Heterocyclic compounds as S1P5 modulators

Abstract

The present specification provides compounds and compositions thereof for modulating S1P5. In some embodiments, the compounds and compositions are used to treat neurological disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 433,230, filed December 16, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] Technical Field FIELD OF THE DISCLOSURE The present disclosure relates generally to compounds, compositions, and methods for making and using compounds and compositions for treating neurological disorders. [Background technology]

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate) is a biologically active sphingolipid synthesized by intracellular sphingolipid turnover and by secreted sphingosine kinases during extracellular action. S1P binds to and stimulates endothelial differentiation gene family members (EDG receptors), G protein-coupled receptors localized to the plasma membrane. There are five receptors in this family: S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P mediates a wide range of cellular responses, including proliferation, cytoskeletal organization and migration, adhesion and tight junctions, and morphogenesis.

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

[0005] Thus, in one aspect, there is provided herein a compound that modulates S1P5 for use in the treatment of neurodegenerative diseases. Summary of the Invention

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

[0007] The embodiments of the present application may be more fully understood by reference to the detailed description and examples, which are intended to be illustrative and not limiting of the embodiments.

[0008] Embodiment A1 is a compound of formula (I): [ka] [In the formula, Each R 1 are independently C1-C6 alkyl, C3-C6 cycloalkyl, or halogen; Each R 2 are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 haloalkyl; x is 0 to 4; R 3 and R 4are each independently 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 selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6b and C1-C6 alkoxy; or R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 forming an optionally substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains 1 to 2 heteroatoms selected from N and O; Each 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 heterocyclyl; Each R 6a and R 6b are independently H or C1-C6 alkyl; and Each R 7 are independently halogen, C1-C6 alkyl, -OH, C1-C6 alkoxy, or -NR 6a R 6b is] or a pharmaceutically acceptable salt thereof.

[0009] Embodiment A2 is a compound of embodiment A1, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently C1-C3 alkyl, C3-C6 cycloalkyl, or halogen.

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

[0011] Embodiment A4 is a compound of any one of embodiments A1-A3, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 is Cl.

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

[0013] Embodiment A6 is a compound of embodiment A5, or a pharmaceutically acceptable salt thereof, wherein: x is 2 or 3; and Each R 2 are independently Cl, F, —CH 3 , —OCH 3 , cyclopropyl, or —CF 3 .

[0014] Embodiment A7 is a compound of embodiment A6, or a pharmaceutically acceptable salt thereof, wherein: x is 2; and Each R 2 is -CH3.

[0015] Embodiment A8 is a compound of any one of embodiments A1 through A7, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4are 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 is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6b and C1-C3 alkoxy; Each R 5a and R 5b are 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- or 6-membered heterocyclyl; and Each R 6a and R 6b are independently H or C1-C3 alkyl.

[0016] Embodiment A9 is a compound of 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), where each cycloalkyl may be optionally substituted with one group selected from -OH and -N(CH3)2.

[0017] Embodiment A10 is a compound of embodiment A9, or a pharmaceutically acceptable salt thereof, wherein: [ka] but, [ka] is.

[0018] Embodiment A11 is a compound of any one of embodiments A1 through A7, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 However, they are combined with the nitrogen atom to which they are bonded to form one or two R 7 forming an optionally substituted 5- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains one heteroatom selected from N and O; Each R 7 are independently halogen, C1-C3 alkyl, -OH, C1-C3 alkoxy, or -NR 6a R 6b and Each R 6a and R 6b are independently H or C1-C3 alkyl.

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

[0020] Embodiment A13 is a compound of embodiment A12, or a pharmaceutically acceptable salt thereof, wherein: [ka] but, [ka] is.

[0021] Embodiment A14 is a compound of any one of embodiments A1-A13, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): [ka] is.

[0022] Embodiment A15 is a compound of any one of embodiments A1 through A14, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IIIa): [ka] [In the formula, 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 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 heterocyclyl; and Each R 6a and R 6b are independently H or C1-C6 alkyl. is.

[0023] Embodiment A16 is a compound of any one of embodiments A1 through A14, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IVa): [ka] [In the formula, [ka] is a 4- to 6-membered heterocyclyl] is.

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

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

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

[0027] Embodiment A20 is a method for treating a neurological disorder in a patient in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments A1 to A17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment A18, wherein the neurological disorder can be Alzheimer's disease or multiple sclerosis. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition As used herein, the terms "characterized by" and "comprising" may be used interchangeably. The terms "characterized by" and "comprising" are to be interpreted as specifying the presence of a stated feature or component, but do not exclude the presence or addition of one or more of that feature, component, or group thereof. Furthermore, the terms "characterized by" and "comprising" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" may be used in place of the terms "characterized by" and "comprising" to provide more specific embodiments 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. In other embodiments, the term "consisting of" excludes any feature or component from any subsequently described scope, except one that is not essential to the technical effect to be achieved.

[0030] As used herein, the term "or" is to be interpreted as an inclusive term, meaning any one or any combination. Thus, "A, B, or C" means any of "A, B, C, A and B, A and C, B and C, A and B and C." Exceptions to this definition occur only when combinations of elements, features, steps, or acts are, for some reason, inherently mutually exclusive.

[0031] Any concentration range, percentage range, ratio range, or integer range herein is understood to include any integer within the stated range, and fractions thereof, as appropriate (e.g., tenths and hundredths of an integer), unless otherwise specified. Additionally, any numerical range recited herein for any physical characteristic (e.g., number of subunits, size, or viscosity of a polymer) is understood to include any integer within the stated range, unless otherwise specified. As used herein, the terms "about" and "approximately" refer to ±20%, ±10%, ±5%, or ±1% of the stated range, value, or structure, unless otherwise specified.

[0032] An "alkyl" group is an alkyl group containing 1 to 10 carbon atoms (C1-C 10A C1-C8 alkyl is a saturated, partially saturated, or unsaturated, straight- or branched-chain acyclic hydrocarbon, typically having 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments, 1 to 6 (C1-C6 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH). Alkyl groups can be substituted or unsubstituted.When alkyl groups as described herein are "substituted," they can be substituted with any of the substituents or substituents found in the example compounds and embodiments of the present disclosure, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino. , aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazone; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when alkyl groups described herein are "substituted," those groups can be substituted with any of the substituents or substituents found in the example compounds and embodiments of the present disclosure, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0033] An "alkyl-OH" group refers to a straight or branched chain alkyl group, as defined above, in which one or more hydrogen atoms are replaced with -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl substituted with one or more -OH groups. The alkyl-OH may include multiple hydroxy groups attached to the same carbon atom or carbon atoms.

[0034] An "alkylene" group refers to the same residues as alkyl, but is divalent. Particular alkylene groups have 1 to 10 carbon atoms (C-C 10Alkylenes generally have 1 to 8 carbon atoms (C1-C8 alkylene). Alternatively, in some embodiments, they have 1 to 6 (C1-C6 alkylene) or 1 to 3 (C1-C3 alkylene) carbon atoms. Examples of alkylenes include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), and octylene (-CH2(CH2)6CH2-).

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

[0036] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms (C6-C8) containing a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). 14 In some embodiments, the aryl group contains 6 to 14 carbons (C6-C 14 aryl), and other groups have 6 to 12 carbon atoms (C6-C 12 aryl) or 6 to 10 carbon atoms (C6-C 10 Particular aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The term "aryl group" also includes groups having fused rings, such as fused aromatic and aliphatic rings (e.g., indanyl, tetrahydronaphthyl, etc.).

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

[0038] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, as defined above, including, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group contains 1 to 6 carbon atoms and is substituted with one or more halogens (C-C haloalkyl), or the haloalkyl group contains 1 to 3 carbon atoms and is substituted with one or more halogens (C-C haloalkyl). The halogens may all be the same or different. Unless otherwise specified, the haloalkyl group may be optionally substituted.

[0039] A "heteroaryl" group is an aromatic ring having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring, with the remaining atoms being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, while other groups contain 6 to 9 atoms or 6 to 10 atoms in the ring moiety. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring is monocyclic or bicyclic. Examples of such radicals include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyri Heteroaryl groups include aryl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0040] "Heterocyclyl" refers to a non-aromatic cycloalkyl in which 1 to 4 ring carbon atoms are independently replaced with heteroatoms selected from O, S, and N. In some embodiments, heterocyclyl groups are 3 to 10-membered rings, while other groups are 3 to 5, 3 to 6, or 3 to 8-membered rings. A heterocyclyl can be attached to other groups at any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include saturated and partially saturated rings. Furthermore, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, with or without attachment to the remainder of the molecule. "Heterocyclyl" also includes bridged polycyclic rings containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono-substituted or multi-substituted, such as, but not limited to, di-, tri-, tetra-, penta-, or hexa-substituted pyridyl or morpholinyl groups, or di-substituted pyridyl or morpholinyl groups with various substituents listed below.

[0041] An "alkoxy" group is an --O-(alkyl), where alkyl is defined above.

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

[0043] When a group other than an alkyl group described herein is "substituted," it may be substituted with any suitable substituent. Examples of substituents include those found in the compounds and embodiments of the present disclosure, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; monocyclic or fused polycyclic or non-fused polycyclic. cycloalkyl, which may be a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be a monocyclic ring or a fused or non-fused polycyclic ring (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); aryl or heteroaryl, which may be a monocyclic ring or a fused or non-fused polycyclic ring (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0044] Embodiments of the present invention are intended to include pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers of the compounds described herein (eg, compounds of Formula (I)).

[0045] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I) include, but are not limited to, metallic salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts formed with lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids (e.g., acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid). Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Examples of specific salts include hydrochloride, formate, and mesylate salts. Others are known to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990), or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0046] Unless otherwise specified, the terms "stereoisomer" or "stereomerically pure," as used herein, mean that one stereoisomer of a particular compound is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center is substantially free of the other enantiomer of that compound. A stereomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. Stereomerically pure compounds typically include those that contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The compounds of the present disclosure may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomers, including mixtures thereof, are included within the embodiments of the present disclosure.

[0047] The use of pure stereoisomers of the disclosed compounds, as well as mixtures of these isomers, are included in the embodiments of the present disclosure.For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound can be used in the methods and compositions of the present disclosure.These isomers can be synthesized asymmetrically or resolved by conventional methods (e.g., chiral columns or chiral resolving agents). For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. See 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 be noted that the compounds of the present disclosure can include E and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof.In certain embodiments, the compounds are isolated as either E or Z isomers.In other embodiments, the compounds are a mixture of E and Z isomers.

[0049] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers may vary depending on the environment in which the compound is present, for example, whether the compound is a solid, in an organic solvent, or in an aqueous solution. For example, in an aqueous solution, pyrazole may exist in the following isomers: [ka] These are considered to be tautomers of each other.

[0050] As one skilled in the art would readily appreciate, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present disclosure.

[0051] It should be noted that compounds of the present disclosure may contain unnatural proportions of isotopes at one or more atoms. For example, compounds may contain radioactive isotopes (e.g., tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 C)) or may be labeled with, for example, deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15The compound may be isotopically enriched in an isotope of N). As used herein, an "isotope" refers to an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the naturally occurring isotopic composition of that atom. "Isotopically enriched" may refer to a compound containing at least one atom having an isotopic composition other than the naturally occurring isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present in an atom. Radiolabeled, isotopically enriched compounds are useful as therapeutics (e.g., cancer therapeutics), research reagents (e.g., binding assay reagents), and diagnostics (e.g., in vivo imaging agents). All isotopes of the compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopes of the disclosed compounds (e.g., compounds enriched in deuterium, carbon-13, and / or nitrogen-15) are provided. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced by an isotope of (D or 2 H) means a compound that is deuterium-substituted, i.e., enriched with deuterium at at least one position of the compound.

[0052] It is understood that each compound of the present disclosure can be provided in the form of any pharmaceutically acceptable salt disclosed herein, regardless of stereoisomeric or isotopic composition.Similarly, it is also understood that isotopic composition can vary regardless of the stereoisomeric composition of each compound mentioned herein.Furthermore, isotopic composition is limited to the elements present in each compound or its salt disclosed herein, but can also vary regardless of the choice of pharmaceutically acceptable salt of each compound.

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

[0054] As used herein, "treatment" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease, or condition itself. In certain embodiments, the disorder is a neurodegenerative disease described herein, or a symptom thereof.

[0055] As used herein, "prevention" refers to a method of delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition, in whole or in part; a method of inhibiting a subject from acquiring a disorder, disease, or condition; or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In certain embodiments, the disorder is a neurodegenerative disease, or symptom thereof, as described herein.

[0056] The term "effective amount" in reference to a compound of the present disclosure means an amount capable of treating or preventing a disorder, disease or condition of the present disclosure, or a symptom thereof.

[0057] As used herein, the term "subject" or "patient" includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, in some embodiments, mammals, and in other embodiments, humans. In some embodiments, the subject is a human suffering from, at risk for, or suffering from an S1P5-mediated disorder.

[0058] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, the invention may also be practiced in a single embodiment that may for clarity be described separately herein.

[0059] compound In some embodiments, the present specification provides a compound of formula (I): [ka] [In the formula, Each R 1 are independently C1-C6 alkyl, C3-C6 cycloalkyl, or halogen; Each R 2 are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 haloalkyl; x is 0 to 4; R 3 and R 4 are each independently 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 selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6b and C1-C6 alkoxy; or R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 forming an optionally substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains 1 to 2 heteroatoms selected from N and O; Each 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 heterocyclyl; Each R 6a and R 6b are independently H or C1-C6 alkyl; and Each R 7 are independently halogen, C1-C6 alkyl, -OH, C1-C6 alkoxy, or -NR6a R 6b is] or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, each R 1 is independently C1-C6 alkyl, C3-C6 cycloalkyl, or halogen. 1 is independently C1-C3 alkyl, C3-C6 cycloalkyl, F, Cl, Br, or I. In some embodiments, each R 1 is independently —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, or Br. 1 is independently methyl, cyclopropyl, F, Cl, or Br. In some embodiments, R 1 is Cl.

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

[0062] In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is cyclopropyl.

[0063] In some embodiments, R 1 is halogen. In some embodiments, R 1is 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, each R 2 is independently halogen, C-C alkyl, C-C alkoxy, C-C cycloalkyl, or C-C haloalkyl. 2 is independently halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C1-C3 haloalkyl. 2 is independently F, Cl, Br, I, -CH, -CHCH, -CHCHCH, -OCH, -OCHCH, -OCHCH, -OCH(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C haloalkyl. 2 is independently F, Cl, —CH, —OCH, cyclopropyl, —CHF, —CHF, or —CF. 2 is independently F, Cl, —CH, —OCH, cyclopropyl, or —CF. In some embodiments, R 2 is -CH3.

[0065] In some embodiments, R 2 is halogen. 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 2is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, R 2 is —CH. In some embodiments, R 2 is -CH2CH3.

[0067] In some embodiments, R 2 is C1-C6 alkoxy. In some embodiments, R 2 is C1-C3 alkoxy. In some embodiments, R 2 is —OCH, —OCHCH, —OCHCHCH, or —OCH(CH). In some embodiments, R 2 is —OCH. In some embodiments, R 2 is -OCH2CH3.

[0068] In some embodiments, R 2 is C-C cycloalkyl. In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2 is cyclopropyl.

[0069] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 2 is C1-C3 haloalkyl. In some embodiments, R 2 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. 2 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl.2 is C haloalkyl. In some embodiments, R 2 is —CHF, —CHF, or —CF. In some embodiments, R 2 is -CF3.

[0070] In some embodiments, x is 0 to 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, each R 5a and R 5b is independently H or C1-C6 alkyl. In some embodiments, each R 5a and R 5b is independently H or C1-C3 alkyl. In some embodiments, each R 5a and R 5b is independently H or -CH, -CHCH, or -CHCHCH. In some embodiments, each R 5a and R 5b is H or -CH3. In some embodiments, each R 5a and R 5b is -CH3.

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

[0073] In some embodiments, each R 5a and R 5b is independently C1-C6 alkyl. In some embodiments, each R 5a and R 5b is independently C1-C3 alkyl. In some embodiments, each R 5a and R 5bis independently -CH, -CHCH, or -CHCH. In some embodiments, each R 5a and R 5b is -CH3.

[0074] In some embodiments, R 5a and R 5b One of the two is H and the other is R 5a and R 5b and the other is C1-C6 alkyl. In some embodiments, R 5a and R 5b One of the two is H and the other is R 5a and R 5b and the other is C1-C3 alkyl (e.g., methyl, ethyl, or propyl). 5a and R 5b One of the two is H and the other is R 5a and R 5b The other 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 heterocyclyl. 5a and R 5b together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl. 5a and R 5b together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl. 5a and R 5b together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl. 5a and R 5b together with the nitrogen atom to which they are attached to form pyrrolidinyl.

[0076] In some embodiments, each R 6a and R 6bis independently H or C1-C6 alkyl. In some embodiments, each R 6a and R 6b is independently H or C1-C3 alkyl. In some embodiments, each R 6a and R 6b is independently H, -CH, -CHCH, or -CHCH. In some embodiments, each R 6a and R 6b is independently H or —CH. In some embodiments, each R 6a and R 6b is -CH3.

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

[0078] In some embodiments, each R 6a and R 6b is independently C1-C6 alkyl. In some embodiments, each R 6a and R 6b is independently C1-C3 alkyl. In some embodiments, each R 6a and R 6b is independently -CH, -CHCH, or -CHCH. In some embodiments, each R 6a and R 6b is -CH3.

[0079] In some embodiments, R 6a and R 6b One of the two is H and the other is R 6a and R 6b and the other is C1-C6 alkyl. In some embodiments, R 6a and R 6b One of the two is H and the other is R 6a and R 6b and the other is C1-C3 alkyl (e.g., methyl, ethyl, or propyl). 6a and R 6b One of the two is H and the other is R 6aand R 6b The other is methyl.

[0080] In some embodiments, each R 7 are independently halogen, C1-C6 alkyl, -OH, C1-C6 alkoxy, or -NR 6a R 6b In some embodiments, each R 7 is halogen, C1-C3 alkyl, -OH, C1-C3 alkoxy, or -NR 6a R 6b In some embodiments, each R 7 is F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, or -NR 6a R 6b In some embodiments, each R 7 is —OH, —CH 3 , —OCH 3 , or —N(CH 3 ) 2 . In some embodiments, each R 7 is halogen. In some embodiments, each R 7 is F, Cl, Br, or I.

[0081] In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C1-C3 alkyl. 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 C1-C3 alkoxy. In some embodiments, R 7 is —OCH, —OCHCH, —OCHCHCH, or —OCH(CH). In some embodiments, R7 is -OCH3.

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

[0085] In some embodiments, R 3 and R 4 are each independently 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 selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6b and C1-C6 alkoxy. 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 wherein each cycloalkyl is optionally selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6b and C1-C6 alkoxy. 3 and R 4are 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 wherein each cycloalkyl is optionally 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 wherein each cycloalkyl is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6b and C1-C3 alkoxy. 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 wherein each cycloalkyl is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6b and C1-C3 alkoxy. 3 and R 4are each independently 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)CH2CH2CH 3、 -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2(CH3)CH2OH, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(cyclopentyl), -CH2(cyclohexyl), -CH2CH2NR 5a R 5b wherein each cycloalkyl is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6b and C1-C3 alkoxy. 3 and R 4 are each independently 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)CH2CH2CH 3、 -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2(CH3)CH2OH, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2(cyclobutyl), -CH2(cyclopentyl), -CH2(cyclohexyl), -CH2CH2NR 5a R 5b wherein each cycloalkyl is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6band C1-C3 alkoxy. In some embodiments, R 3 and R 4 are each 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, where each cycloalkyl is optionally halogen, C1-C3 alkyl, C1 haloalkyl, -OH, -NR 6a R 6b and C1-C3 alkoxy. In some embodiments, R 3 and R 4 are each 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, where each cycloalkyl is optionally 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 are each independently H, -CH, -CH(CH), -CHCH(CH), -CHCHCH(CH), -CHCHOH, -CHCHOCH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH(cyclopropyl), -CH(cyclohexyl), -CHCHN(CH), where each cycloalkyl is optionally substituted with one group selected from -OH and -N(CH).

[0086] In some embodiments, [ka] teeth, [ka] is.

[0087] In some embodiments, R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 In some embodiments, R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 In some embodiments, R forms a 5- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl optionally further contains 1 to 2 heteroatoms selected from N and O. 3 and R 4 are combined with the nitrogen atom to which they are attached to form one or two R 7 In some embodiments, R 3 and R 4 are combined with the nitrogen atom to which they are attached to form one R 7 In some embodiments, R 3 and R 4 are combined with the nitrogen atom to which they are attached to form one R 7The heterocyclyl optionally contains one or more heteroatoms selected from N and O, and the R 7 is -OH, -CH3, -OCH3, or -N(CH3)2. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0088] In some embodiments, [ka] teeth, [ka] is.

[0089] In some embodiments, the compound of Formula (I) has the formula (II): [ka] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described in formula (I).

[0090] In some embodiments, the compound of Formula (I) has the formula (III): [ka] [In the formula, R 3 and R 4 is as described in formula (I).

[0091] In some embodiments, the compound of Formula (I) has the formula (IIIa): [ka] [In the formula, 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 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 heterocyclyl; and Each R 6a and R 6b are independently H or C1-C6 alkyl. is a compound of

[0092] In some embodiments, the compound of Formula (I) has Formula (IIIb) or Formula (IIIc): [ka] [In the formula, 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 selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6band 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 heterocyclyl; and Each R 6a and R 6b are independently H or C1-C6 alkyl. is a compound of

[0093] In some embodiments, the compound of Formula (I) has the formula (IV): [ka] [In the formula, R 1 , R 2 , R 7 and x is as described in formula (I); and [ka] is a 4- to 6-membered heterocyclyl.

[0094] In some embodiments, the compound of Formula (I) has the formula (IVa): [ka] [In the formula, R 7 is as described in formula (I); and [ka] is a 4- to 6-membered heterocyclyl.

[0095] In the description herein, it is understood that each description, variation, embodiment, or aspect of one moiety may be combined with each description, variation, embodiment, or aspect of another moiety, as if each combination of descriptions were specifically and individually listed. For example, R 1 Any description, variation, embodiment, or aspect of 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7 and x may be combined with any description, variation, embodiment, or aspect of x, as if each combination were specifically and individually listed. It is understood that any description, variation, embodiment, or aspect of formula (I) applies equally to and is described, where applicable, for other formulas detailed herein, as if every description, variation, embodiment, or aspect were listed separately and individually for all formulas. For example, where applicable, any description, variation, embodiment, or aspect of formula (I) applies equally to and is described, where applicable, for any formula detailed herein (e.g., formulas (II), (III), (IIIa), (IIIb), (IIIc), (IV), and (IVa)), as if every description, variation, embodiment, or aspect were listed separately and individually for all formulas.

[0096] In some embodiments, provided is a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. It is understood that any or all stereochemical configurations, including any enantiomers or diastereomers, and any tautomers or other forms, of any of the disclosed compounds, including those in Table 1, are described herein. [Table 1] [Table 2] [Table 3] [Table 4] or a pharmaceutically acceptable salt thereof.

[0097] It is understood that combinations of substituents and / or variables within the formulae described herein are permissible only if such combinations result in stable compounds.

[0098] Furthermore, all compounds of formula (I) that exist in free base or free acid form may be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid in a manner known to those skilled in the art. Salts of compounds of formula (I) may be converted into their free base or free acid forms by conventional methods.

[0099] Synthesis method The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or the methods described herein. For example, but not by way of limitation, compounds of formula (I) can be prepared as outlined in Scheme 1 and Scheme 2, as well as in the Examples described herein. It should be noted that it is recognized that the procedures shown in the described Schemes and Examples can be modified to obtain the desired products.

[0100] [ka] In the scheme, X is a halogen (e.g., Br); and R 1 , R 2 , and x are defined as in formula (I). Scheme 1 shows a synthetic route to acid intermediate I, which can be used to prepare compounds of Formula (I). Reductive amination of a and b gives c, which is then coupled with d, for example, under palladium catalyzed conditions, to give e. Acidic deprotection of e gives amine f, which is coupled with g to give h. In the final step, hydrolysis of ester h gives acid intermediate 1.

[0101] [ka] In the scheme, R 1 , R 2 , R 3 , R 4 , and x is as described in formula (I). Scheme 2 shows a synthetic route to compounds of formula (I): Acid intermediate 1 is coupled with amine reagent 1 (eg, HATU) to give compounds of formula (I).

[0102] How to use An embodiment of the present disclosure provides a method for modulating sphingosine 1-phosphate receptor 5 (S1P5) in a patient in need of treatment, comprising administering to the subject an effective amount of a compound of Formula (I). Modulation (e.g., inhibition or activation) of S1P5 can be assessed and demonstrated by various methods known in the art. Kits and commercially available assays may be used to determine whether and to what extent S1P5 is modulated (e.g., inhibited or activated).

[0103] In some embodiments, the present application provides a method for modulating S1P5, comprising contacting S1P5 with an effective amount of a compound of formula (I), or any embodiment or variation thereof. In some embodiments, the compound of formula (I) inhibits S1P5. In other embodiments, the compound of formula (I) activates S1P5. In some embodiments, the compound of formula (I) is an agonist of S1P5. In some embodiments, the compound of formula (I) is an antagonist of S1P5.

[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) may enhance 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%, 86-100%, 87-100%, 88-100%, 89-100%, 90-100%, 91-100%, 92-100%, 93-100%, 94-100%, 95-100%, 96-100%, 97-100%, 98-100%, 99-100%, 100-100%, 101-100%, 102-102%, 103-103%, 104-104%, 105-105%, 106-106%, 107-107%, 108-108%, 109-109%, 110-109%, 111-109%, 112-109%, 113-109%, 114-109%, 115-109%, 116-109%, 117-109%, 118-109%, 119-109%, 120-109%, 121-109%, 122-109%, 123-109%, 124-124%, 125-109%, Adjust from 5-100%, 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 patient in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, the present application provides a method for inhibiting a neurological disorder in a patient, comprising administering to the subject an effective amount of a compound of Formula (I). Examples of neurological disorders include, but are not limited to, Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), migraine, Bell's palsy, ataxia, cerebral aneurysm, epilepsy, seizures, acute spinal cord injury, Guillain-Barré syndrome, meningitis, Niemann-Pick disease, and Parkinson's disease. In some embodiments, the neurological disorder is Alzheimer's disease or multiple sclerosis. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments, the neurological disorder is multiple sclerosis.

[0106] In some embodiments, administering a compound of Formula (I) to a subject susceptible to a neurological disorder prevents the subject from developing any symptoms of the neurological disorder (e.g., tumor growth or metastasis). In some embodiments, administering a compound of Formula (I) to a subject who does not yet exhibit symptoms of a neurological disorder prevents the subject from developing any symptoms of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need thereof alleviates the severity of the neurological disorder in the subject. In some embodiments, administering a compound of Formula (I) to a patient in need thereof stabilizes the neurological disorder (prevents or slows the worsening of the neurological disorder). In some embodiments, administering a compound of Formula (I) to a patient in need thereof delays the onset or recurrence of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need thereof slows the progression of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need thereof results in partial remission of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need thereof results in complete remission of the neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment reduces the dosage of one or more other drugs required to treat a neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment enhances the effectiveness of another drug used to treat a neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment slows the progression of a neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need improves the quality of life of a subject suffering from a neurological disorder. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment prolongs the survival of a subject suffering from a neurological disorder.

[0107] In certain aspects, provided herein are methods for preventing a subject susceptible to a neurological disorder from developing any symptoms of the neurological disorder, comprising administering to the subject a compound of Formula (I). In some embodiments, provided herein are methods for preventing a subject from developing any symptoms of the neurological disorder by administering a compound of Formula (I) to a subject who does not yet exhibit symptoms of the neurological disorder.

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

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

[0110] In some embodiments, the present application provides a method of slowing the progression of a neurological disorder in a subject, comprising administering to the subject a compound of Formula (I). In some embodiments, the method results in partial amelioration of the neurological disorder. In some embodiments, the method results in complete amelioration 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] Also provided herein are methods for slowing the progression of a neurological disorder in a subject, comprising administering to the subject a compound of Formula (I). In some embodiments, the methods improve the quality of life of a subject suffering from a neurological disorder. In some embodiments, the methods extend the survival of a subject suffering from a neurological disorder.

[0113] In another aspect, the present application provides a method for treating neurological symptoms caused by a disease in a patient in need of treatment, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, the present application provides a method for inhibiting neurological symptoms caused by a disease in a patient in need of treatment, comprising administering to the subject an effective amount of a compound of Formula (I). In some embodiments, administering a compound of Formula (I) to a subject susceptible to a disease that causes neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of Formula (I) to a subject who has not yet exhibited neurological symptoms of a disease that causes neurological symptoms prevents the subject from developing any neurological symptoms. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment reduces the severity of neurological symptoms caused by the disease in the subject. In some embodiments, administering a compound of Formula (I) to a patient in need of treatment stabilizes neurological symptoms of the disease (prevents or delays the worsening of neurological symptoms). In some embodiments, administering a compound of Formula (I) to a patient in need of treatment delays the onset or recurrence of neurological symptoms caused by the disease. In some embodiments, administering a compound of Formula (I) to a patient in need thereof slows the progression of neurological symptoms caused by the disease. In some embodiments, administering a compound of Formula (I) to a patient in need thereof partially ameliorates the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a patient in need thereof completely ameliorates the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a patient in need thereof reduces the dosage of one or more other medications required to treat the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a patient in need thereof enhances the efficacy of another medication used to treat the neurological symptoms of the disease. In some embodiments, administering a compound of Formula (I) to a patient in need thereof slows the progression of the disease causing neurological symptoms. In some embodiments, administering a compound of Formula (I) to a patient in need thereof improves the quality of life of a subject suffering from a disease causing neurological symptoms.In some embodiments, administering a compound of Formula (I) to a patient in need thereof prolongs survival 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 useful for treating Alzheimer's disease, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme disease arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathies, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, scleroderma, graft-versus-host disease, organ transplant rejection (including, but not limited to, bone marrow transplant and solid organ transplant rejection), acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atheroma, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, granulomatosis with polyangiitis, Henoch-Schönlein purpura, microscopic polyangiitis of the kidney, chronic active pneumonia, uveitis, septic shock, toxic shock syndrome, septic syndrome, cachexia, infections, parasitic diseases, acute transverse myelitis, Huntington's disease, Parkinson's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignant tumors, heart failure, myocardial infarction, Addison's disease, sporadic polyglandular deficiency syndrome type 1 and polyglandular deficiency syndrome type 2, Schmidt's syndrome , acute (adult) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthritis, arthropathy, reactive arthritis, psoriatic arthritis, arthritis associated with ulcerative colitis, enteropathic synovitis, arthritis associated with chlamydia, yersinia, and salmonella, atherosclerosis, atopic allergy, autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA bullous dermatosis, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalomyelitis / Royal-Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosis Acute hepatitis, autoimmune hepatitis of unknown cause, acquired immunodeficiency syndrome, acquired immunodeficiency-related disease, hepatitis B, hepatitis C, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, infertility, female infertility, ovarian failure, premature menopause, fibrotic lung disease, chronic wounds, idiopathic pulmonary fibrosis (CFA), post-inflammatory interstitial lung disease, fibrosis, interstitial pneumonia, interstitial lung disease associated with collagen diseases, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis,Pulmonary disease associated with Sjögren's syndrome, pulmonary disease associated with ankylosing spondylitis, diffuse pulmonary disease associated with vasculitis, pulmonary disease associated with hemosiderosis, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, pulmonary disease with lymphocytic infiltration, post-infectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (standard autoimmune hepatitis or lupoid hepatitis), type 2 autoimmune hepatitis (anti-LKM-1 antibody positive hepatitis), autoimmune hypoglycemia, Acanthosis nigricans associated with type B insulin resistance, hypoparathyroidism, acute immune disorders associated with organ transplantation, chronic immune disorders associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritis, microscopic vasculitis of the kidney, Lyme disease, discoid lupus erythematosus, idiopathic male infertility or NOS, autoimmunity against sperm, multiple sclerosis (all subtypes), sympathetic Ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, autoimmune hypothyroidism with goiter (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, phacogenic uveitis, primary Vasculitis, leukoplakia, acute liver disease, chronic liver disease, alcoholic cirrhosis, alcoholic liver injury, cholestasis, specific liver diseases, drug-induced hepatitis, non-alcoholic steatohepatitis, allergies and asthma, group B streptococcus (GBS) infection, psychiatric disorders (such as depression and schizophrenia), Th2 and Th1 cell-mediated diseases, acute and chronic pain (different types of pain), and cancer and hematopoiesis of the lung, breast, stomach, bladder, colon, pancreas, ovary, prostate and rectum. Malignant tumors (leukemia and lymphoma), and hematopoietic malignancies (leukemia and lymphoma), abetalipoproteinemia, peripheral cyanosis, 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, ectopic atrial rhythm, AIDS-associated dementia, alcoholic hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis,Allograft rejection, alpha-1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration of the spinal cord, anti-CD3 antibody therapy, antiphospholipid syndrome, antireceptor hypersensitivity reaction, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (persistent or paroxysmal), atrial flutter, atrioventricular block, B-cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt lymphoma, burns, cardiac arrhythmias, myocardial stunning syndrome, cardiac tumors, cardiomyopathy, inflammatory reactions after cardiopulmonary bypass, cartilage graft rejection, cerebellar cortical changes Sexuality, cerebellar disorders, multifocal atrial tachycardia, chemotherapy-related disorders, chronic myeloid leukemia (CML), chronic alcoholism, chronic inflammatory diseases, 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, blood culture-negative sepsis, cystic fibrosis, cytokine therapy-related disorders, chronic traumatic encephalopathy, demyelinating diseases, dengue hemorrhagic fever, dermatitis, skin diseases, diabetes, diabetic atherosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglia disease , adult Down syndrome, drug-induced movement disorders due to central nervous system dopamine receptor blockers, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrine abnormalities, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hemophagocytic lymphohistiocytosis, rejection of fetal thymus transplants, Friedreich's ataxia, functional peripheral arterial disease, fungal sepsis, gas gangrene, gastric ulcer, glomerulonephritis, rejection of any organ or tissue graft, sepsis due to gram-negative bacteria, sepsis due to gram-positive bacteria, granuloma due to intracellular foreign bodies, hairy cell leukemia, pantothecin Phosphate kinase-associated neurodegeneration, Hashimoto's disease, hay fever, heart transplant rejection, hemochromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, bleeding, hepatitis (A), His bundle arrhythmia, HIV infection / HIV-associated peripheral neuropathy, Hodgkin's lymphoma, hyperkinetic movement disorder, hypersensitivity reaction, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorder, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-dependent cellular cytotoxicity, asthenia, infantile spinal muscular atrophy, aortic inflammation, influenza A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, ischemia,Ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, Legionella infection, leishmaniasis, leprosy, corticospinal tract disorders, lipedema, liver transplant rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytoma, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic migraine, mitochondrial disease, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple system atrophy (olivopontocerebellar atrophy, Shy-Drager syndrome, and Machado-Joseph disease), myasthenia gravis, nontuberculous mycobacteria Myelodysplastic syndrome (MAI), tuberculosis, myelodysplastic syndrome, myocardial infarction, ischemic heart disease, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrotic syndrome, neurodegenerative disease, neurogenic muscular atrophy, febrile neutropenia, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disease, OKT3 therapy, orchitis / epididymitis, orchitis / spermatic tract reconstruction surgery, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic cancer, paraneoplastic neurological syndrome / hypercalcemia associated with malignant tumors, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral arterial disease, peripheral vascular disease, peritonitis, pernicious anemia, new Mocystis (carinii) pneumonia, pneumonia, POEMS syndrome (syndrome of polyneuropathy, organomegaly, endocrine abnormalities, monoclonal gammopathy, and skin abnormalities), postoperative perfusion syndrome, post-myocardial infarction incision syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and Raynaud's disease, Refsum's disease, regular narrow-complex tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcoma, scleroderma, senile chorea, dementia with Lewy bodies, seronegative arthropathy, circulatory failure, sickle cell anemia, skin allograft rejection, skin abnormality syndrome , small intestinal transplant rejection, solid tumors, certain arrhythmias, spinal ataxia, spinocerebellar degeneration, streptococcal myositis, organic disease of the cerebellum, subacute sclerosing panencephalitis, syncope, cardiovascular syphilis, systemic anaphylaxis, systemic inflammatory response syndrome, systemic juvenile rheumatoid arthritis, T-cell acute lymphoblastic leukemia, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxic symptoms, transplant, trauma / bleeding, type III allergy (immune complex hypersensitivity), type IV allergy (delayed hypersensitivity), unstable angina, uremia, urosepsis, urticaria, valvular heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, ventricular fibrillation,Viral and fungal infections, viral encephalitis / aseptic meningitis, virus-associated hemophagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, any organ or tissue xenograft rejection, acute pain, age-associated memory impairment (AAMI), attention deficit disorder with anxiety, generalized attention deficit disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, cancer pain, central neuropathic pain, central post-stroke pain, chemotherapy-induced neurological disorders, cognitive dysfunction in psychiatric disorders, cognitive dysfunction associated with aging and neurodegenerative diseases, diabetes Cognitive impairment associated with diabetes, cognitive impairment in schizophrenia, complex regional pain syndrome, cognitive decline in Alzheimer's disease and Alzheimer's dementia, attention disorders, dementia, dementia associated with Down's syndrome, dementia with Lewy bodies, depression associated with Cushing's syndrome, central nervous system decline associated with traumatic brain injury, diseases with memory impairment, dizziness, substance abuse, epilepsy, sensory neuropathy associated with HIV infection, Huntington's disease, hyperalgesia including neuropathic pain, inflammation and inflammatory diseases, inflammatory hyperalgesia, inflammatory pain, insulin Neuron resistance syndrome, jet lag syndrome, circulatory insufficiency, learning disabilities, major depressive disorder, medullary thyroid carcinoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, emotional lability, motion sickness, multiple sclerosis pain, narcolepsy, the need for neovascularization associated with skin graft angiogenesis and circulatory insufficiency, the need for neovascularization associated with wound healing, neuropathic pain, neuropathy, neuropathy secondary to tumor invasion, non-inflammatory pain, obesity, obsessive-compulsive disorder, painful diabetic neuropathy, panic disorder, pain in Parkinson's disease, hypersomnia, phantom limb pain, It is useful for treating a disorder selected from Pick's disease, polycystic ovary syndrome, post-traumatic stress disorder, post-herpetic neuralgia, post-mastectomy pain, post-operative pain, psychotic depression, schizoaffective disorder, seizures, senile dementia, sepsis syndrome, sleep disorders, smoking cessation, spinal cord injury pain, steroid-induced acute psychosis, subclassifications of neuropathic pain including peripheral neuropathic pain syndrome, substance abuse including alcoholism, microvascular angina, Tourette's syndrome, treatment-resistant depression, trigeminal neuralgia, type II diabetes, vertigo, and vestibular disorders.

[0115] Pharmaceutical Compositions and Routes of Administration The compounds may be administered orally, topically, or parenterally to a subject in conventional formulations (e.g., capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions).

[0116] The compounds of the present disclosure may be administered orally, topically, or parenterally to a subject in conventional formulations (e.g., capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions). Suitable formulations may be prepared by common methods using conventional organic or inorganic additives. Such additives include, for example, 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., cellulose, methylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and the like. For example, magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavorings (e.g., citric acid, menthol, glycine, or powdered orange), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (I) in the pharmaceutical composition may be a level that exerts the desired effect.

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

[0118] The compound of formula (I) can be conveniently administered orally.In some embodiments, when the compound of formula (I) is administered orally, it is administered with food and water.In other embodiments, the compound of formula (I) is dispersed in water or juice (for example, apple juice or orange juice) or any other liquid, and is orally administered as a solution or suspension.

[0119] The compounds of the present disclosure may be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the health care practitioner and will depend in part on the site of the disease.

[0120] In certain embodiments, provided herein is a capsule comprising a compound of Formula (I) without other carriers, excipients, or vehicles.

[0121] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include an excipient, a diluent, or a mixture thereof. In certain embodiments, the composition is a pharmaceutical composition.

[0122] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions are formulated into dosage forms containing a daily dose or a manageable portion of the daily dose, which may be a single tablet or capsule or a manageable volume of solution. In some embodiments, solutions are prepared from water-soluble salts (e.g., hydrochlorides). Generally, all compositions are prepared according to methods known in medicinal chemistry. Capsules can be prepared by mixing a compound of Formula (I) with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Typical carriers and diluents include, but are not limited to, inert powdered substances such as various types of starch, powdered cellulose (e.g., crystalline cellulose and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), grain flours, and similar edible powders.

[0123] Tablets can be manufactured by direct compression, wet granulation compression, or dry granulation compression. These formulations typically contain diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose). Convenient natural and synthetic thickeners include gum arabic, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes also serve as binders.

[0124] In tablet formulations, lubricants may be necessary to prevent coloring agents from adhering to the tablet and punch. Lubricants may be selected from lubricating solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oil. Tablet disintegrants are substances that swell when wet, causing the tablet to disintegrate and release the compound. These include starch, clay, cellulose, algin, and gums. More specifically, corn starch, potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose may be used, as well as sodium lauryl sulfate. Tablets may be coated with sugar as a flavoring agent or with a film-forming protecting agent to modify the tablet's dissolution characteristics. The composition may also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0125] When it is desired to administer the compound of formula (I) as a suppository, a common base can be used.Cocoa butter is a conventional suppository base, and waxes can be added to slightly raise the melting point.In particular, water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0126] By appropriate formulation, it is possible to delay or prolong the effect of the compound of formula (I). For example, the compound of formula (I) can be prepared into slowly dissolving pellets and then incorporated into tablets or capsules, or can be incorporated as a sustained-release implant device. This technique also includes preparing pellets with different dissolution rates and filling a mixture of the pellets into capsules. Tablets or capsules can be coated with a film that is difficult to dissolve for a predictable period of time. The compound of formula (I) can be dissolved or suspended in an oily vehicle or emulsified vehicle that allows it to be slowly dispersed in serum, even in parenteral formulations, the duration of action can be extended.

[0127] Example of implementation The present disclosure is further illustrated by the following embodiments.

[0128] Embodiment 1. Formula (I): [ka] [In the formula, Each R 1 are independently C1-C6 alkyl, C3-C6 cycloalkyl, or halogen; Each R 2 are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 haloalkyl; x is 0 to 4; R 3 and R 4 are each independently 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 selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —NR 6a R 6b and C1-C6 alkoxy; or R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 forming an optionally substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains 1 to 2 heteroatoms selected from N and O; Each 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 heterocyclyl; Each R 6a and R 6b are independently H or C1-C6 alkyl; and Each R 7 are independently halogen, C1-C6 alkyl, -OH, C1-C6 alkoxy, or -NR 6a R 6b is] or a pharmaceutically acceptable salt thereof.

[0129] Embodiment 2. During the ceremony, Each R 1 are independently C1-C3 alkyl, C3-C6 cycloalkyl, or halogen; 2. A compound of embodiment 1, or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 3. During the ceremony, Each R 1 are independently -CH3, cyclopropyl, F, Cl, or Br; 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 4. During the ceremony, Each R 1 The compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is Cl.

[0132] Embodiment 5. During the ceremony, x is 1 to 4; and Each R 2 are independently halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C1-C3 haloalkyl; A compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 6. During the ceremony, x is 2 or 3; and Each R2 is independently Cl, F, —CH 3 , —OCH 3 , cyclopropyl, or —CF 3 , or a pharmaceutically acceptable salt thereof.

[0134] Embodiment 7. During the ceremony, x is 2; and Each R 2 is -CH3, The compound of embodiment 6, or a pharmaceutically acceptable salt thereof.

[0135] Embodiment 8. During the ceremony, 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 is optionally selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OH, —NR 6a R 6b and C1-C3 alkoxy; Each R 5a and R 5b are 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- or 6-membered heterocyclyl; and Each R 6a and R 6b are independently H or C1-C3 alkyl; A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 9. During the ceremony, R 3 and R 4are independently H, -CH, -CH(CH), -CHCH(CH), -CHCHCH(CH), -CHCHOCH, -CHCHOH, -CHCHN(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH(cyclopropyl), -CH(cyclohexyl), or -CHCH(pyrrolidinyl), wherein each cycloalkyl is optionally substituted with one group selected from -OH and -N(CH); The compound of embodiment 8, or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 10. During the ceremony, [ka] but, [ka] 10. The compound of embodiment 9, wherein:

[0138] Embodiment 11. During the ceremony, R 3 and R 4 However, they are combined with the nitrogen atom to which they are bonded to form one or two R 7 forming an optionally substituted 5- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains one heteroatom selected from N and O; Each R 7 are independently halogen, C1-C3 alkyl, -OH, C1-C3 alkoxy, or -NR 6a R 6b and Each R 6a and R 6b are independently H or C1-C3 alkyl; A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof.

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

[0140] Embodiment 13. During the ceremony, [ka] but, [ka] 13. The compound of embodiment 12, wherein:

[0141] Embodiment 14. wherein the compound has the formula (II): [ka] 14. The compound of any one of embodiments 1 to 13, wherein:

[0142] Embodiment 15. wherein the compound has the formula (IIIa): [ka] [In the formula, R 3 is H or C1-C6 alkyl; R 4is 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 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 heterocyclyl; and Each R 6a and R 6b are independently H or C1-C6 alkyl] 15. The compound of any one of embodiments 1 to 14, wherein:

[0143] Embodiment 16. 3. The compound of formula (IVa): [ka] [In the formula, [ka] is a 4- to 6-membered heterocyclyl] 15. The compound of any one of embodiments 1 to 14, wherein:

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

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

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

[0147] EMBODIMENT 20 A method for treating a neurological disorder in a patient in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18.

[0148] EMBODIMENT 21 21. The method of embodiment 20, wherein said neurological disease is Alzheimer's disease or multiple sclerosis.

[0149] Example The following examples are provided for illustrative purposes and are not intended to be limiting. Compounds were named using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and follows the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art may modify the procedures of the described examples to obtain the desired products.

[0150] Salts of the compounds described herein can be prepared by standard methods, such as adding an acid (e.g., TFA, formic acid, or HCl) to the mobile phase during chromatographic purification, or stirring the product after chromatographic purification with an acidic solution (e.g., hydrochloric acid).

[0151] The following abbreviations may be relevant to this application: [Table 5]

[0152] Synthesis Examples Example S1. Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I) [ka]

[0153] Synthesis of methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate [ka] A solution of ZnCl (1.9 M, Me-THF, 19.8 mL, 37.54 mmol, 2.00 equiv) and NaBHCN (4.72 g, 75.09 mmol, 4.00 equiv) in methanol (8 mL) was stirred at room temperature for 10 minutes, followed by the addition of 4-bromo-2,6-dimethyl-benzaldehyde (4 g, 18.77 mmol, 1.00 equiv) and methyl piperidine-4-carboxylate (5.38 g, 37.55 mmol, 2.00 equiv) and stirring at 80 °C overnight, when LCMS showed the reaction was complete. The reaction mixture was poured into DCM / HO (1 / 1, 100 mL). The separated organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (eluent: 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. LCMS(ESI, m / z): 340[M+H] +

[0154] Synthesis of methyl 1-(4-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2,6-dimethylbenzyl)-piperidine-4-carboxylate [ka] To a stirred solution of tert-butyl 3-iodoazetidine-1-carboxylate (13.24 g, 46.75 mmol, 10.0 equiv.) in DMF (75 mL), zinc powder (4.41 g, 67.48 mmol, 15.0 equiv.) was added and stirred at 60 °C for 5 hours. Methyl 1-(4-bromo-2,6-dimethylbenzyl)piperidine-4-carboxylate (1.5 g, 4.41 mmol, 1.00 equiv.), Pd(dba) (807 mg, 0.88 mmol, 0.200 equiv.), and tri(o-tolyl)phosphine (1.34 g, 4.41 mmol, 1.00 equiv.) were then added and stirred at 80 °C overnight. LCMS indicated the reaction was complete. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (C18 silica, elution: 100% ACN) 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. LCMS(ESI, m / z): 417 [M+H] +

[0155] Synthesis of methyl 1-(4-(azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylate-2,2,2-trifluoroacetaldehyde [ka] 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) was added TBSOTf (1.53 mL, 8.64 mmol, 2.00 equiv) dropwise at room temperature and stirred at room temperature for 1 hour. After LCMS showed the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (C18 silica, elution: 22% ACN / 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. LCMS(ESI, m / z): 317 [M+H] +

[0156] Synthesis of methyl 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)-piperidine-4-carboxylate [ka] 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-dichloro-benzene (2.86 g, 12.64 mmol, 2.00 equiv) in 1,4-dioxane (2 mL), RuPhos Pd G3 (884 mg, 0.95 mmol, 0.15 equiv), RuPhos (442 mg, 0.95 mmol, 0.15 equiv), and CsCO3 (6.16 g, 18.96 mmol, 3.00 equiv) were added and stirred overnight at 90 °C under a nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was diluted with EtOAc (20 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (C18 silica, elution: 90% ACN / 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. LCMS(ESI, m / z): 461 [M+H] +

[0157] Synthesis of 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I) [ka] 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, and LCMS showed the reaction was complete. The reaction mixture was acidified to pH 5-6 with acetic acid and then concentrated under reduced pressure. The resulting 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: elution from 30% to 60% B over 7 min; wavelength: 254 / 220 nm; retention time: 5.92 min) to give 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. 1 H NMR (400MHz, DMSO-d6) δ 7.24(d, J=7.6Hz, 2H), 7.03(s, 2H), 6.74(t, J=7.6Hz, 1H), 4.80(t, J=8.0Hz, 2H), 4.34(t, J=8.0Hz, 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) LCMS(ESI, m / z): 447 [M+H] + Analysis conditions: Column: YMCMeteoric C18 BIO, 2.1*30mm, 2.7μm; Mobile phase A: Water (5mM NH4HCO3), Mobile phase B: Acetonitrile; Flow rate: 1.20mL / min; Gradient: 10%B to 95%B in 1.20min, followed by 95% in 0.58min, then 95%B to 10%B in 0.05min; 254nm; Retention time: 0.849min

[0158] Example S2. Synthesis of amide compound 1-26 General Amide Synthesis [ka] Starting material: 1-(4-(1-(2,6-dichlorophenyl)azetidin-3-yl)-2,6-dimethylbenzyl)piperidine-4-carboxylic acid (acid intermediate I, 650 mg) was dissolved in DMF (9.0 mL) (solution 1). Coupling agent: HATU (715.937 mg) was dissolved in DMF (10.8 mL) (solution 2). The corresponding amine component (amine reagent I, 2.85 equiv., 0.115 mmol, Table 2) was added to a reaction vial, followed by the addition of 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 equiv.), HATU (0.299 mL of solution 2, 0.052 mmol, 1.3 equiv.), and Hunig's base (0.042 mL, 0.241 mmol, 6 equiv.). The resulting mixture was placed in a Bohdan Miniblock XT and stirred at 400 rpm for 6 h at room temperature. The crude reaction mixture was purified by preparative reverse-phase chromatography (conditions: column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by UV (220 nm) and MS (ESI positive mode). Fractions containing the desired product were combined and dried in a centrifugal evaporator. Analytical reverse phase chromatography was used to determine final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; 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 positive / negative mode). Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; 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 positive / negative mode). 1 1 H NMR was measured in deuterated DMSO. The amine reagents I used in the reactions to produce compounds 1 to 26 are shown in Table 2. In Table 2, each number corresponds to the final compound of the same number. For example, the amine reagent number 1 in Table 2 is used to produce compound 1. [Table 6] [Table 7]

[0159] The characteristic data of compounds 1 to 26 are shown in Table 3. [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0160] Biological Examples Example B1. Preparation of cell membranes Recombinant S1P5 receptor expressed in CHO cells was injected at 500 cm 2Cells were cultured in 100-well culture trays and, upon reaching confluence, were rinsed and detached with cell detachment buffer (10 mM HEPES, 154 mM NaCl, 6.85 mM EDTA, pH 7.4). Cells were then pelleted by centrifugation, resuspended in membrane preparation buffer (10 mM HEPES and 10 mM EDTA, pH 7.4), and homogenized using a Polytron homogenizer (PT1200E, Kinematica, Luzern, Switzerland). Cell proteins were pelleted by centrifugation (48,000 x g) for 30 minutes at 4°C. The resulting supernatant was discarded, and the pellet was resuspended in membrane preparation buffer and homogenized a second time, then centrifuged again as above. The final cell protein pellet was suspended in ice-cold resuspension buffer (10 mM HEPES and 0.1 mM EDTA, pH 7.4), aliquoted, and stored at -80°C until use.

[0161] Example B2. GTPγS Binding Assay In a 96-well non-binding surface plate, 35Functional binding assays for [S]-GTPγS were performed in a final volume of 200 μL. Test compounds were serially diluted in DMSO and added to the assay plate (total volume 0.4 μL) using a D300e digital dispenser (Tecan). A 400 μM stock solution was made from 100 nmol of S1P pellet in 10 mM Na2CO3 (containing 2% β-cyclodextrin), and a control sphingosine-1-phosphate (S1P) was prepared separately. Serial dilutions of S1P were made in complete assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.1% bovine serum albumin (BSA, fatty acid-free), and 30 μg / mL saponin, pH 7.4) and added to wells already containing DMSO (0.4 μL). Complete assay buffer was then added to all wells except the nonspecific binding (NSB) wells, for a total volume of 40 μL. For NSB wells, 40 μL of 50 μM GTPγS (Sigma Aldrich, cat# G8634, St. Louis, MO) was added per well to 0.4 μL of DMSO. The assay was initiated by adding 120 μL / well of CHO-S1P receptor membrane solution containing membrane protein (40 μg / mL), guanosine diphosphate (GDP, 16.67 μM, Sigma Aldrich, cat# G7127, St. Louis, MO), and WGA PVT SPA beads (2.5 mg / mL) in complete buffer. The assay plate was then sealed and incubated at room temperature for 30 minutes with gentle agitation. Next, 1 nM [ 3540 μL of [S]-GTPγS (PerkinElmer, cat# NEG030X250UC, Waltham, MA) / assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl, and 1 mM EDTA, pH 7.4) was added per well to the assay plate to a final concentration of 200 pM. The plate was further incubated for 40 minutes at room temperature with gentle agitation. The assay was terminated by centrifugation of the plate at 1000 rpm for 3 minutes in an Eppendorf high-speed centrifuge (5810R, Hamburg, Germany). G protein-bound radioactivity was measured using a MicroBeta2 microplate scintillation counter (PerkinElmer, Waltham, MA). Because G protein-bound radioactivity directly correlates with receptor activation and G protein coupling, this assay allows for measurement of S1P5 agonist function. The results are shown in Table 4. [Table 13] ++++ indicates binding of 1 nM<~≦10 nM. +++ indicates binding of 10 nM<~≦100 nM. ++ indicates binding of 100 nM<~≦1,000 nM. + indicates binding of 1,000 nM <~ ≤ 10,000 nM.

[0162] For purposes of clarity of understanding, the present invention has been described in some detail by way of illustration and example, but such illustrations and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Each R 1 independently C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl, or halogen; Each R 2 are independently halogens, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, or C 1 -C 6 is haloalkyl; x is 0 to 4; R 3 and R 4 are independently H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), C 3 -C 6 Cycloalkyl, -(C 1 -C 6 alkylene)(C 3 -C 6 cycloalkyl), or -(C 1 -C 6 Alkylene)NR 5a R 5b wherein each cycloalkyl optionally contains halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OH, -NR 6a R 6b , and C 1 -C 6 alkoxy; or R 3 and R 4 are combined with the nitrogen atom to which they are attached to form 1 to 5 R 7 forming an optionally substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains 1 to 2 heteroatoms selected from N and O; Each R 5a and R 5b are independently H or C 1 -C 6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R 6a and R 6b are independently H or C 1 -C 6 is alkyl; and Each R 7 are independently halogens, C 1 -C 6 Alkyl, -OH, C 1 -C 6 Alkoxy, or -NR 6a R 6b is] or a pharmaceutically acceptable salt thereof.

2. During the ceremony, Each R 1 But independently C 1 -C 3 Alkyl, C 3 -C 6 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl, or halogen.

3. During the ceremony, Each R 1 But independently -CH 3 , cyclopropyl, F, Cl, or Br, or a pharmaceutically acceptable salt thereof.

4. During the ceremony, Each R 1 The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is Cl.

5. During the ceremony, x is 1 to 4; and Each R 2 are independently halogens, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 3 -C 6 Cycloalkyl, or C 1 -C 3 haloalkyl, 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. During the ceremony, x is 2 or 3; and Each R 2 are independently Cl, F, -CH 3 , -OCH 3 , cyclopropyl, or -CF 3 That is, 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof.

7. During the ceremony, x is 2; and Each R 2 Ga-CH 3 7. The compound of claim 6, wherein:

8. During the ceremony, R 3 and R 4 However, independently H, C 1 -C 5 Alkyl, C 1 -C 3 Alkyl-OH, -(C 1 -C 3 alkylene)-O-(C 1 -C 3 alkyl), C 3 -C 6 Cycloalkyl, -(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), or -(C 1 -C 3 Alkylene)NR 5a R 5b wherein each cycloalkyl optionally contains halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -OH, -NR 6a R 6b , and C 1 -C 3 optionally substituted with 1 to 2 groups selected from alkoxy; Each R 5a and R 5b but independently H or C 1 -C 3 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl; and Each R 6a and R 6b but independently H or C 1 -C 3 is alkyl, 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. During the ceremony, R 3 and R 4 However, independently H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 (cyclopropyl), -CH 2 (cyclohexyl), or -CH 2 CH 2 (pyrrolidinyl), where each cycloalkyl is optionally —OH and —N(CH 3 ) 2 optionally substituted with one group selected from 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof.

10. During the ceremony, 【Chemistry 2】 but, 【Transformation 3】 10. The compound of claim 9, wherein:

11. During the ceremony, R 3 and R 4 However, they are combined with the nitrogen atom to which they are bonded to form one or two R 7 forming an optionally substituted 5- to 6-membered heterocyclyl, wherein the heterocyclyl optionally further contains one heteroatom selected from N and O; Each R 7 are independently halogens, C 1 -C 3 Alkyl, -OH, C 1 -C 3 Alkoxy, or -NR 6a R 6b and Each R 6a and R 6b but independently H or C 1 -C 3 is alkyl, 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

12. During the ceremony, R 3 and R 4 However, together with the nitrogen atom to which they are attached, they form one R 7 forming a 5- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl optionally further contains one heteroatom selected from N and O; and R 7 -OH, -CH 3 , -OCH 3 , or -N(CH 3 ) 2 That is, 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

13. During the ceremony, 【Chemistry 4】 but, 【Transformation 5】 13. The compound of claim 12, wherein:

14. wherein the compound has the formula (II): 【Transformation 6】 14. The compound of any one of claims 1 to 13, wherein:

15. wherein the compound has the formula (IIIa): 【Transformation 7】 [In the formula, R 3 is H or C 1 -C 6 is alkyl; R 4 is H, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH, -(C 1 -C 6 alkylene)-O-(C 1 -C 6 alkyl), C 3 -C 6 Cycloalkyl, -(C 1 -C 6 alkylene)(C 3 -C 6 cycloalkyl), or -(C 1 -C 6 Alkylene)NR 5a R 5b wherein each cycloalkyl optionally contains halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OH, -NR 6a R 6b , and C 1 -C 6 optionally substituted with 1 to 5 groups selected from alkoxy; R 5a and R 5b are independently H or C 1 -C 6 alkyl; or R 5a and R 5b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; and Each R 6a and R 6b are independently H or C 1 -C 6 alkyl] 15. The compound of any one of claims 1 to 14, wherein:

16. 3. The compound of formula (IVa): 【Transformation 8】 [In the formula, 【Chemistry 9】 is a 4- to 6-membered heterocyclyl.

15. The compound of any one of claims 1 to 14, wherein:

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

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

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

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

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