Heterocyclic compounds as modulators of S1P5

Abstract

The present application provides compounds and compositions thereof for modulating S1P5. In some embodiments, compounds and compositions are provided for the treatment of neurological diseases.

Description

Cross - Reference to Related Applications

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 433,230, filed on December 16, 2022, which is incorporated herein by reference in its entirety for any purpose. Technical Field

[0002] This application generally relates to compounds, compositions, methods for preparing them, and the use of such compounds and compositions for treating nervous system diseases. Background Art

[0003] Sphingosine - 1 - phosphate (S1P; (2S,3R,4E)-2 - amino - 3 - hydroxyoctadec - 4 - enyl - 1 - phosphate) is a bioactive sphingolipid that is synthesized by the metabolic conversion of intracellular sphingolipids and the extracellular action of secreted sphingosine kinases. S1P binds to and stimulates members of the endothelial differentiation gene family of receptors (EDG receptors), which are G - protein - coupled receptors located in the plasma membrane. 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 numerous cellular responses, including proliferation, cytoskeletal organization and migration, assembly of adherens junctions and tight junctions, and morphogenesis.

[0004] S1P5 is mainly expressed in the central nervous system. In particular, S1P5 is highly expressed in oligodendrocytes (oligodendroglia) and oligodendrocyte progenitor cells (Jaillard, C. et al., J. Neuroscience, 2005, 25(6), 1459 - 1469; Novgorodov, A.S. et al., FASEB J., 2007, 21, 1503 - 1514). Oligodendrocytes are a type of glial cell that forms myelin (myelin sheath) by binding to the axons of nerve cells. Compounds that bind to S1P5 can modulate the function of S1P5 and can be used to treat neurodegenerative diseases.

[0005] Thus, in one aspect, this application provides compounds that modulate S1P5 for treating neurodegenerative diseases. Summary of the Invention

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

[0007] The embodiments of this application can be more fully understood by reference to specific embodiments and examples that are intended to illustrate non - limiting embodiments.

[0008] Embodiment A1 is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 each independently is C1-C6 alkyl, C3-C6 cycloalkyl or halo; R 2 each independently is halo, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 haloalkyl; x is 0-4; R 3 and R 4 each independently is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , wherein each cycloalkyl is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group optionally substituted with 1-5 R 7 groups, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O; R 5a and R 5b each independently is H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; R 6a and R 6b each independently is H or C1-C6 alkyl; and R 7 each independently is halo, C1-C6 alkyl, -OH, C1-C6 alkoxy or -NR 6a R 6b .

[0009] Embodiment A2 is the compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein: R 1 each independently is C1-C3 alkyl, C3-C6 cycloalkyl or halo.

[0010] Embodiment A3 is the compound according to Embodiment A1 or A2 or a pharmaceutically acceptable salt thereof, wherein: R 1 are each independently -CH3, cyclopropyl, F, Cl or Br.

[0011] Embodiment A4 is the compound according to any one of Embodiments A1 - A3 or a pharmaceutically acceptable salt thereof, wherein: R 1 are each Cl.

[0012] Embodiment A5 is the compound according to any one of Embodiments A1 - A4 or a pharmaceutically acceptable salt thereof, wherein: x is 1 - 4; and R 2 are each independently a halogen group, C1 - C3 alkyl, C1 - C3 alkoxy, C3 - C6 cycloalkyl or C1 - C3 haloalkyl.

[0013] Embodiment A6 is the compound according to Embodiment A5 or a pharmaceutically acceptable salt thereof, wherein: x is 2 or 3; and R 2 are each independently Cl, F, -CH3, -OCH3, cyclopropyl or -CF3.

[0014] Embodiment A7 is the compound according to Embodiment A6 or a pharmaceutically acceptable salt thereof, wherein: x is 2; and R 2 are each -CH3.

[0015] Embodiment A8 is the compound according to any one of Embodiments A1 - A7 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are independently H, C1 - C5 alkyl, C1 - C3 alkyl - OH, -(C1 - C3 alkylene)-O-(C1 - C3 alkyl), C3 - C6 cycloalkyl, -(C1 - C3 alkylene)(C3 - C6 cycloalkyl) or -(C1 - C3 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1 - 2 groups selected from halogen group, C1 - C3 alkyl, C1 - C3 haloalkyl, -OH, -NR 6a R 6b and C1 - C3 alkoxy; R 5a and R 5b are each independently H or C1 - C3 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group; and R 6a and R 6b are each independently H or C1-C3 alkyl.

[0016] Embodiment A9 is the compound according to Embodiment A8 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl) or -CH2CH2(pyrrolidinyl), wherein each cycloalkyl is optionally substituted with a group selected from -OH and -N(CH3)2.

[0017] Embodiment A10 is the compound according to Embodiment A9 or a pharmaceutically acceptable salt thereof, wherein: is

[0018] Embodiment A11 is the compound according to any one of Embodiments A1-A7 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group optionally substituted with 1-2 R 7 groups, wherein the heterocyclic group optionally contains an additional heteroatom selected from N and O; R 7 are each independently halo, C1-C3 alkyl, -OH, C1-C3 alkoxy or -NR 6a R 6b ; and R 6a and R 6b are each independently H or C1-C3 alkyl.

[0019] Embodiment A12 is the compound according to Embodiment A11 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group optionally substituted with one R 7A group-substituted 5- to 6-membered heterocyclic group, wherein the heterocyclic group optionally contains an additional heteroatom selected from N and O; and R 7 is -OH, -CH3, -OCH3 or -N(CH3)2.

[0020] Embodiment A13 is a compound according to Embodiment A12 or a pharmaceutically acceptable salt thereof, wherein: is

[0021] Embodiment A14 is a compound according to any one of Embodiments A1 - A13 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):

[0022] Embodiment A15 is a compound according to any one of Embodiments A1 - A14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIa): wherein: R 3 is H or C1-C6 alkyl; R 4 is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1 - 5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; R 5a and R 5b are independently H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; and R 6a and R 6b are each independently H or C1-C6 alkyl.

[0023] Embodiment A16 is a compound according to any one of Embodiments A1 - A14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IVa): Wherein is a 4- to 6-membered heterocyclic group.

[0024] Embodiment A17 is a compound selected from the compounds in Table 1 and a pharmaceutically acceptable salt thereof.

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

[0026] Embodiment A19 is a method of modulating sphingosine 1-phosphate receptor 5 (S1P5), which comprises contacting S1P5 with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A1-A17 or a pharmaceutical composition according to Embodiment A18.

[0027] Embodiment A20 is a method of treating a subject in need of treatment for a neurological disorder, which comprises administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A1-A17 or a pharmaceutical composition according to Embodiment A18, optionally wherein the neurological disorder is Alzheimer's disease or multiple sclerosis. Specific Embodiments Definitions

[0028] As used in this application, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" shall be construed as defining the presence of the recited features or components, but not excluding the presence or addition of one or more features or components or groups thereof. Additionally, the terms "comprising" and "including" are intended to include the instances covered by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide a more specific embodiment of the invention.

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

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

[0031] In the specification of the present application, unless otherwise specified, any concentration range, percentage range, ratio range or integer range shall be understood to include any integer value within the said range and, where appropriate, its fractions (e.g., one-tenth and one-hundredth of an integer). In addition, unless otherwise specified, any numerical range related to any physical characteristic (such as polymer subunit, dimension or thickness) described in the present application shall be understood to include any integer within the said range. Unless otherwise specified, as used in the present application, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value or structure.

[0032] An "alkyl" group is a saturated, partially saturated or unsaturated straight-chain or branched-chain acyclic hydrocarbon having 1 to 10 carbon atoms (C1-C 10alkyl), typically 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 2 to 6 carbon atoms (C2-C6 alkyl). In some embodiments, 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-chain alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), and the like. The alkyl group may be substituted or unsubstituted. When the alkyl group described in this application is referred to as "substituted", it may be substituted by any substituent, such as those found in the exemplary compounds and embodiments disclosed in this application, as well as halogen; hydroxy; alkoxy; cycloalkoxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkoxy, cycloalkylalkoxy, arylalkoxy, heterocyclylalkoxy, heteroarylalkoxy, heterocycloalkylalkoxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino, arylalkylamino, heterocyclylalkylamino, heteroarylalkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazino; acylhydrazino; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when an alkyl group as described in this application is referred to as "substituted", it can be substituted with any substituent, such as those found in the exemplary compounds and embodiments disclosed in this application, and halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

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

[0034] The "alkylene" group refers to a residue that is the same as alkyl but divalent. Specific alkylene groups are those having 1 to 10 carbon atoms (C1-C 10 alkylene), usually 1 to 8 carbon atoms (C1-C8 alkylene), or in some embodiments 1 to 6 carbon atoms (C1-C6 alkylene) or 1 to 3 carbon atoms (C1-C3 alkylene). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylidene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), etc.

[0035] The "cycloalkyl" group is a saturated or partially saturated cyclic alkyl having 3 to 10 carbon atoms with a single ring or multiple fused or bridged rings that can be optionally substituted (C3-C 10cycloalkyl). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), and in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), from 3 to 6 (C3-C6 cycloalkyl), or from 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl is a saturated cycloalkyl. Such saturated cycloalkyls include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and similar groups; or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and similar groups. In other embodiments, the cycloalkyl is an unsaturated cycloalkyl. Examples of unsaturated cycloalkyls particularly include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl can be substituted or unsubstituted. Such substituted cycloalkyls include, for example, cyclohexanol and similar groups.

[0036] The "aryl" group is an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl) with 6 to 14 carbon atoms (C6-C 14 aryl). In some embodiments, the aryl contains 6 to 14 carbon atoms (C6-C 14 aryl) in the ring portion of the group, and in other embodiments contains 6 to 12 carbon atoms (C6-C 12 aryl) or even 6 to 10 carbon atoms (C6-C 10 aryl). Specific aryls include phenyl, biphenyl, naphthyl, etc. The aryl can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and similar groups).

[0037] "Halogen" or "halo" is fluorine, chlorine, bromine, or iodine.

[0038] "Haloalkyl" refers to an alkyl group as defined above, which is substituted by one or more halo groups 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 by one or more halo groups (C1-C6 haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted by one or more halo groups (C1-C3 haloalkyl). The halo groups can be all the same, or the halo groups can be different. Unless otherwise specifically stated, the haloalkyl group can be optionally substituted.

[0039] A "heteroaryl" group is an aromatic ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl contains 3 to 6 ring atoms in the ring portion of the group, and in other embodiments contains 6 to 9 atoms or even 6 to 10 atoms. 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, the following groups, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furyl, benzofuryl, indolyl (e.g., indol-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. The heteroaryl group may be substituted or unsubstituted.

[0040] "Heterocyclic group" is a non-aromatic cycloalkyl group in which 1 to 4 ring carbon atoms are independently substituted with heteroatoms selected from O, S, and N. In some embodiments, the heterocyclic group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclic group can also be bonded to other groups at any ring atom (i.e., at any carbon or heteroatom of the heterocycle). The heterocycloalkyl group can be substituted or unsubstituted. The heterocyclic group includes saturated as well as partially saturated ring systems. Further, regardless of the connection to the rest of the molecule, the term heterocyclic group is intended to encompass any non-aromatic ring containing at least one heteroatom, which can be fused to an aryl or heteroaryl ring. The phrase also includes bridged polycyclic systems containing heteroatoms. Representative examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thioxanyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups can be mono-substituted or substituted more than once, e.g., but not limited to, pyridyl or morpholinyl groups, which are 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted or disubstituted with, for example, the multiple substituents listed below.

[0041] "Alkoxy" group is -O-(alkyl), where alkyl is as defined above.

[0042] "Carboxyl" group is a group of the formula -C(O)OH.

[0043] When the groups (except for alkyl groups) described in the present application are referred to as "substituted", they may be substituted by any suitable one or more substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed in the present application, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclic, 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 aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuryl); aryloxy; aralkyloxy; heterocycloxy; and heterocycloalkoxy.

[0044] Embodiments of the present application are intended to cover pharmaceutically acceptable salts, tautomers, isotopomers and stereoisomers of the compounds provided in the present application (such as compounds of formula (I)).

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases as well as organic acids and 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'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic acids and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, 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, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid and methanesulfonic acid. Thus, examples of specific salts include hydrochloride, formate and mesylate. Other salts known in the art can be found, for example, in 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).

[0046] As used in this application and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to a stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. Typical stereoisomerically pure compounds contain 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, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed in this application may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed in this application, including mixtures thereof.

[0047] The embodiments disclosed in the present application cover the use of stereoisomerically pure forms of the compounds disclosed in the present application and the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed in the present application. These isomers can be prepared by asymmetric synthesis 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, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0048] It should also be noted that the compounds disclosed in the present application can include E isomers and Z isomers or mixtures thereof, as well as cis isomers and trans isomers or mixtures thereof. In certain embodiments, the compounds are isolated as E isomers or Z isomers. In other embodiments, the compounds are mixtures of E isomers and Z isomers.

[0049] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound exists and may vary, for example, depending on whether the compound is a solid or is in an organic or aqueous solution. For example, in an aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0050] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present application.

[0051] It should also be noted that the compounds disclosed in the present application may contain non-natural proportions of atomic isotopes on one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, for example, enriched with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N). As used in the present application, "isotopologues" are isotopically enriched compounds. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of that 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 that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are used as therapeutic agents (e.g., cancer therapeutic agents), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the compounds described in the present application, whether radioactive or not, are intended to be covered within the scope of the embodiments provided in the present application. In some embodiments, isotopologues of the compounds disclosed in the present application are provided, for example, the isotopologues are compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used in the present application, "deuterated" means a compound in which at least one hydrogen (H) has been replaced with deuterium (represented by D or 2 H), i.e., the compound is enriched with deuterium at at least one position.

[0052] It should be understood that, regardless of the stereoisomeric composition or isotopic composition, each compound disclosed in the present application can be provided in the form of any pharmaceutically acceptable salt discussed in the present application. Similarly, it should be understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound mentioned in the present application. In addition, although the isotopic composition is limited to those elements present in the corresponding compounds or their salts disclosed in the present application, it can vary in other ways independently of the selection of the pharmaceutically acceptable salts of the corresponding compounds.

[0053] It should be noted that if there is an inconsistency between the described structure and the name of the structure, the described structure shall prevail.

[0054] As used in the present application, "treating" means the complete or partial remission of a disorder, disease or condition or one or more symptoms associated with the disorder, disease or condition, or slowing or preventing the further progression or worsening of those symptoms, or alleviating or eradicating the cause of the disorder, disease or condition itself. In one embodiment, the disorder is a neurodegenerative disease or its symptoms as described in the present application.

[0055] As used in the present application, "preventing" means delaying and / or preventing the full or partial onset, recurrence or spread of a disorder, disease or condition; preventing a subject from suffering from a disorder, disease or condition; or a method of reducing the risk of a subject suffering from a disorder, disease or condition. In one embodiment, the disorder is a neurodegenerative disease or its symptoms as described in the present application.

[0056] The term "effective amount" in relation to the compounds disclosed in the present application means an amount capable of treating or preventing the disorders, diseases or conditions or their symptoms disclosed in the present application.

[0057] As used in the present application, the term "subject" or "patient" includes animals, including but not limited to the following animals: for example, cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, in one embodiment a mammal, and in another embodiment a human. In one embodiment, the subject is a human suffering from or at risk of suffering from an S1P5-mediated disease or its symptoms.

[0058] Although various features of the present 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 present invention may be described in the context of separate embodiments of the present application for clarity, the present invention may also be implemented in a single embodiment. Compound

[0059] In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: R 1 are each independently a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a halogen group; R 2 are each independently a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group or a C1-C6 haloalkyl group; x is 0-4; R 3 and R 4 are each independently H, a C1-C6 alkyl group, a C1-C6 alkyl-OH group, -(C1-C6 alkylene)-O-(C1-C6 alkyl) group, a C3-C6 cycloalkyl group, -(C1-C6 alkylene)(C3-C6 cycloalkyl) group or -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl group is optionally substituted with 1-5 groups selected from a halogen group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, -OH, -NR 6a R 6b and a C1-C6 alkoxy group; or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group optionally substituted with 1-5 R 7 groups, where the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O; R 5a and R 5b are each independently H or a C1-C6 alkyl group; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; R 6a and R 6b are each independently H or a C1-C6 alkyl group; and R 7 are each independently a halogen group, a C1-C6 alkyl group, -OH, a C1-C6 alkoxy group or -NR 6a R 6b .

[0060] In some embodiments, R 1 are each independently a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a halogen group. In some embodiments, R 1 are each independently a C1-C3 alkyl group, a C3-C6 cycloalkyl group, F, Cl, Br or I. In some embodiments, R 1Each is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl or Br. In some embodiments, R 1 Each is independently methyl, cyclopropyl, F, Cl or Br. In some embodiments, R 1 is Cl.

[0061] In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 is a C1-C3 alkyl group. In some embodiments, R 1 is -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 1 is -CH3.

[0062] In some embodiments, R 1 is a C3-C6 cycloalkyl group. In some embodiments, R 1 is a C3-C5 cycloalkyl group. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 1 is cyclopropyl.

[0063] In some embodiments, R 1 is a halogen group. In some embodiments, R 1 is F, Cl, Br or I. In some embodiments, R 1 is F, Cl or Br. In some embodiments, R 1 is Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is Br.

[0064] In some embodiments, R 2 Each is independently a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group or a C1-C6 haloalkyl group. In some embodiments, R 2 Each is independently a halogen group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group or a C1-C3 haloalkyl group. In some embodiments, R 2 Each is independently F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a C1 haloalkyl group. In some embodiments, R 2Each is independently F, Cl, -CH3, -OCH3, cyclopropyl, -CH2F, -CHF2 or -CF3. In some embodiments, R 2 Each is independently F, Cl, -CH3, -OCH3, cyclopropyl or -CF3. In some embodiments, R 2 is -CH3.

[0065] In some embodiments, R 2 is a halogen group. In some embodiments, R 2 is F, Cl, Br or I. In some embodiments, R 2 is F or Cl. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl.

[0066] In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 is a C1-C3 alkyl group. In some embodiments, R 2 is -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3.

[0067] In some embodiments, R 2 is a C1-C6 alkoxy group. In some embodiments, R 2 is a C1-C3 alkoxy group. In some embodiments, R 2 is -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 2 is OCH3. In some embodiments, R 2 is -OCH2CH3.

[0068] In some embodiments, R 2 is a C3-C6 cycloalkyl group. In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 2 is cyclopropyl.

[0069] In some embodiments, R 2 is a C1-C6 haloalkyl group. In some embodiments, R 2 is a C1-C6 haloalkyl group containing 1-13 halogen atoms. In some embodiments, R 2 is a C1-C3 haloalkyl group. In some embodiments, R 2is a C1-C3 haloalkyl group containing 1-7 halogen atoms. In some embodiments, R 2 is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2 or -CH2CCl3. In some embodiments, R 2 is a C1 haloalkyl group. In some embodiments, R 2 is -CH2F, -CHF2 or -CF3. In some embodiments, R 2 is -CF3.

[0070] In some embodiments, x is 0-4. In some embodiments, x is 2 or 3. 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.

[0071] In some embodiments, R 5a and R 5b are each independently H or a C1-C6 alkyl group. In some embodiments, R 5a and R 5b are each independently H or a C1-C3 alkyl group. In some embodiments, R 5a and R 5b are each independently H or -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 5a and R 5b are each H or -CH3. In some embodiments, R 5a and R 5b are each -CH3.

[0072] In some embodiments, R 5a and R 5b are each H.

[0073] In some embodiments, R 5a and R 5b are each independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b are each independently a C1-C3 alkyl group. In some embodiments, R 5a and R 5b are each independently -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 5a and R 5b are each -CH3.

[0074] In some embodiments, R5a and R 5b one of which is H and R 5a and R 5b the other of which is a C1-C6 alkyl group. In some embodiments, R 5a and R 5b one of which is H and R 5a and R 5b the other of which is a C1-C3 alkyl group, such as methyl, ethyl or propyl. In some embodiments, R 5a and R 5b one of which is H and R 5a and R 5b the other of which is methyl.

[0075] In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form a 5-membered heterocyclic group. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl or piperidinyl. In some embodiments, R 5a and R 5b together with the nitrogen atom to which they are attached form pyrrolidinyl.

[0076] In some embodiments, R 6a and R 6b are each independently H or a C1-C6 alkyl group. In some embodiments, R 6a and R 6b are each independently H or a C1-C3 alkyl group. In some embodiments, R 6a and R 6b are each independently H, -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 6a and R 6b are each independently H or -CH3. In some embodiments, R 6a and R 6b are each -CH3.

[0077] In some embodiments, R 6a and R 6b are each H.

[0078] In some embodiments, R6a and R 6b are each independently a C1-C6 alkyl group. In some embodiments, R 6a and R 6b are each independently a C1-C3 alkyl group. In some embodiments, R 6a and R 6b are each independently -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, R 6a and R 6b are each -CH3.

[0079] In some embodiments, one of R 6a and R 6b is H and the other of R 6a and R 6b is a C1-C6 alkyl group. In some embodiments, one of R 6a and R 6b is H and the other of R 6a and R 6b is a C1-C3 alkyl group, such as methyl, ethyl, or propyl. In some embodiments, one of R 6a and R 6b is H and the other of R 6a and R 6b is methyl.

[0080] In some embodiments, R 7 are each independently a halogen group, a C1-C6 alkyl group, -OH, a C1-C6 alkoxy group, or -NR 6a R 6b . In some embodiments, R 7 are each a halogen group, a C1-C3 alkyl group, -OH, a C1-C3 alkoxy group, or -NR 6a R 6b . In some embodiments, R 7 are each F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, or -NR 6a R 6b . In some embodiments, R 7 are each -OH, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R 7 are each a halogen group. In some embodiments, R 7 are each F, Cl, Br, or I.

[0081] In some embodiments, R 7is a C1-C6 alkyl group. In some embodiments, R 7 is a C1-C3 alkyl group. In some embodiments, R 7 is -CH3, -CH2CH3 or -CH2CH2CH3. In some embodiments, R 7 is -CH3.

[0082] In some embodiments, R 7 is -OH.

[0083] In some embodiments, R 7 is a C1-C3 alkoxy group. In some embodiments, R 7 is -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2. In some embodiments, R 7 is -OCH3.

[0084] In some embodiments, R 7 is -NR 6a R 6b . In some embodiments, R 7 is -N(CH3)2. In some embodiments, R 7 is -NH(CH3).

[0085] In some embodiments, R 3 and R 4 are each independently H, a C1-C6 alkyl group, a C1-C6 alkyl-OH group, a -(C1-C6 alkylene)-O-(C1-C6 alkyl) group, a C3-C6 cycloalkyl group, a -(C1-C6 alkylene)(C3-C6 cycloalkyl) group or a -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl group is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy groups. In some embodiments, R 3 and R 4 are each independently H, a C1-C5 alkyl group, a C1-C3 alkyl-OH group, a -(C1-C3 alkylene)-O-(C1-C3 alkyl) group, a C3-C6 cycloalkyl group, a -(C1-C3 alkylene)(C3-C6 cycloalkyl) group, or a -(C1-C3 alkylene)NR 5a R 5b , where each cycloalkyl group is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6band substituted by a group of C1-C6 alkoxy. In some embodiments, R 3 and R 4 are each independently H, C1-C5 alkyl, C1-C3 alkyl-OH, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl), or -(C1-C3 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted by 1-2 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy. In some embodiments, R 3 and R 4 are each independently H, C1-C5 alkyl, C1-C3 alkyl-OH, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl), or -(C1-C3 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted by 1-2 groups selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy. In some embodiments, R 3 and R 4 are each independently H, C1-C5 alkyl, C1-C3 alkyl-OH, -(C1-C2 alkylene)-O-(C1 alkyl), C3-C6 cycloalkyl, -(C1 alkylene)(C3-C6 cycloalkyl), or -(C2 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted by 1-2 groups selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy. In some embodiments, R 3 and R 4Each independently is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH(CH3)2, -CH2(CH3)CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH2CH2CH3, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2(CH3)CH2OH, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(cyclopentyl), -CH2(cyclohexyl), -CH2CH2NR 5a R 5b , where each cycloalkyl group is optionally substituted with 1 - 2 groups selected from halo, C1 - C3 alkyl, C1 - C3 haloalkyl, -OH, -NR 6a R 6b and C1 - C3 alkoxy. In some embodiments, R 3 and R 4 Each independently is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH(CH3)2, -CH2(CH3)CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH2CH2CH3, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2(CH3)CH2OH, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(cyclopentyl), -CH2(cyclohexyl), -CH2CH2NR 5a R 5b , where each cycloalkyl group is optionally substituted with one group selected from halo, C1 - C3 alkyl, C1 - C3 haloalkyl, -OH, -NR 6a R 6b and C1 - C3 alkoxy. In some embodiments, R 3 and R 4Each is independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OH, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl), -CH2CH2N(CH3)2, wherein each cycloalkyl is optionally substituted with a group selected from halo, C1-C3 alkyl, C1 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy. In some embodiments, R 3 and R 4 Each is independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OH, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl), -CH2CH2N(CH3)2, wherein each cycloalkyl is optionally substituted with a group selected from F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -OH, -NR 6a R 6b , -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2. In some embodiments, R 3 and R 4 Each is independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OH, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl), -CH2CH2N(CH3)2, wherein each cycloalkyl is optionally substituted with a group selected from -OH and -N(CH3)2.

[0086] In some embodiments, is:

[0087] In some embodiments, R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group optionally substituted with 1-5 R 7 groups, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O. In some embodiments, R 3 and R 4Together with the nitrogen atom to which they are attached, form an optionally 1-5 R 7 group-substituted 5- to 6-membered heterocyclic group, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O. In some embodiments, R 3 and R 4 Together with the nitrogen atom to which they are attached, form an optionally 1-2 R 7 group-substituted 5- to 6-membered heterocyclic group, wherein the heterocyclic group optionally contains one additional heteroatom selected from N and O. In some embodiments, R 3 and R 4 Together with the nitrogen atom to which they are attached, form an optionally one R 7 group-substituted 5- to 6-membered heterocyclic group, wherein the heterocyclic group optionally contains one additional heteroatom selected from N and O. In some embodiments, R 3 and R 4 Together with the nitrogen atom to which they are attached, form an optionally one R 7 group-substituted 5- to 6-membered heterocyclic group, wherein the heterocyclic group optionally contains one additional heteroatom selected from N and O; wherein R 7 is –OH, -CH3, -OCH3 or -N(CH3)2. In some embodiments, the heterocyclic group is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0088] In some embodiments, is:

[0089] In some embodiments, the compound of formula (I) is a compound of formula (II): wherein R 1 、R 2 、R 3 and R 4 are as described for formula (I).

[0090] In some embodiments, the compound of formula (I) is a compound of formula (III): wherein R 3 and R 4 are as described for formula (I).

[0091] In some embodiments, the compound of formula (I) is a compound of formula (IIIa): Wherein: R 3 is H or C1-C6 alkyl; R 4 is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , wherein each cycloalkyl is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; R 5a and R 5b are independently H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; and R 6a and R 6b are each independently H or C1-C6 alkyl.

[0092] In some embodiments, the compound of formula (I) is a compound of formula (IIIb) or formula (IIIc): Wherein: R 3 is C1-C6 alkyl; R 4 is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , wherein each cycloalkyl is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; R 5a and R 5b are independently H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; and R 6a and R6b Each independently is H or a C1-C6 alkyl group.

[0093] In some embodiments, the compound of formula (I) is a compound of formula (IV): wherein R 1 , R 2 , R 7 and x are as described for formula (I); and is a 4- to 6-membered heterocyclic group.

[0094] In some embodiments, the compound of formula (I) is a compound of formula (IVa): wherein R 7 is as described for formula (I); and is a 4- to 6-membered heterocyclic group.

[0095] In the description of the present application, it should be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts, as if each combination of the specifically and separately listed descriptions were the case. For example, each description, variation, embodiment or aspect of R 1 provided in the present application for formula (I) can be combined with each description, variation, embodiment or aspect of R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7 and x, as if each combination were specifically and separately listed. It should also be understood that, where applicable, all descriptions, variations, embodiments or aspects of formula (I) apply equally to the other formulas detailed in the present application and are equally described, as if each description, variation, embodiment or aspect were specifically and separately listed for all formulas. For example, where applicable, all descriptions, variations, embodiments or aspects of formula (I) apply equally to any formula detailed in the present application, such as formula (II), (III), (IIIa), (IIIb), (IIIIc), (IV) and (IVa) and are equally described, as if each description, variation, embodiment or aspect were specifically and separately listed for all formulas.

[0096] In some embodiments, the present application provides a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. It should be understood that the present application describes any and all stereochemical forms (including any enantiomeric or diastereomeric forms) of any compound of the present application (including those in Table 1), as well as any tautomers or other forms. Table 1. or a pharmaceutically acceptable salt thereof.

[0097] It should be understood that in the specification of the present application, combinations of substituents and / or variables of the described formulae are permitted only if such combinations result in stable compounds.

[0098] In addition, all compounds of formula (I) in the free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with appropriate inorganic or organic bases or inorganic or organic acids by methods known to those skilled in the art. The salts of the compounds of formula (I) can be converted into their free base or free acid form by standard techniques. Synthetic methods

[0099] The compounds described in the present application can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided in the present application. By way of example and not limitation, the compounds of formula (I) can be prepared by the procedures outlined in Schemes 1 and 2 and the procedures outlined in the examples described in the present application. It should be noted that those skilled in the art will know how to modify the procedures set forth in the illustrative schemes and examples to obtain the desired products. Scheme 1. wherein X is a halogen group (such as Br); and R 1 、R 2 and x are as defined for formula (I).

[0100] Scheme 1 shows the synthetic route of acid intermediate I, which can be used to prepare the compounds of formula (I). Reductive amination of a and b gives c, which is then coupled with d under, for example, palladium-catalyzed conditions to form e. Acid deprotection of e gives amine f, and f is coupled with g to give h. In the last step, the ester h is hydrolyzed to give acid intermediate 1. Scheme 2. wherein R 1 、R 2 、R 3 、R4 and x are as described for formula (I).

[0101] Scheme 2 shows the synthetic route of the compound of formula (I). The acid intermediate 1 is coupled with the amine reagent 1 using, for example, HATU to obtain the compound of formula (I). Method of use

[0102] Embodiments of the present application provide a method for modulating sphingosine-1-phosphate receptor 5 (S1P5) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I). The modulation of S1P5 (e.g., inhibition or activation) can be evaluated and demonstrated in numerous ways known in the art. Kits and commercially available assays can be used to determine whether S1P5 is modulated (e.g., inhibited or activated) and to what extent.

[0103] In one aspect, the present application provides a method of modulating S1P5 or any embodiment or variant thereof, which comprises contacting S1P5 with an effective amount of a compound of formula (I). 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.

[0104] In some embodiments, the compound of formula (I) modulates the activity of S1P5 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compound of formula (I) modulates the activity of S1P5 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0105] In another aspect, the present application provides a method for treating a neurological disorder in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I). In some embodiments, the present application provides a method for preventing a neurological disorder in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of formula (I). Non-limiting examples of neurological disorders include Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), migraine, Bell's Palsy, ataxia, cerebral aneurysm, epilepsy, seizure, acute spinal cord injury, Guillain-Barre syndrome, meningitis, Niemann-Pick disease, and Parkinson's disease. In some embodiments, the neurological disorder is Alzheimer's disease or multiple sclerosis. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments, the neurological disorder is multiple sclerosis.

[0106] In some embodiments, administering a compound of formula (I) to a subject susceptible to a neurological disorder prevents any symptoms of the neurological disorder from occurring in the subject. In some embodiments, administering a compound of formula (I) to a subject who has not yet exhibited symptoms of a neurological disorder prevents any symptoms of the neurological disorder from occurring in the subject. In some embodiments, administering a compound of formula (I) to a subject in need thereof reduces the severity of the neurological disorder in the subject. In some embodiments, administering a compound of formula (I) to a subject in need thereof stabilizes the neurological disorder (prevents or delays the worsening of the neurological disorder). In some embodiments, administering a compound of formula (I) to a subject in need thereof delays the onset or recurrence of the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof slows the progression of the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof provides partial relief of the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof provides complete relief of the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof reduces the dosage of one or more other drugs required to treat the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof enhances the effect of another drug used to treat the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof slows the progression of the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof improves the quality of life of a subject suffering from the neurological disorder. In some embodiments, administering a compound of formula (I) to a subject in need thereof prolongs the survival of a subject suffering from the neurological disorder.

[0107] In one aspect, the present application provides a method of preventing any symptoms of a neurological disorder from occurring in a subject susceptible to the neurological disorder, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the present application provides a method of preventing any symptoms of a neurological disorder from occurring in a subject who has not yet exhibited symptoms of the neurological disorder, the method comprising administering a compound of formula (I) to the subject.

[0108] In some aspects, the present application provides a method of reducing the severity of a neurological disorder in a subject, the method comprising administering a compound of formula (I) to the subject. In some embodiments, the present application provides a method of stabilizing a neurological disorder in a subject, which comprises administering a compound of formula (I) to the subject. In some embodiments, the method prevents the worsening of the neurological disorder. In some embodiments, the method delays the worsening of the neurological disorder.

[0109] In another aspect, the present application provides a method for delaying the onset or recurrence of a neurological disorder in a subject, the method comprising administering to the subject a compound of formula (I).

[0110] In some embodiments, the present application provides a method for slowing the progression of a neurological disorder in a subject, the method comprising administering to the subject a compound of formula (I). In some embodiments, the method provides partial remission of the neurological disorder. In some embodiments, the method provides complete remission of the neurological disorder.

[0111] In a further aspect, the present application provides a method for reducing the dosage of one or more other drugs required to treat a neurological disorder in a subject, the method comprising administering to the subject a compound of formula (I). In some embodiments, the present application provides a method for enhancing the effect of another drug used to treat a neurological disorder in a subject, the method comprising administering to the subject a compound of formula (I).

[0112] The present application also provides a method for delaying the progression of a neurological disorder in a subject, the method comprising administering to the subject a compound of formula (I). In some embodiments, the method improves the quality of life of a subject suffering from a neurological disorder. In some embodiments, the method prolongs the survival of a subject suffering from a neurological disorder.

[0113] In another aspect, the present application provides methods for treating neurological symptoms caused by a disease in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I). In some embodiments, the present application provides methods for preventing neurological symptoms caused by a disease in a subject in need thereof, which comprise administering to the subject an effective amount of a compound of formula (I). In some embodiments, administering a compound of formula (I) to a subject susceptible to a disease that causes neurological symptoms prevents any neurological symptoms from occurring in the subject. In some embodiments, administering a compound of formula (I) to a subject who has not yet exhibited neurological symptoms of a disease that causes neurological symptoms prevents any neurological symptoms from occurring in the subject. In some embodiments, administering a compound of formula (I) to a subject in need thereof reduces the degree of 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 (prevents or delays the worsening of the neurological symptoms). In some embodiments, administering a compound of formula (I) to a subject in need thereof delays the onset or recurrence of a neurological disease caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need thereof slows the progression of neurological symptoms caused by the disease. In some embodiments, administering a compound of formula (I) to a subject in need thereof provides partial relief of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need thereof provides complete relief of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need thereof reduces the dose of one or more other drugs required to treat a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need thereof enhances the effect of treating the neurological symptoms of the disease. In some embodiments, administering a compound of formula (I) to a subject in need thereof delays the progression of a disease that causes neurological symptoms. In some embodiments, administering a compound of formula (I) to a subject in need thereof 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 thereof prolongs the survival period of a subject suffering from a disease that causes neurological symptoms. In some embodiments, the disease is Niemann-Pick disease.

[0114] In some embodiments, the compounds of formula (I) are used for the treatment of a disorder selected from: Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes, 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, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic polyangiitis of the kidney, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, sporadic type I polyglandular deficiency and type II polyglandular deficiency, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative spondyloarthropathy, arthropathy, Reiter's disease, psoriatic arthritis, ulcerative colitis arthropathy, enteropathic synovitis, arthropathies associated with Chlamydia, Yersinia, and Salmonella, atherosclerosis / arteriosclerosis, atopic allergy, autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs positive haemolytic anaemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalomyelitis / chronic fatigue syndrome (Royal Free Disease), chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency disease 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 diseases, chronic wound healing, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, fibrosis, interstitial pneumonia, connective tissue disease-related interstitial lung disease, mixed connective tissue disease-related lung disease, systemic sclerosis-related interstitial lung disease, rheumatoid arthritis-related interstitial lung disease, systemic lupus erythematosus-related interstitial lung disease, dermatomyositis / polymyositis-related interstitial lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis-related lung disease, vasculitic diffuse lung disease, hemosiderosis-related lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans organizing pneumonia, chronic eosinophilic pneumonia, lymphocytic interstitial lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune diseases associated with organ transplantation, chronic immune diseases associated with organ transplantation, osteoarthropathy, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, NOS kidney diseases, glomerulonephritis, microscopic polyangiitis of the kidney, Lyme disease, discoid lupus erythematosus, idiopathic or NOS male infertility, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid diseases, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lens-associated uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver disease, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiopathic liver disease, drug-induced hepatitis, non-alcoholic fatty liver disease, allergy and asthma, group B streptococcus (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2- and Th1-mediated diseases,Acute and chronic pain (different forms of pain), as well as cancers such as lung cancer, breast cancer, gastric cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, and rectal cancer, and hematological malignancies (leukemia and lymphoma), as well as hematological malignancies (leukemia and lymphoma), abetalipoproteinemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infections, acute pancreatitis, acute renal failure, adenocarcinoma, atrial ectopic beats, AIDS dementia complex, alcohol-induced 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, anti-receptor hypersensitivity, aortic aneurysm and peripheral aneurysm, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (persistent or paroxysmal), AF, atrioventricular block, B-cell lymphoma, bone marrow transplant rejection, bone marrow transplant (BMT) rejection reaction, atrioventricular bundle branch block, Burkitt lymphoma, burns, arrhythmia, cardiac coma syndrome, cardiac tumors, cardiomyopathy, extracorporeal circulation inflammatory response, cartilage metastasis rejection, cerebellar cortical degeneration, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy-related disorders, chronic myelogenous leukemia (CML), chronic alcoholism, chronic inflammatory conditions, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate poisoning, colorectal cancer, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture-negative sepsis, cystic fibrosis, cytokine therapy-related disorders, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, skin conditions, diabetes (diabetes), diabetes mellitus, diabetic atherosclerotic disease, diffuse Lewy body disease, dilated cardiomyopathy, basal ganglia disorders, Down's Syndrome in middle age, drug-induced movement disorders caused by blocking CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrine diseases, epiglottitis, Epstein Barr virus infection, erythromelalgia, extrapyramidal and cerebellar diseases, familial hemophagocytic lymphohistiocytosis, fetal thymus implant rejection,Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, transplant rejection of any organ or tissue, Gram-negative sepsis, Gram-positive sepsis, granulomas caused by intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arrhythmias, HIV infection / HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, debility, infantile spinal muscular atrophy, aortic inflammation, influenza A, exposure to ionizing radiation, iridocyclitis / uveitis / optic neuritis, ischemia, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, Legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipoedema, liver transplant rejection, lymphoedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic migraine, mitochondrial multisystem disorders, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multisystem degeneration (MencelDejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndromes, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular atrophies, neutropenic fever, non-Hodgkin lymphoma, occlusion of the abdominal aorta and its branches, arterial occlusive diseases, okt3 therapy, orchitis / epididymitis, orchitis / vasectomy reversal surgery, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic cancer, carcinoid syndrome / malignant hypercalcemia, parathyroid transplant rejection reaction, pelvic inflammatory disease, perennial rhinitis, pericardial diseases, peripheral atherosclerotic arterial diseases, peripheral vascular disorders, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome), post-perfusion syndrome,Post pump syndrome, post myocardial infarction pericardiotomy syndrome, pre-eclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiotherapy, Raynaud's phenomenon and disease, Raynaud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, senile chorea, dementia with Lewy bodies, seronegative arthropathy, shock, sickle cell anemia, skin allograft rejection, cutaneous change syndrome, small intestine transplant rejection, solid tumor, specific arrhythmia, spinocerebellar ataxia, spinocerebellar degeneration, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing panencephalitis, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxicity, transplantation, trauma / hemorrhage, 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, virus-associated hemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, polar 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 nervous system pain syndrome, central post-stroke pain, chemotherapy-induced neuropathy, cognitive deficits and dysfunction in patients with mental disorders, cognitive deficits associated with aging and neurodegeneration, cognitive deficits associated with diabetes, cognitive deficits in schizophrenia, complex regional pain syndrome, decline in cognitive function 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 hypofunction associated with traumatic brain injury, diseases with memory loss, dizziness, drug 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, insufficient blood circulation, learning difficulties, major depressive disorder, medullary thyroid carcinoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, mood changes, motion sickness, multiple sclerosis pain, narcolepsy,The need for new blood vessel growth associated with skin graft vascularization and lack of blood circulation, the need for new blood vessel growth associated with wound healing, neuropathic pain, neuropathy, secondary neuropathy infiltrated by tumors, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, pain in Parkinson's disease, pathological somnolence, phantom limb pain, Pick's Disease, polycystic ovary syndrome, post-traumatic stress disorder, post-herpetic neuralgia, pain after mastectomy, pain after surgery, psychotic depression, schizoaffective disorder, seizure, Alzheimer's disease, sepsis syndrome, sleep disorder, smoking cessation, pain after spinal cord injury, steroid-induced acute psychosis, sub-classification of neuropathic pain (including peripheral neuropathic pain syndromes), drug abuse (including alcohol abuse), Syndrome X, Tourette's syndrome, treatment-resistant depression, trigeminal neuralgia, type II diabetes, vertigo and vestibular disorders., Drug Compositions and Routes of Administration

[0115] The compounds provided by the present application can be administered to a subject via oral, topical or parenteral routes in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0116] The compounds disclosed in the present application can be administered to a subject by oral, topical or parenteral routes in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable dosage forms can be prepared by conventional 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), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methyl paraben or propyl paraben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents (e.g., hydroxypropyl methylcellulose), diluents (e.g., water) and base waxes (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition can be at a level that will exert the desired effect.

[0117] The dose of the compound of formula (I) to be administered to a subject can vary widely and can depend on the judgment of the healthcare practitioner. In any given case, the amount of the compound of formula (I) administered will depend on factors such as the solubility of the active ingredient, the dosage form used and the route of administration.

[0118] For convenience, the compound of formula (I) can be administered orally. In one embodiment, when administered orally, the compound of formula (I) is administered with food and water. In another embodiment, the compound of formula (I) is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0119] The compounds disclosed herein can also be administered to the ear, nose, eye or skin by intradermal, intramuscular, intraperitoneal, transdermal, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, transmucosal, via inhalation or topical routes, etc. The mode of administration is determined by the judgment of the healthcare practitioner and can depend in part on the location of the medical condition.

[0120] In one embodiment, the present application provides capsules containing the compound of formula (I) without additional carriers, excipients or vehicles.

[0121] In another embodiment, the present application provides a composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0122] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions, etc. The composition may be formulated to contain a daily dose or a convenient fraction of the daily dose in dosage unit form, and the dosage unit may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as the hydrochloride salt. 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 into the capsules. Commonly used carriers and diluents include, but are not limited to, inert powdery substances such as many different kinds of starches, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose), cereal flours, and similar edible powders.

[0123] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrants as well as the compound. Typical diluents include, for example, various types of starches, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugars. Powdered cellulose derivatives can also be used. Typical tablet binders are substances such as starches, gelatin, and sugars (such as lactose, fructose, glucose, etc.). Natural gums and synthetic gums are also suitable, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidone, etc. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0124] Lubricants may be required in tablet formulations to prevent the tablets and punches from sticking in the dye. Lubricants can be selected from smooth solids such as talc, magnesium stearate, and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon wetting, causing the tablets to break and release the compound. They include starches, clays, celluloses, alginates, and gums. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethyl cellulose, as well as sodium lauryl sulfate can be used. Tablets can be sugar-coated as flavoring agents and sealants, or coated with film-forming protective agents to modify the dissolution characteristics of the tablets. The composition can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0125] When it is desired to administer a compound of formula (I) as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base and can be modified by adding wax to slightly increase its melting point. Water-miscible suppository bases, including polyethylene glycols of various molecular weights in particular, are widely used.

[0126] The effects of the compounds of formula (I) can be delayed or extended by appropriate formulations. For example, slowly dissolving pellets of the compounds of formula (I) can be prepared and incorporated into tablets or capsules or as a sustained-release implantable device. The techniques also include preparing pellets of several different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be film-coated to resist dissolution over a predictable period of time. Even parenteral formulations can be made into long-acting formulations by dissolving or suspending the compounds of formula (I) in an oily or emulsified vehicle such that they are slowly dispersed in the serum. Exemplary embodiments

[0127] The present application is further described by the following embodiments.

[0128] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: R 1 Each independently is a C1-C6 alkyl, C3-C6 cycloalkyl or halo group; R 2 Each independently is a halo group, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 haloalkyl; x is 0-4; R 3 And R 4 Each independently is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b And C1-C6 alkoxy; Or R 3 And R 4 Together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group optionally substituted with 1-5 R 7 Groups, wherein the heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O; R5a and R 5b each independently is H or a C1-C6 alkyl group; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; R 6a and R 6b each independently is H or a C1-C6 alkyl group; and each R 7 independently is a halogen group, a C1-C6 alkyl group, -OH, a C1-C6 alkoxy group or -NR 6a R 6b .

[0129] Embodiment 2. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 each independently is a C1-C3 alkyl group, a C3-C6 cycloalkyl group or a halogen group.

[0130] Embodiment 3. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 each independently is -CH3, cyclopropyl, F, Cl or Br.

[0131] Embodiment 4. The compound according to any one of Embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein: R 1 each is Cl.

[0132] Embodiment 5. The compound according to any one of Embodiments 1-4 or a pharmaceutically acceptable salt thereof, wherein: x is 1-4; and R 2 each independently is a halogen group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group or a C1-C3 haloalkyl group.

[0133] Embodiment 6. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein: x is 2 or 3; and R 2 each independently is Cl, F, -CH3, -OCH3, cyclopropyl or -CF3.

[0134] Embodiment 7. The compound according to Embodiment 6 or a pharmaceutically acceptable salt thereof, wherein: x is 2; and R 2 each is -CH3.

[0135] Embodiment 8. The compound according to any one of Embodiments 1-7 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are independently H, C1-C5 alkyl, C1-C3 alkyl-OH, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl), or -(C1-C3 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1-2 groups selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy; R 5a and R 5b are each independently H or C1-C3 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group; and R 6a and R 6b are each independently H or C1-C3 alkyl.

[0136] Embodiment 9. The compound according to Embodiment 8 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl) or -CH2CH2(pyrrolidinyl), where each cycloalkyl is optionally substituted with a group selected from -OH and -N(CH3)2.

[0137] Embodiment 10. The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein: is

[0138] Embodiment 11. The compound according to any one of Embodiments 1-7 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form an optionally 1-2 R-substituted7 A group-substituted 5- to 6-membered heterocyclic group, wherein said heterocyclic group optionally contains an additional heteroatom selected from N and O; R 7 Each independently is a halogen group, a C1-C3 alkyl group, -OH, a C1-C3 alkoxy group or -NR 6a R 6b ; and R 6a and R 6b Each independently is H or a C1-C3 alkyl group.

[0139] Embodiment 12. The compound according to embodiment 11 or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group optionally substituted by one R 7 group, wherein said heterocyclic group optionally contains an additional heteroatom selected from N and O; and R 7 is -OH, -CH3, -OCH3 or -N(CH3)2.

[0140] Embodiment 13. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein: is

[0141] Embodiment 14. The compound according to any one of embodiments 1-13 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):

[0142] Embodiment 15. The compound according to any one of embodiments 1-14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIa): Wherein: R 3 is H or a C1-C6 alkyl group; R 4 is H, a C1-C6 alkyl group, a C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), a C3-C6 cycloalkyl group, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , wherein each cycloalkyl group is optionally substituted by 1-5 selected from halogen groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OH, -NR 6a R6b substituted with a group of C1-C6 alkoxy; R 5a and R 5b are independently H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; and R 6a and R 6b are each independently H or C1-C6 alkyl.

[0143] Embodiment 16. A compound according to any one of Embodiments 1-14 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IVa): wherein is a 4- to 6-membered heterocyclic group.

[0144] Embodiment 17. A compound selected from the compounds of Table 1 and a pharmaceutically acceptable salt thereof.

[0145] Embodiment 18. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0146] Embodiment 19. A method of modulating sphingosine 1-phosphate receptor 5 (S1P5), which comprises contacting S1P5 with an effective amount of a compound according to any one of Embodiments 1-17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Embodiment 18.

[0147] Embodiment 20. A method of treating a neurological disorder in a subject in need thereof, which comprises administering to the subject an effective amount of a compound according to any one of Embodiments 1-17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Embodiment 18.

[0148] Embodiment 21. The method according to Embodiment 20, wherein the neurological disorder is Alzheimer's disease or multiple sclerosis. Examples

[0149] The following examples are presented by way of illustration and not limitation. Compounds were named using the automated name generation tool provided by ChemBiodraw Ultra (CambridgeSoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art may modify the procedures set forth in the illustrative examples to obtain the desired products.

[0150] The salts of the compounds described in this application can be prepared by standard methods, such as those that include an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product after chromatographic purification with a solution of an acid (e.g., aqueous HCl).

[0151] The following abbreviations may be relevant to this application. Abbreviation Synthetic Examples Example S1. Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I)

[0152] Synthesize methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate. A solution of ZnCl2 (1.9 M in Me-THF, 19.8 mL, 37.54 mmol, 2.00 equivalents) and NaBH3CN (4.72 g, 75.09 mmol, 4.00 equivalents) in methanol (8 mL) was stirred at room temperature for 10 min. Then 4-bromo-2,6-dimethyl-benzaldehyde (4 g, 18.77 mmol, 1.00 equivalent) and methyl piperidine-4-carboxylate (5.38 g, 37.55 mmol, 2.00 equivalents) were added. The resulting mixture was stirred at 80 °C overnight. LCMS showed completion of the reaction. The reaction mixture was poured into DCM / H2O (1 / 1, 100 mL). The separated organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with PE / EA, 3 / 1) to give methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (3.5 g, 54.8%) as a pale yellow oil.

[0153] LCMS (ESI, m / z): 340 [M+H] + 。

[0154] Synthesize methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate. To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (13.24 g, 46.75 mmol, 10.0 equiv) in DMF (75 mL) was added zinc powder (4.41 g, 67.48 mmol, 15.0 equiv). The resulting mixture was stirred at 60 °C for 5 h. Then 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate methyl ester (1.5 g, 4.41 mmol, 1.00 equiv), Pd2(dba)3 (807 mg, 0.88 mmol, 0.200 equiv) and tris(ortho-tolyl)phosphine (1.34 g, 4.41 mmol, 1.00 equiv) were added. The resulting mixture was stirred at 80 °C overnight. LCMS showed completion of the reaction. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on C18 silica gel (eluting with 100% CAN) to give methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.8 g, 98.0%) as a pale yellow oil.

[0155] LCMS (ESI, m / z): 417 [M+H] + 。

[0156] Synthesis of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate - 2,2,2-trifluoroacetaldehyde. To a stirred solution of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.8 g, 4.32 mmol, 1.00 equiv) in DCM (2 mL) at room temperature was added dropwise TBSOTf (1.53 mL, 8.64 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 1 h. LCMS showed completion of the transformation. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on C18 silica gel (eluting with 22% CAN / water (0.05% TFA)) to give methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate - 2,2,2-trifluoroacetaldehyde (1.3 g, 95.1%) as a pale yellow oil.

[0157] LCMS (ESI, m / z): 317 [M+H] + 。

[0158] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate. To a stirred solution of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate--2,2,2-trifluoroacetaldehyde (2 g, 6.32 mmol, 1.00 equiv) and 2-bromo-1,3-dichlorobenzene (2.86 g, 12.64 mmol, 2.00 equiv) in 1,4-dioxane (2 mL) was added RuPhos Pd G3 (884 mg, 0.95 mmol, 0.15 equiv), RuPhos (442 mg, 0.95 mmol, 0.15 equiv) and Cs2CO3 (6.16 g, 18.96 mmol, 3.00 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. LCMS showed completion of the reaction. The reaction mixture was diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica gel (eluting with 90% CAN / water (10 mM NH4HCO3)) to afford methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (500 mg, 17.1%) as a pale yellow oil.

[0159] LCMS (ESI, m / z): 461 [M+H] + 。

[0160] Synthesize 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I). A mixture of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate (25 mg, 0.54 mmol, 1.00 equiv) and LiOH (39 mg, 1.63 mmol, 1.00 equiv) in THF (2.5 mL) and water (2.5 mL) was stirred at room temperature overnight. LCMS showed completion of the reaction. The reaction mixture was acidified to pH 5 - 6 by addition of acetic acid and then 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 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 60% B in 7 min; wavelength: 254 / 220 nm; RT: 5.92 min) to afford 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (165.1 mg, 66.7%) as a white solid.

[0161] 1 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 7.6 Hz, 2H), 7.03 (s, 2H), 6.74 (t, J = 7.6 Hz, 1H), 4.80 (t, J = 8.0 Hz, 2H), 4.34 (t, J = 8.0 Hz, 2H), 3.71 - 3.64 (m, 1H), 3.38 (s, 2H), 2.69 - 2.66 (m, 2H), 2.33 (s, 6H), 2.20 - 2.14 (m, 1H), 2.08 - 2.02 (m, 2H), 1.76 - 1.72 (m, 2H), 1.48 - 1.40 (m, 2H).

[0162] LCMS (ESI, m / z): 447 [M + H] + . Analytical conditions: Column: YMC Meteoric 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: within 1.20 min, 10% B to 95% B, hold at 95% for 0.58 min, within 0.05 min, 95% B to 10% B; 254 nm; RT: 0.849 min. Example S2. Synthesis of amide compound 1 - 26

[0163] General synthesis of amide Dissolve the starting material 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I, 650 mg) in 9.0 mL of DMF (solution 1). Dissolve the coupling reagent HATU (715.937 mg) in 10.8 mL of DMF (solution 2). Place the respective amine component (amine reagent I, 2.85 equivalents, 0.115 mmol, Table 2) in a reaction vial and add 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (0.250 mL of solution 1, 0.040 mmol, 1 equivalent), HATU (0.299 mL of solution 2, 0.052 mmol, 1.3 equivalents), and Hunig's base (0.042 mL, 0.241 mmol, 6 equivalents). Place the mixture in a Bohdan Miniblock XT and stir at 400 rpm at room temperature for 6 hours. Purify the crude reaction mixture by preparative reverse-phase chromatography under the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C. UV (220 nm) and MS (ESI+) trigger fraction collection. Combine the fractions containing the desired product and dry by centrifugal evaporation.

[0164] Use analytical reverse-phase chromatography to determine the final purity.

[0165] Injection 1 conditions: column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; mobile phase A: ACN / H2O (5:95), containing 0.05% TFA; mobile phase B: ACN / H2O (95:5), containing 0.05% TFA; temperature: 50 °C; gradient: 0 - 100% B (0.0 - 3.0 min), 100% B (3.0 - 3.5 min); flow rate: 1.0 mL / min; detection: UV (220 nm) and MS (ESI+ / -).

[0166] Injection 2 conditions: column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; mobile phase A: ACN / H2O (5:95), containing 10 mM AA; mobile phase B: ACN / H2O (95:5), containing 10 mM AA; temperature: 50 °C; gradient: 0 - 100% B (0.0 - 3.0 min), 100% B (3.0 - 3.5 min); flow rate: 1.0 mL / min; detection: UV (220 nm) and MS (ESI+ / -).

[0167] 11H NMR was obtained in deuterated DMSO.

[0168] The amine reagent I used for each reaction to produce Compounds 1-26 is shown in Table 2. In Table 2, the identification numbers correspond to the final compounds with the same numbers. For example, the amine reagent related to number 1 in Table 2 was used to prepare Compound 1. Table 2. Amine Reagent I

[0169] The characterization data of Compounds 1-26 are shown in Table 3. Table 3. Characterization Data of Compounds 1-26 Biological Examples Example B1. Cell Membrane Preparation

[0170] CHO cells expressing the recombinant S1P5 receptor were cultured in 500 cm 2 culture dishes. Once confluent, they were rinsed and detached with cell-lifting buffer (10 mM HEPES, 154 mM NaCl, 6.85 mM EDTA, pH 7.4). Then the cells were pelleted by centrifugation, resuspended, and homogenized in membrane preparation buffer (10 mM HEPES and 10 mM EDTA, pH 7.4) using a Polytron PT 1200E homogenizer (Kinematica, Luzern, Switzerland). The cellular proteins were pelleted by centrifugation at 48,000 x g for 30 minutes at 4 °C. The resulting supernatant was discarded, and the pellet was resuspended again in the membrane preparation buffer, homogenized a second time, and then centrifuged again as described above. The final cellular protein pellet was suspended in ice-cold resuspension buffer (10 mM HEPES and 0.1 mM EDTA, pH 7.4), aliquoted, and stored at -80 °C for later use. Example B2. GTPγS Binding Assay

[0171] Functional binding assays of 35 S]-GTPγS were performed in 96-well non-binding plates with a final volume of 200 μL. Test compounds were serially diluted in DMSO and added to the assay plates in a total volume of 0.4 μL using a Tecan D300E digital pipettor. Control sphingosine-1-phosphate (S1P) was prepared separately by making a 400 μM stock solution with a precipitate of 100 nmol of S1P in 10 mM Na2CO3 with 2% β-cyclodextrin. Serial dilutions of S1P were made using complete assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.1% fatty acid-free bovine serum albumin (BSA), and 30 μg / mL saponin, pH 7.4) and transferred to wells that already contained 0.4 μL of DMSO. Then all wells except for the non-specific binding (NSB) wells were loaded with complete assay buffer to a total volume of 40 μL. For the NSB wells, 40 μL / well of 50 μM GTPγS (Sigma Aldrich, cat#G8634, St. Louis, MO) was added to wells containing 0.4 μL of DMSO. The assay was initiated by adding 120 μL / well of a CHO-S1P receptor membrane solution containing 40 μg / mL membrane protein, 16.67 μM guanosine diphosphate (GDP; Sigma Aldrich, cat#G7127, St. Louis, MO), and 2.5 mg / mL WGAPVT SPA beads in complete buffer. The assay plates were then sealed and incubated at room temperature with gentle agitation for 30 minutes. Next, 40 μL / well of 1 nM 35 S]-GTPγS (PerkinElmer, cat#NEG030X250UC, Waltham, MA) in basal assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, and 1 mM EDTA, pH 7.4) was added to the assay plates to give a final concentration of 200 pM, and the plates were further incubated at room temperature with gentle agitation for 40 minutes. The assay was terminated by centrifuging the plates at 1000 rpm for 3 minutes using an Eppendorf 5810R centrifuge (Eppendorf, Hamburg, Germany), and G protein-bound radioactivity was quantified using a MicroBeta2 microplate scintillation counter (PerkinElmer, Waltham, MA). Since G protein-bound radioactivity is directly related to receptor activation and coupling to G protein, this assay is a measure of S1P5 agonism. The results are shown in Table 4. Table 4. S1P5 GTPγS binding of exemplary compounds. ++++ indicates binding between greater than 1 nM and ≤ 10 nM +++ indicates binding between greater than 10 nM and ≤ 100 nM ++ indicates binding between greater than 100 nM and ≤ 1,000 nM + indicates binding between greater than 1,000 nM and ≤ 10,000 nM

[0172] Although, for purposes of clarity of understanding, the present invention has been described in some detail by way of illustration and example, such illustration and example should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited in this application are hereby incorporated by reference in their entirety into this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 each independently is a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a halogen group; R 2 each independently is a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group or a C1-C6 haloalkyl group; x is 0 - 4; R 3 and R 4 each independently is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1-5 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; or R 3 and R 4 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group optionally substituted with 1-5 R 7 groups, wherein said heterocyclic group optionally contains 1-2 additional heteroatoms selected from N and O; R 5a and R 5b each independently is H or a C1-C6 alkyl group; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; R 6a and R 6b each independently is H or a C1-C6 alkyl; and R 7 Each independently is a halogen group, a C1-C6 alkyl group, -OH, a C1-C6 alkoxy group or -NR 6a R 6b 。 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Each independently is a C1-C3 alkyl group, a C3-C6 cycloalkyl group or a halogen group.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R 1 Each independently is -CH3, cyclopropyl, F, Cl or Br.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 3, wherein: R 1 Each is Cl.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 4, wherein: x is 1 - 4; and R 2 Each independently represents a halogen group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, or a C1-C3 haloalkyl group.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein: x is 2 or 3; and R 2 Each independently is Cl, F, -CH3, -OCH3, cyclopropyl or -CF3.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein: x is 2; and R 2 Each is -CH3.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 7, wherein: R 3 and R 4 are independently H, C1-C5 alkyl, C1-C3 alkyl-OH, -(C1-C3 alkylene)-O-(C1-C3 alkyl), C3-C6 cycloalkyl, -(C1-C3 alkylene)(C3-C6 cycloalkyl) or -(C1-C3 alkylene)NR 5a R 5b , wherein each cycloalkyl group is optionally substituted with 1-2 groups selected from halo, C1-C3 alkyl, C1-C3 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy; R 5a and R 5b each independently is H or a C1-C3 alkyl group; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group; and R 6a and R 6b each independently is H or a C1-C3 alkyl group.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R 3 and R 4 are independently H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclohexyl) or -CH2CH2(pyrrolidinyl), wherein each cycloalkyl is optionally substituted with a group selected from -OH and -N(CH3)2.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein: For 11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 7, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group optionally substituted with 1 to 2 R 7 groups, wherein said heterocyclic group optionally contains an additional heteroatom selected from N and O; R 7 each independently represents a halogen group, a C1-C3 alkyl group, -OH, a C1-C3 alkoxy group or -NR 6a R 6b ; and R 6a and R 6b are each independently H or a C1-C3 alkyl group.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein: R 3 and R 4 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group optionally substituted with one R 7 group, wherein said heterocyclic group optionally contains an additional heteroatom selected from N and O; and R 7 is -OH, -CH3, -OCH3 or -N(CH3)2.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: For 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 13, wherein the compound is a compound of formula (II):

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14, wherein the compound is a compound of formula (IIIa): wherein: R 3 is H or a C1-C6 alkyl group; R 4 is H, C1-C6 alkyl, C1-C6 alkyl-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), C3-C6 cycloalkyl, -(C1-C6 alkylene)(C3-C6 cycloalkyl) or -(C1-C6 alkylene)NR 5a R 5b , where each cycloalkyl is optionally substituted with 1-5 groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -NR 6a R 6b and C1-C6 alkoxy; R 5a and R 5b are independently H or C1-C6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; and R 6a and R 6b each independently is H or a C1-C6 alkyl group.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 14, wherein the compound is a compound of formula (IVa): wherein is a 4- to 6-membered heterocyclic group.

17. A compound selected from the compounds of Table 1 and a pharmaceutically acceptable salt thereof.

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

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

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

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