; mobile phase A: 0.1% formic acid / water; mobile phase B: acetonitrile). The desired fractions were lyophilized to give 1-(2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)benzyl)-3-methylazetidin-3-ol formate (39.0 mg, 0.082 mmol, 18.89% yield, 97.2% purity) as an off-white semisolid.

[0501] 1H NMR (400MHz, MeOD): 7.32-7.37(m,1H),7.15-7.21(m,3H),6.74(t,J=8.00Hz,1H),4.34-4.39(m,4H),4.86(s,3H),3.84-3.86(m,2 H),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] + . Example S51. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzyl)-3-methylazetidin-3-ol (51)

[0502] Synthesis of tert-butyl 3-(3-ethyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (13.82g, 211mmol) in anhydrous DMF (40mL) was added 1,2-dibromoethane (0.121mL, 1.409mmol) and heated to 75°C. After 15min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.180mL, 1.409mmol) was added and stirred at ambient temperature for another 30min. A solution of tert-butyl 3-iodine azetidine-1-formate (9.97g, 35.2mmol) in 10mL anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30min, followed by addition of 4-bromo-2-ethyl-6-methylbenzaldehyde (3.2g, 14.09mmol) and XPhos Pd G4 (1.2g, 1.409mmol) in 20mL DMF. The reaction mixture was stirred at 80°C for 2h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 3-(3-ethyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate (3.0 g, 9.89 mmol, 70.2% yield) as a white solid; LCMS Method 1; LCMS (ESI, m / z): 204.2 [M-100] + .

[0503] Synthesis of 4-(azetidin-3-yl)-2-ethyl-6-methylbenzaldehyde To a stirred solution of tert-butyl 3-(3-ethyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate (1.0 g, 3.30 mmol) in anhydrous dichloromethane (20 mL) was added trifluoroacetic acid (1.524 mL, 19.78 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction process was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 4-(azetidine-3-yl)-2-ethyl-6-methylbenzaldehyde TFA (1.0 g, 89% yield) as a brown semi-solid; LCMS method 1; LCMS (ESI, m / z): 204.2 [M + H] + .

[0504] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2- ethyl -6- methylbenzaldehyde TFA (1.0 g, 3.15 mmol) and 1,3- dichloro -2- iodobenzene (1.032 g, 3.78 mmol) in anhydrous 1,4- dioxane (20 mL) is added CsCO (3.59 g, 11.03 mmol). The reaction mixture is then degassed with nitrogen for 10 min, followed by the addition of RuPhos Pd G3 (0.264 g, 0.315 mmol) and heated to 80 ° C. After 16 h, TLC analysis indicates the complete conversion of the starting material. The reaction mixture is then cooled to room temperature and filtered through a pad of celite, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (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] + .

[0505] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylphenyl)-3-methylazetidin-3-ol (51) To 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 stirred at 25° C. for 1 h. After 1 h, sodium cyanoborohydride (54.1 mg, 0.861 mmol) was added and 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, and the residue was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250x21.2) mm, 10 micron mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile). The desired fractions were lyophilized to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2-ethyl-6-methylphenyl)-3-methylazetidin-3-ol formate (13 mg, 0.028 mmol, 4.86% yield, 99.84% purity) as a white semisolid.

[0506] 1 H NMR (400 MHz, MeOD): δ7.22-7.19 (m, 4H), δ6.75-6.71 (t, J = 8 Hz, 1H), δ4.41-4.38 (t, J = 6.4 Hz, 2H), δ4.32 (s, 2H), δ3.88-3.86 (m, 2H), δ3.75-3.69 (m, 3H), δ2.84-2.78 (q, J = 7.6 Hz, 2H), δ2.47 (s, 3H), δ1.49 (s, 3H), δ1.26-1.22 (t, J = 7.6 Hz, 3H) (two protons combined with the solvent signal); LCMS method 1, LCMS (ESI, m / z): 419.2 [M+H] + . Example S52. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzyl)-3-methylazetidin-3-ol (52)

[0507] Synthesis of tert-Butyl 3-(3,5-diethyl-4-formylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (2.71 g, 41.5 mmol) in anhydrous DMF (30 mL) was added 1,2-dibromoethane (4.78 μL, 0.055 mmol) and heated to 75 ° C. After 15 min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (265 μL, 2.074 mmol) was added and stirred at ambient temperature for another 30 min. A solution of tert-butyl 3-iodine azetidine-1-formate (3.52 g, 12.44 mmol) in 10 mL of anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30 min, followed by addition of 4-bromo-2,6-diethylbenzaldehyde (1.0 g, 4.15 mmol) and XPhos Pd G4 (0.535 g, 0.622 mmol) in 20 mL of DMF. The reaction mixture was stirred at 80 ° C for 2 h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) (eluted with 0-50% ethyl acetate / petroleum ether) to afford tert-butyl 3-(3,5-diethyl-4-formylphenyl)azetidine-1-carboxylate (910 mg, 69.3% yield) as a yellow liquid; LCMS method 1, LCMS (ESI, m / z): 218.1 [M-100] + .

[0508] Synthesis of 4-(azetidin-3-yl)-2,6-diethylbenzaldehyde To a stirred solution of tert-butyl 3-(3,5-diethyl-4-formylphenyl)azetidine-1-carboxylate (950 mg, 2.99 mmol) in anhydrous dichloromethane (20 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction process was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 4-(azetidine-3-yl)-2,6-diethylbenzaldehyde TFA (800 mg, 2.390 mmol, 80% yield) as a yellow liquid; LCMS method 1; LCMS (ESI, m / z): 218.2 [M + H] + .

[0509] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- diethylbenzaldehyde TFA salt (1.1 g, 3.68 mmol) and 1,3- dichloro -2- iodobenzene (1206 mg, 4.42 mmol) in anhydrous 1,4- dioxane (20 mL) was added cesium carbonate (3.7 g, 11.04 mmol). The reaction mixture was then degassed with nitrogen for 10 min, followed by addition of RuPhos Pd G3 (308 mg, 0.368 mmol) and heated to 80 ° C. After 16 h, TLC analysis indicated the complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzaldehyde (365 mg, 27.3% yield) as a light yellow solid; LCMS Method 1, LCMS (ESI, m / z): 362.0 [M+H] + .

[0510] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzyl)-3-methylazetidin-3-ol (52) To the stirring solution of 3-methylazetidine-3-ol TFA salt (250mg, 1.242mmol) in MeOH (5mL) is added sodium bicarbonate (208mg, 2.484mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. Zinc chloride (169mg, 1.242mmol) is added to the free amine and 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2,6- diethylbenzaldehyde (450mg, 1.242mmol) in 5mL MeOH and stirred for 1h at 25 DEG C. After 1h, sodium cyanoborohydride (117mg, 1.863mmol) is added and heated to 65 DEG C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250×21.2) mm, 10 micron) mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile). The desired fractions were lyophilized to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diethylbenzyl)-3-methylazetidine carboxylate (201.2 mg, 0.415 mmol, 33.4% yield, 98.9% purity) as a white semisolid.

[0511] 1 H NMR (400 MHz, MeOD): 7.14-7.20 (m, 2H), 6.72-6.74 (m, 2H), 6.70 (m, 1H), 4.38-4.40 (m, 2H), 3.73-3.90 (m, 2H), 3.69-3.72 (m, 1H), 3.40 (m, 2H), 3.28-3.33 (m, 2H), 2.78-2.84 (m, 4H), 1.45 (s, 3H), 1.23 (t, J = 7.60 Hz, 6H) (two protons combined with the solvent signal); LCMS method 2; LCMS (ESI, m / z): 433.2 [M+H] + . Example S53. 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diisopropylbenzyl)-3-methylazetidin-3-ol (53)

[0512] Synthesis of tert-Butyl 3-(4-Formyl-3,5-diisopropylphenyl)azetidine-1-carboxylate To a suspension of activated zinc (2.91g, 44.6mmol) in anhydrous DMF (30mL) was added 1,2-dibromoethane (0.192ml, 2.229mmol) and heated to 75°C. After 15min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.285ml, 2.229mmol) was added and stirred at ambient temperature for another 30min. A solution of tert-butyl 3-iodine azetidine-1-formate (3.79g, 13.37mmol) in 10mL anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30min, followed by addition of 4-bromo-2,6-diisopropylbenzaldehyde (1.2g, 4.46mmol) and XPhos Pd G4 (0.575g, 0.669mmol) in 20mL DMF. The reaction mixture was stirred at 80°C for 2h. After the reaction was complete, the reaction was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 3-(4-formyl-3,5-diisopropylphenyl)azetidine-1-carboxylate (841 mg, 54.5% yield); LCMS method 1, LCMS (ESI, m / z): 246.2 [M-100] + .

[0513] Synthesis of 4-(azetidin-3-yl)-2,6-diisopropylbenzaldehyde To a stirred solution of tert-butyl 3-(4-formyl-3,5-diisopropylphenyl)azetidine-1-carboxylate (1.15 g, 3.33 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (2.0 mL, 26.0 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction process was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 4-(azetidine-3-yl)-2,6-diisopropylbenzaldehyde TFA (1.04 g, 87% yield) as a brown semi-solid; LCMS method 2; LCMS (ESI, m / z): 246.1 [M + H] + .

[0514] Synthesis of 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diisopropylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2,6- diisopropylbenzaldehyde TFA salt (836 mg, 2.445 mmol) and 1,3- dichloro -2- iodobenzene (801 mg, 2.93 mmol) in anhydrous 1,4- dioxane (20 mL) was added cesium carbonate (7.34 mmol). The reaction mixture was then degassed with nitrogen for 10 min, followed by the addition of RuPhos Pd G3 (205 mg, 0.245 mmol) and heated to 80 ° C. After 16 h, TLC analysis indicated the complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a pad of celite, washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diisopropylbenzaldehyde (207 mg, 21.69% yield) as a light yellow semisolid; LCMS Method 1, LCMS (ESI, m / z): 390.2 [M+H] + .

[0515] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diisopropylbenzyl)-3-methylazetidin-3-ol (53) To the stirring solution of 3-methylazetidine-3-ol TFA salt (232mg, 1.153mmol) in MeOH (5mL) is added sodium bicarbonate (193mg, 2.3mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. Zinc chloride (157mg, 1.153mmol) is added to the free amine and 4- (1- (2,6- dichlorophenyl) azetidine -3- bases) -2,6- diisopropylbenzaldehyde (450mg, 1.153mmol) in 5mL MeOH and stirred for 1h at 25 DEG C. After 1h, sodium cyanoborohydride (109mg, 1.729mmol) is added and heated to 65 DEG C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40; column: Luna C18 (250×21.2) mm, 10 micron) mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile). The desired fractions were lyophilized to give 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-diisopropylbenzyl)-3-methylazetidin-3-ol formate (194.9 mg, 0.373 mmol, 32.4% yield, 97.2% purity) as a white semisolid.

[0516] 1 H NMR (400 MHz, MeOD): 7.34 (s, 2H), 7.20-7.22 (m, 2H), 6.73-6.77 (m, 1H), 4.93 (s, 2H), 4.36-4.40 (m, 2H), 4.21 (s, 2H), 3.68-3.77 (m, 3H), 3.54-3.56 (m, 2H), 3.38 (m, 2H), 1.48 (s, 3H), 1.28-1.33 (m, 12H); LCMS method 1, LCMS (ESI, m / z): 461.2 [M+H] + . Example S54. 1-(2-Cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol (54)

[0517] Synthesis of tert-butyl 3-(3-cyclopropyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate To a suspension of activated zinc powder (4.37g, 66.9mmol) in anhydrous DMF (20mL) was added 1,2-dibromoethane (0.126g, 0.669mmol) and heated to 75°C. After 15min, the reaction mixture was cooled to room temperature, trimethylsilyl chloride (0.073g, 0.669mmol) was added and stirred at ambient temperature for another 30min. A solution of tert-butyl 3-iodine azetidine-1-formate (5.68g, 20.07mmol) in 5mL anhydrous DMF was then added to the reaction mixture and stirred at room temperature for another 30min, followed by addition of 4-bromo-2-cyclopropyl-6-methylbenzaldehyde (1.6g, 6.69mmol) and XPhos Pd G4 (0.576g, 0.669mmol) in 10mL DMF. The reaction mixture was stirred at 80°C for 2h. After the reaction was complete, the reaction mixture was cooled to ambient temperature and quenched with a saturated ammonium chloride solution. The crude material was filtered through a pad of celite and washed with ethyl acetate. The filtrate was then transferred to a separatory funnel and washed with cold water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (100-200 mesh) eluting with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 3-(3-cyclopropyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate (0.858 g, 40.7% yield); LCMS method 1; LCMS (ESI, m / z): 216.1 [M-100] + .

[0518] Synthesis of 4-(azetidin-3-yl)-2-cyclopropyl-6-methylbenzaldehyde To a stirred solution of tert-butyl 3-(3-cyclopropyl-4-formyl-5-methylphenyl)azetidine-1-carboxylate (1 g, 3.17 mmol) in anhydrous dichloromethane (30 mL) was added trifluoroacetic acid (0.733 mL, 9.51 mmol) at 0 ° C. The reaction mixture was then stirred at ambient temperature and the reaction process was monitored by TLC analysis. After 1 h, TLC analysis indicated complete conversion of the starting material. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with ether to obtain 4-(azetidine-3-yl)-2-cyclopropyl-6-methylbenzaldehyde TFA (0.82, 79% yield) as a yellow solid; LCMS method 1, LCMS (ESI, m / z): 216.0 [M + H] + .

[0519] Synthesis of 2-chloropropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde To a solution of 4- (azetidine -3- bases) -2- cyclopropyl -6- methylbenzaldehyde TFA (724 mg, 2.199 mmol) and 1,3- dichloro -2- iodobenzene (600 mg, 2.199 mmol) in anhydrous 1,4- dioxane (20 mL) was added cesium carbonate (2149 mg, 6.60 mmol). The reaction mixture was degassed with nitrogen for 10 min, then RuPhos Pd G3 (92 mg, 0.110 mmol) was added and heated to 80 ° C. After 16 h, TLC analysis indicated the complete conversion of the starting material. The reaction mixture was then cooled to room temperature and filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (230-400 mesh) eluting with 0-50% ethyl acetate in petroleum ether to give 2-chloropropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzaldehyde (400 mg, 0.910 mmol, 41.4% yield) as a yellow solid; LCMS Method 1, LCMS (ESI, m / z): 360.0 [M+H] + .

[0520] Synthesis of 1-(2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol (54) To the stirring solution of 3-methylazetidine-3-ol TFA (84mg, 0.416mmol) in MeOH (5mL) is added sodium bicarbonate (70.0mg, 0.833mmol), then stirred at room temperature for 1h. The mixture is filtered through diatomaceous earth and concentrated to produce free amine. Zinc chloride (68.1mg, 0.500mmol) is added to the free amine and 2-chloropropyl-4-(1-(2,6-dichlorophenyl)azetidine-3-yl)-6-methylbenzaldehyde (150mg, 0.416mmol) in 5mL MeOH and stirred for 1h at 25°C. After 1h, sodium cyanoborohydride (52.4mg, 0.832mmol) is added and heated to 65°C for 12h. The reaction mixture is diluted with dichloromethane (10mL) and washed with saturated ammonium chloride solution and water (20mL). The combined organic layers were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure. The crude material was purified by preparative HPLC (diluent: THF:water:ACN (50:10:40); column-1: Xbridge C8 (250 x 19) mm, 5 microns; mobile phase A: 0.1% formic acid / water; mobile phase B: acetonitrile). The desired fractions were lyophilized to give 1-(2-cyclopropyl-4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-6-methylbenzyl)-3-methylazetidin-3-ol formate (30 mg, 0.062 mmol, 14.94% yield, 99% purity) as an off-white solid.

[0521] 1 H NMR (400 MHz, MeOD): δ 7.21 (t, J = 8.00 Hz, 3H), 7.01 (s, 1H), 6.74 (t, J = 7.60 Hz, 1H), 4.51 (s, 2H), 4.35-4.38 (m, 2H), 3.91-3.93 (m, 2H), 3.81 (m, 2H), 3.65-3.81 (m, 1H), 2.47 (s, 3H), 2.11-2.17 (m, 1H), 1.51 (s, 3H), 1.06-1.11 (m, 2H), 0.74-0.77 (m, 2H) (2H combined with solvent signal); LCMS method 1, LCMS (ESI, m / z): 433.2 [M+2H] + . Example S55. 1-((4-(1-(2,6-di...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is -C≡C-, -HC=CH-, -CH2CH2-, -CH2O-, or key; Each R 1 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; x is 0-5; R 2 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 haloalkyl; R 3a and R 3b Each is H; or R 2 and R 3a Together with the carbon atoms to which they are attached, they form a fused cyclopentyl group; or R 2 and R 4 Together with the carbon atoms to which they are attached, they form fused phenyl groups; R 4 is H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X 1 and X 2 N or CR independently 5 ; Each R 5 are independently H, halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 6 is H; R 7 is C1-C6 alkyl-OH; or R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form n R 8 a 4- to 6-membered heterocyclic group substituted with a radical; n is 1-5; and Each R 8 are independently halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -OH, The condition is that at least one R 8 It is -OH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: L is -C≡C-, -CH2CH2-, -CH2O- or a bond.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: L is 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C6 cycloalkyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: for 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: R 2 is H, halo, C1-C3 alkyl, C3-C6 cycloalkyl or C1-C3 haloalkyl; and R 3a and R 3b Each is H.

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

8. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 4 Together with the carbon atoms to which they are attached they form a fused phenyl group.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: R 4 It is H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C6 cycloalkyl.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein: Each R 5 are independently H, halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C6 cycloalkyl.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: for 12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein: R 6 is H; and R 7 It is C1-C6 alkyl-OH.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 Together with the nitrogen atoms to which they are attached, they form as well as Each R 8 are independently halo, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or -OH.

14. The compound according to any one of claims 1 to 11 and 13 or a pharmaceutically acceptable salt thereof, wherein: for 15. A compound according to any one of claims 1-5, 7 and 9-14 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II):

16. A compound according to any one of claims 1-6 and 8-14 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

17. A compound selected from the group consisting of the compounds listed 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 sphingosine-1-phosphate receptor 5 (S1P5), comprising contacting S1P5 with 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.

20. A method for treating a nervous system disease in a subject in need thereof, 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, optionally wherein the nervous system disease is Alzheimer's disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis.

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