Inhibitors of Spinster homolog 2 (SPNS2) for therapeutic use

Abstract

This disclosure provides SPNS2 inhibitor compounds of formula I, where T, U, V, W, X, R 1 , R 2 , and m are defined herein. The disclosure also provides pharmaceutically acceptable salts and / or tautomers of the compounds of formula I described herein. Methods of using them in the treatment of diseases requiring immunomodulatory and / or antifibrotic activity are also provided. TIFF2026514377000599.tif18128TIFF2026514377000600.tif104158

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 492,062, filed on 24 March 2023, and U.S. Provisional Patent Application No. 63 / 512,698, filed on 10 July 2023, which are incorporated as if they were entirely contained herein.

[0002] Government licensing rights This invention was made with government support under grant number R01 AI144026, awarded by the National Institutes of Health. The government has certain rights to the invention. [Background technology]

[0003] background Sphingosine 1-phosphate (S1P) is a chemotactic lipid. This role requires compartmentalization, which is partially provided by S1P transporters on the cell surface. There are two distinct types of S1P transporters: SPNS2 (endothelial cells, microglial cells) and MFSD2B (erythrocytes, platelets). When S1P release is linked to S1P degradation in tissue parenchyma, a difference in S1P concentration occurs between extracellular (high) and intracellular (low) regions. In blood, the S1P gradient helps maintain the integrity of the endothelial barrier, while other S1P concentration gradients control the placement of immune cells.

[0004] S1P is particularly important for the release of lymphocytes from secondary lymphoid tissues to efferent lymphoid cells. S1P receptor modulators (SRMs) shield lymphocytes from S1P by desensitizing the S1P1 receptor. However, SRM agonist activity at endothelial and cardiac S1P1 receptors causes adverse events such as bradycardia and macular edema upon initial administration. Therefore, other methods are needed to modulate the migration of immune cells by blocking S1P signaling. [Overview of the project]

[0005] overview In various aspects, the present disclosure meets this and other needs by providing compounds according to Formula I and their pharmaceutically acceptable salts as SPNS2 inhibitors that avoid adverse effects on targets: TIFF2026514377000002.tif18128

[0006] X is C6 - C 10 , 10 , 12 , 10 , 10 , 10 , 10 aryl or 5 - to 10 - member heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S).

[0007] R 1 and R 2 are independently selected from the group consisting of H, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkoxy, C3 - C8 cycloalkyl, C1 - C6 haloalkyl, CN, and halo.

[0008] W is a bond, O, NH, -NHC(O)-, or -O-(N=)C(R)- (where R is H or C1 - C6 alkyl).

[0009] In some aspects, U is (A) a 6 - to 8 - member heterocycloalkyl, optionally fused, bridged, or spiro - fused, where two ring atoms are N. In these aspects, V is H, C1 - C 14 alkyl, C2 - C 12 alkenyl, (C6 - C 10 )aryl, (C6 - C 10 )heteroaryl, -C1 - C 10 alkyl-(C6 - C 10 )aryl, -C2 - C 12 alkenyl-(C6 - C 10 )aryl, -C1 - C 10 alkyl-(C3 - C8)cycloalkyl, -(3 - to 14 - member heterocycloalkyl) (where 1 to 4 heterocycloalkyl members are independently selected from N, O, and S), -(C1 - C 10Selected from the group consisting of alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S).

[0010] In another embodiment, U is (B) a monocyclic 4- to 7-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl members are independently selected from N, O, and S). In these embodiments, V is H, -C1-C 14 Alkyl, -C1~C 10 Alkyl-O-(C3~C 14 ) Cycloalkyl, -C1~C 10 Alkyl-O-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-NR x -(C6~C 10 ) Aryl, -C1~C 10 Alkyl-NR x C(O)(C6~C 10 ) Aryl, -C1~C 10 Alkyl-C(O)NR x (C6~C 10 ) Aryl, -C2~C 12 Alkenyl-O-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-O-(C6~C 10 )heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S), and -C2~C 12 Alkenyl-O-(C6~C 10 ) Selected from the group consisting of heteroaryls (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S).

[0011] T is -C(O)- or -NR x It is C(O)-.

[0012] R x It is either H or a C1-C6 alkyl group.

[0013] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0014] In Formula I, each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl are hydroxy, halo, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, -NR'2, -NHC(O)(OC1-C6 alkyl), -NO2, -CN, oxo, -C(O)OH, -C(O)O(C1-C6 alkyl), -C1-C6 alkyl(C1-C6 alkoxy), -C(O)NH2, C1-C6 alkoxy, C3-C 14 Cycloalkyl, -C(O)C1~C6alkyl, -OC1~C6alkyl, -Si(C1~C6alkyl)3, -S(O) O~2 -(C1~C6 alkyl), C6~C 10 Aryl, -(C1~C6 alkyl)(C6~C 10 aryl), 3-14 member heterocycloalkyl and -(C1-C6 alkyl)-(3-14 member heterocycle) (where 1-4 heterocycle members are independently selected from N, O, and S), as well as -O(C6-C 14 It may be substituted with 1 to 5 substituents independently selected from the group consisting of aryls.

[0015] Each R' independently consists of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C6-C 10 The group is selected from aryls, 3-14 member heterocycloalkyls and -(C1-C6 alkyl)-(3-14 member heterocycloalkyls) (where 1-4 ring members are independently selected from N, O, and S), and 5-10 member heteroaryls (where 1-4 heteroaryl members are independently selected from N, O, and S).

[0016] Another aspect of this disclosure is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, this disclosure also provides a method for inhibiting SPNS2, which includes contacting spinster homolog 2 (SPNS2) with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0018] In yet another aspect, the present disclosure provides a method for treating a patient suffering from a neoplastic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0019] In yet another aspect, the Disclosure provides a method for treating a patient suffering from an allergic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present disclosure provides a method for treating a patient suffering from an autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the present disclosure provides a method for treating a patient with a fibrotic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0022] [Figure 1] Figure 1 shows representative datasets for each Spns2-dependent S1P transport blocker (STB) in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Mice (female, C57BL / 6 strain, 11 weeks old) were vaccinated with MOG35-55 peptide and treated with pertussis toxin on day 0. When symptoms appeared in the animals, they were randomly assigned to the treatment group (N=12), and clinical scores were measured until day 35. Therapeutic agents were administered once daily via enteral nutrition. The dose for the positive control (fingolimod, FTY720) was 3 mg / kg / day. Two representative STB compounds, A and B, of this disclosure were administered at doses of 30 and 10 mg / kg / day, respectively. [Modes for carrying out the invention]

[0023] Detailed explanation For the immune system to function properly, the correct temporal arrangement of immune cells is essential. The chemotactic lipid sphingosine 1-phosphate (S1P) is crucial for the correct arrangement of immune cells. The release of lymphocytes from secondary lymphoid tissues such as lymph nodes, for example, depends on S1P signaling. The role of S1P in lymphocyte transport was discovered when investigating the mechanism of action of the immunosuppressant fingolimod (FTY720). Phosphorylated FTY720, an active metabolite of fingolimod, desensitizes lymphocytes' S1P1 receptors, preventing these cells from detecting S1P. 1 The resulting lymphopenia serves as a pharmacodynamic marker for such S1P1 receptor agonists. Fingolimod and other S1P receptor modulators are currently used to treat autoimmune diseases such as relapsing-remitting multiple sclerosis. 2 This class of drugs has several effects on its target, including bradycardia and impaired endothelial barrier function upon initial administration. 2 Therefore, alternative strategies are needed to modulate the immune system at the S1P signaling level. This disclosure addresses this need.

[0024] S1P is widely synthesized, but its intracellular accumulation is limited by degradation and transport. In lymph nodes (LNs), for example, S1P concentrations are kept low by active catabolism by S1P lyase. 1 In mouse strains lacking the S1P transporter SPNS2, S1P in the lymph is almost undetectable, suggesting that lymphatic endothelial cells excrete S1P into the lymph via SPNS2, creating a lymph-LN S1P concentration gradient. 3Similarly, the plasma S1P gradient is maintained by significant S1P catabolism in tissue parenchyma (excluding blood), linked to the excretion of S1P into plasma by red blood cells (RBCs). In mouse strains lacking the S1P transporter MFSd2b, RBC S1P levels are abnormally high and plasma S1P levels are decreased, indicating that MFSd2b, which is distantly related to SPNS2, provides S1P to the plasma. 4,5 Unlike SPNS2-deficient mice, Mfsd2b-deficient mice do not show a decrease in circulating lymphocyte count. 4 The plasma-tissue S1P concentration gradient is important for maintaining the integrity of the endothelial barrier. 6,7 .

[0025] Given the role of the catabolic enzyme S1P lyase in maintaining low LN S1P levels, it is predicted that S1P lyase inhibitors eliminate the lymph-LN S1P gradient, thereby modulating the immune system by interfering with lymphocyte migration, similar to S1P1 agonists. Indeed, S1P lyase deficiency, whether caused by genetic engineering of mice or administration of S1P lyase inhibitors, elevates S1P levels in tissues, including lymph nodes, leading to lymphopenia. 1,8 However, it was found that administering selective S1P lyase inhibitors to rats and inducing systemic deletion of the S1P lyase gene (Sgpl1) in mice were both nephrotoxic. 8 .

[0026] In mice lacking SPNS2, either through germline or endothelial-specific deletion, S1P levels in thoracic duct lymph are almost undetectable (i.e., reduced more than 10-fold), but the effect on the vascular S1P gradient is minimal (various reports indicate a 0-45% decrease in plasma S1P in SPNS2-deficient mouse strains). 9~12These results, when considered in the context of the accepted mechanism of action of S1P receptor modulators (see above), lead to the prediction that SPNS2 inhibitors, like S1P lyase inhibitors, reduce the S1P gradient in the lymph, thereby inhibiting lymphocyte migration and replicating the therapeutic effect of S1P1 receptor agonists. Indeed, studies using SPNS2-dependent S1P transport inhibitors previously disclosed by the inventors have demonstrated that circulating lymphocyte counts in mice and rats decrease as a function of the administration of the inhibitors. 13,14 .

[0027] The use of SPNS2 inhibitors in immuno-oncology may stem from other mouse genetic studies. 15 In a screening of 810 mouse strains with deletions of different germline genes, Spns2 - / - Mice were found to have significantly reduced lung metastatic colony formation when intravenously injected with B16-F10 melanoma cells. This effect was also observed in other lung metastatic colony formation models and similar models in the liver. As expected, lymphopenia Spns2 - / - In mice, the total number of immune cells in the lungs decreased, but natural killer (NK) and CD8 cells were found in the lung's normal cell population. + Effector cells increased proportionally. 15 .

[0028] The use of Spns2 inhibitors in antifibrotic therapy may stem from another study that utilized both mutant mouse lines and one of our Spns2 inhibitors. 16 Specifically, in two models of renal fibrosis, mice lacking Spns2 in pericytes and a Spns2 inhibitor (SLF1081851) were used. 13 Mice treated with this method showed significantly less fibrosis and improved function in damaged kidneys. 16 .

[0029] Therefore, results obtained from studies of Spns2-deficient mice indicate that SPNS2 inhibitors have immunomodulatory effects. The SPNS2 inhibitors of this disclosure replicate the SPNS2-deficient phenotype in terms of immunomodulation, enabling inhibition of S1P transport as a viable therapeutic strategy and providing a chemical biology tool for investigating the physiological function of S1P in vivo, which has not been available until now.

[0030] definition "Alkyl" refers to a linear or branched hydrocarbyl containing 1 to approximately 20 carbon atoms. For example, alkyls may have 1 to 14 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Exemplary alkyls include linear alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, as well as branched isomers of linear alkyl groups, for example, non-limitingly, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), and -CH2 This also includes CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, etc. Therefore, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Alkyl groups may be unsubstituted or substituted with one or more substituents listed below herein.

[0031] The term "substituted alkyl" refers to an alkyl group substituted at one or more positions, for example, at position 1, 2, 3, 4, 5, or even 6, where the substituents, through the substitutions described herein, can bond to any available atom to form a stable compound. "Optionally substituted alkyl" refers to an alkyl group or a substituted alkyl group.

[0032] "Haloalkyl" refers to an alkyl group as defined herein, substituted with at least one, for example, 1 to 8 halo substituents.

[0033] The terms "halogen," "halide," and "halo" all refer to -F, -Cl, -Br, or -I.

[0034] The term "alkenyl" refers to a linear or branched hydrocarbyl group containing 2 to about 20 carbon atoms, having 1 to 3, 1 to 2, or at least 1 carbon-carbon double bonds. The alkenyl group may be unsubstituted or substituted with one or more substituents as described below herein.

[0035] "Substitutive alkenyl" refers to an alkenyl in which one or more positions, for example, 1, 2, 3, 4, 5, or even 6, are substituted, and the substituents, through substitution as described herein, can bond to any available atom to form a stable compound. "Optionally substituted alkenyl" refers to an alkenyl or a substituted alkenyl.

[0036] "Alkyne" or "alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond. Examples of (C2-C8)alkynyl groups include, but not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentine, 2-pentine, 1-hexine, 2-hexine, 3-hexine, 1-heptine, 2-heptine, 3-heptine, 1-octyne, 2-octyne, 3-octyne, and 4-octyne. The alkynyl group may be unsubstituted or substituted with one or more substituents listed below herein.

[0037] "Substitutive alkynyl" refers to an alkynyl in which one or more positions, for example, 1, 2, 3, 4, 5, or even 6, are substituted, and the substituents, through the substitutions described herein, can bond to any available atom to form a stable compound. "Optionally substituted alkynyl" refers to an alkynyl or a substituted alkynyl.

[0038] The term "alkoxy" refers to an -O-alkyl group having the indicated number of carbon atoms. For example, (C1-C6) alkoxy groups include -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl, and -O-neohexyl.

[0039] A "haloalkoxy" is an alkoxy as defined herein, substituted with at least one, for example, 1 to 8 halo substituents.

[0040] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, which is either saturated, as in "cycloalkyl," or unsaturated, as in "cycloalkenyl." The term "cycloalkenyl" specifically refers to cyclic alkenyls, such as C3-C6 cycloalkenyls. Cycloalkyls may be bonded via any atom. For example, cycloalkyls also refer to fused rings, such as those in which a cycloalkyl is fused to an aryl or heteroaryl ring as defined herein. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. Cycloalkyls may be unsubstituted or substituted with one or more substituents as described herein.

[0041] "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions, for example, 1, 2, 3, 4, 5, or even 6, are substituted, and the substituents, through the substitutions described herein, can bond to any available atom to form a stable compound. "Optionally substituted cycloalkyl" refers to a cycloalkyl group or a substituted cycloalkyl group.

[0042] When used alone or as part of another term, "aryl" means having a specified number of carbon atoms, whether condensed or not, or if no number is specified, C6-C6. 14 This refers to a carbocyclic aromatic group having up to 14 carbon atoms, such as aryl groups. Specific examples of aryl groups include phenyl, naphthyl, biphenyl, phenantrenyl, and naphthacenyl (see, for example, Lang's Handbook of Chemistry (Dean, JA ed.), 13th edition, Table 7-2

[1985] ). A specific example of an aryl group is phenyl. "Aryl" also includes aromatic ring systems that may be fused with a cycloalkyl ring as defined herein. The aryl group may be unsubstituted or substituted with one or more substituents listed below herein.

[0043] A “substituted aryl” is an aryl that is independently substituted with one or more substituents that bond to any available atom to form a stable compound, where the substituents are as described herein. “Optionally substituted aryl” means an aryl or a substituted aryl.

[0044] The term "heteroatom" refers to N, O, and S. Compounds of this disclosure containing an N or S atom may be oxidized to the corresponding N-oxide, sulfoxide, or sulfone compound.

[0045] "Heteroaryl" refers to a monocyclic aromatic ring structure containing 5 to 10 ring atoms, e.g., 5 or 6 ring atoms, either alone or in combination with any other part described herein, or a bicyclic aromatic group having 8 to 10 atoms and containing one or more heteroatoms independently selected from the group consisting of O, S, and N, e.g., 1 to 4, 1 to 3, or 1 to 2 heteroatoms. Heteroaryls are also intended to contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary ring nitrogen. The carbon or heteroatoms become bonding sites in the heteroaryl ring structure so that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridadinyl, pyrazinyl, quinaoxalyl, indolidinyl, benzo[b]thienyl, quinazolinyl, prinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Heteroaryl groups may be unsubstituted or substituted with one or more substituents listed below herein.

[0046] Unless otherwise specified, a “substituted heteroaryl” is a heteroaryl independently substituted with one or more substituents, e.g., 1, 2, 3, 4, or 5, and also 1, 2, or 3, and also 1 substituent, which bond to any available atom to form a stable compound, where the substituents are as described herein. “Optionally substituted heteroaryl” means a heteroaryl or a substituted heteroaryl.

[0047] "Hypercycloalkyl" means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic, or polycyclic ring system having 3 to 14, for example, 3 to 6 atoms, in which 1 to 3 carbon atoms in the ring are replaced by heteroatoms such as O, S, or N. Heterocycloalkyls may be condensed with 5 to 6-membered aryl or heteroaryl rings and contain oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary ring nitrogen. The bonding sites of the heterocycloalkyl ring are located on carbon or heteroatoms so as to maintain a stable ring. Examples of heterocycloalkyls include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. Heterocycloalkyls may be unsubstituted or substituted with one or more substituents as described below herein.

[0048] "Optionally substituted heterocycloalkyl" refers to a heterocycloalkyl substituted with one to three substituents, e.g., one, two, or three substituents, that bond to any available atom to form a stable compound, where the substituents are as described herein.

[0049] The terms "nitrile" or "cyano" can be used interchangeably and refer to the -CN group bonded to the carbon atoms of heteroaryl, aryl, and heterocycloalkyl rings.

[0050] The term "oxo" refers to a =O atom bonded to a saturated or unsaturated moiety. The =O atom can bond to a carbon, sulfur, or nitrogen atom that is part of a cyclic or acyclic moiety.

[0051] "Hydroxyl" or "hydroxy" refers to the -OH group.

[0052] The substituent -CO2H is, It may be substituted with a biologically equivalent substituent such as TIFF2026514377000003.tif91128, where R is R as defined herein. A It has the same definition. For example, see page 203 of THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996).

[0053] The compounds described herein may exist in various isomeric forms, including configurational, geometric, and conformational isomers, for example, cis or trans conformations. Compounds may also exist in one or more tautomeral forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass all isomeric forms of the compounds, including the tautomeral forms of the compounds disclosed herein. Compounds disclosed herein may also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may result from the loss of water. The specific composition of the open-chain and cyclized forms may vary depending on how the compounds were isolated, stored, or administered. For example, a compound may exist primarily in an open-chain form under acidic conditions but cyclize under neutral conditions. All forms are included in this disclosure.

[0054] Some of the compounds described herein may have chiral centers and therefore may exist in different enantiomer and diastereomer forms. The compounds described herein may be in the form of optical isomers or diastereomers. Accordingly, this disclosure encompasses the compounds described herein, including their optical isomers, diastereomers, and mixtures thereof, including racemic mixtures, and their uses. Optical isomers of the compounds of this disclosure may be obtained by known techniques such as asymmetric synthesis, chiral chromatography, pseudo-mobile bed techniques, or by chemical separation of stereoisomers through the use of optically active resolving agents.

[0055] Unless otherwise specified, the term “stereoisomer” means one stereoisomer of a compound that substantially does not contain the other stereoisomer of that compound. Thus, a stereoisomerically pure compound having one chiral center substantially does not contain the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers substantially does not contain the other diastereomer of the compound. A typical stereoisomerically pure compound contains more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of the other stereoisomer of the compound, for example, more than 90% by weight of one stereoisomer of the compound and less than 10% by weight of the other stereoisomer of the compound, or more than 95% by weight of one stereoisomer of the compound and less than 5% by weight of the other stereoisomer of the compound, or more than 97% by weight of one stereoisomer of the compound and less than 3% by weight of the other stereoisomer of the compound, or more than 99% by weight of one stereoisomer of the compound and less than 1% by weight of the other stereoisomer of the compound. The stereoisomers described above may be considered as compositions comprising two stereoisomers present in the respective weight percentages described herein.

[0056] In the event of any discrepancy between a diagrammed structure and the name assigned to it, the diagrammed structure takes precedence. Furthermore, if the stereochemistry of a structure or part of a structure is not indicated, for example, by a thick or dashed line, the structure or part of a structure is interpreted as encompassing all of its stereoisomers. In some cases, however, where more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry. Those skilled in organic synthesis will be able to determine whether a compound was prepared as a single enantiomer from the method used to prepare them.

[0057] As used herein, and unless otherwise specified, the term “compound” is inclusive in that it includes the compound or its pharmaceutically acceptable salts, stereoisomers, and / or tautomers. Thus, for example, the compound of formula I includes pharmaceutically acceptable salts of the compound.

[0058] In this disclosure, “pharmaceutically acceptable salt” means a pharmaceutically acceptable organic or inorganic acid or base salt of a compound described herein. Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansilate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate. Contains te), lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-meten-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosaliculate, sulfamate, tannate, tartrate, teoclate, tosylate, triethiozide, and valerate. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, a pharmaceutically acceptable salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0059] The terms “to treat,” “to treat,” and “treatment” refer to the improvement or elimination of a disease or symptoms associated with a disease. In certain aspects, such terms refer to minimizing the spread or exacerbation of a disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient having such a disease.

[0060] The terms “prevent,” “prevention,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease in a patient resulting from the administration of a preventive or therapeutic agent.

[0061] The term "effective dose" refers to the amount of the compound or other active ingredient described herein that is sufficient to produce a therapeutic or preventive benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with the disease. Furthermore, the therapeutic effective dose of the compounds described herein means the amount of the therapeutic agent alone or in combination with other therapeutic agents that produces a therapeutic benefit in the treatment or prevention of a disease. When used in relation to the compounds described herein, the term may include amounts that enhance the overall therapy, alleviate or avoid the symptoms or causes of the disease, enhance the therapeutic effect of other therapeutic agents, or have a synergistic effect with other therapeutic agents.

[0062] "Patient" or "subject" includes animals such as humans, cattle, horses, sheep, lambs, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, animals are mammals such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human, for example, a human infant, child, adolescent, or adult.

[0063] "Inhibitor" refers to a compound that causes dose-dependent lymphopenia and a moderate decrease in plasma S1P. In this embodiment, the inhibitor binds to SPNS2.

[0064] compound As outlined above, this disclosure provides compounds according to Formula I, pharmaceutically acceptable salts thereof, and / or tautomers. TIFF2026514377000004.tif18128

[0065] X is C6~C 10 The ring is either aryl or a 5-10 member heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S).

[0066] R 1 and R 2 The group is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C1-C6 haloalkyl, CN, and halo.

[0067] W is a bond, O, NH, -NHC(O)-, or -O-(N=)C(R)- (where R is H or C1-C6 alkyl).

[0068] In some embodiments, U is a 6- to 8-membered heterocycloalkyl group which may be condensed, crosslinked, or spirocondensed, with two ring atoms being N. In these embodiments, V is H, C1-C 14 Alkyl, C2~C 12 Alkenil, (C6~C 10 )aryl, (C6~C 10 ) Heteroaryl, -C1~C 10 Alkyl-(C6~C 10 ) Aryl, -C2~C 12 Alkenyl-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-(C3~C8)cycloalkyl,-(3~14 member heterocycloalkyl) (where 1~4 heterocycloalkyl members are independently selected from N, O, and S),-(C1~C 10 Selected from the group consisting of alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S);

[0069] In another aspect, U is (B) monocyclic 4- to 7-member heterocycloalkyl (where 1 to 4 of the heterocycloalkyl members are independently selected from N, O, and S). In these aspects, V is H, -C1-C 14 alkyl, -C1-C 10 alkyl-O-(C6-C 10 )aryl, -C1-C 10 alkyl-NR x -(C6-C 10 )aryl, -C1-C 10 alkyl-NR x C(O)(C6-C 10 )aryl, -C1-C 10 alkyl-C(O)NR x (C6-C 10 )aryl, -C2-C 12 alkenyl-O-(C6-C 10 )aryl, -C1-C 10 alkyl-O-(C6-C 10 )heteroaryl (where 1 to 4 of the heteroaryl ring members are independently selected from N, O, and S), and -C2-C 12 alkenyl-O-(C6-C 10 )heteroaryl (where 1 to 4 of the heteroaryl ring members are independently selected from N, O, and S), and is selected from the group consisting of.

[0070] T is -C(O)- or -NR x C(O)-.

[0071] R x is H or C1-C6 alkyl.

[0072] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0073] In Formula I, each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is hydroxy, halo, C1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, -NR'2, -NHC(O)(OC1-C6 alkyl), -NO2, -CN, oxo, -C(O)OH, -C(O)O(C1-C6 alkyl), -C1-C6 alkyl(C1-C6 alkoxy), -C(O)NH2, C1-C6 alkoxy, C1-C6 alkyl, C3-C 14 cycloalkyl, -C(O)C1-C6 alkyl, -OC1-C6 alkyl, -Si(C1-C6 alkyl)3, -S(O) O~2 -(C1-C6 alkyl), C6-C 10 aryl, -(C1-C6 alkyl)(C6-C 10 aryl), 3- to 14-member heterocycloalkyl and -(C1-C6 alkyl)-(3- to 14-member heterocycle) (where 1 to 4 heteroatoms are independently selected from N, O, and S), and -O(C6-C 14 aryl), and may be substituted with 1 to 5 substituents independently selected from the group consisting of

[0074] Each R' is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 aryl, 3- to 14-member heterocycloalkyl and -(C1-C6 alkyl)-(3- to 14-member heterocycloalkyl) (where 1 to 4 ring members are independently selected from N, O, and S), and 5- to 10-member heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and is selected from the group consisting of

[0075] In various embodiments, U is a 6- to 8-member heterocycloalkyl which may be substituted, and in which two ring atoms are N, and may be fused, bridged, or spiro-fused, and V is H, C1-C 14 alkyl, C2-C 12 alkenyl, (C6-C 10 )aryl, (C6-C 10) Heteroaryl, -C1~C 10 Alkyl-(C6~C 10 ) Aryl, -C2~C 12 Alkenyl-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-(C3~C8)cycloalkyl,-(3~14 member heterocycloalkyl) (where 1~4 heterocycloalkyl members are independently selected from N, O, and S),-(C1~C 10 Selected from the group consisting of alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S).

[0076] In some aspects of U following (A), V is C1~C 14 It is alkyl. In an exemplary embodiment, V is C8~C 12 It is alkyl.

[0077] In additional embodiments where U conforms to (A), U may be substituted. Selected from the group consisting of TIFF2026514377000005.tif20145.

[0078] In various embodiments, U is a (B) optionally substituted monocyclic 4-7 membered heterocycloalkyl (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), and V is H, -C1-C 14 Alkyl, -C1~C 10 Alkyl-O-(C3~C 14 ) Cycloalkyl, -C1~C 10 Alkyl-O-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-NR x -(C6~C 10 ) Aryl, -C1~C 10 Alkyl-NR x C(O)(C6~C 10 ) Aryl, -C1~C 10 Alkyl-C(O)NR x (C6~C 10) Aryl, -C2~C 12 Alkenyl-O-(C6~C 10 ) Aryl, -C1~C 10 Alkyl-O-(C6~C 10 )heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S), and -C2~C 12 Alkenyl-O-(C6~C 10 ) Selected from the group consisting of heteroaryls (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S).

[0079] In various embodiments of U according to (B), U is a monocyclic 5- to 7-membered heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O). Examples of heterocycloalkyls include pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl, which may be substituted. In exemplary embodiments, U is piperazinyl.

[0080] In some aspects of U following (B), V is -C1~C 10 Alkyl-O-(C6~C 10 ) is aryl. In exemplary embodiments, V is C3~C8 alkyl-O-phenyl. In exemplary embodiments, V is C3~C8 alkyl-O-phenyl, and phenyl is C3~C 14 It is substituted with a cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopropyl.

[0081] In various embodiments optionally combined with any other embodiments described herein, X is C6~C 10 It is an aryl compound. In an exemplary embodiment, X is a phenyl compound.

[0082] In additional embodiments optionally combined with any other embodiments described herein, W is either a bond or an O. For example, in one embodiment, W is a bond.

[0083] In any additional embodiments optionally combined with any other embodiments described herein, T is -NR x It is C(O)-. In some embodiments, R x H is H.

[0084] In other embodiments optionally combined with any other embodiments described herein, T is -C(O)-.

[0085] In yet another embodiment, optionally combined with any other embodiment described herein, m is 0.

[0086] In various forms, this disclosure is, U is a 6-8 member heterocycloalkyl group, (A) having two ring atoms that are N, which may be substituted and may be condensed, crosslinked, or spirocondensed. X is C6~C 10 It is Ariel, T, R x H is -NR x C(O)-, V is C8~C 12 It is alkyl, W is a bond, m is 0. The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0087] In various forms, this disclosure is, U is a (B) optionally substituted 5-7 member heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O), X is C6~C 10 It is Ariel, T, R x H is -NR x C(O)-, V is -C1~C 10 Alkyl-O-(C6~C 10 ) is an aryl, W is a bond, m is 0. The compound or its pharmaceutically acceptable salts are also provided.

[0088] This disclosure provides specific examples of compounds of formula I and their pharmaceutically acceptable salts and / or tautomers, as shown in Tables 1 and 2 below. IC for each compound 50 Inhibition of spinster homolog 2 (Spns2), a sphingosine 1-phosphate transporter reported in the table, was measured according to the protocol described in the literature. See also YK Kharel et al. SLAS Discovery 28 (2023) 284-287; RG Fritzemeier et al. J. Med. Chem. 65 (2022) 7656-7681; S. Tanaka et al. Sci. Transl. Med. 14 (2022) 658; AL Burgio et al. J. Med. Chem. 66 (8) (2023) 5873-5891.

[0089] (Table 1) Examples of compounds of formula I (A: IC 50 <1μM;B:IC 50 >1μM) TIFF2026514377000006.tif123144TIFF2026514377000007.tif232144TIFF2026514377 000008.tif230144TIFF2026514377000009.tif239144TIFF2026514377000010.tif23714 4TIFF2026514377000011.tif226144TIFF2026514377000012.tif233144TIFF2026514377 000013.tif226144TIFF2026514377000014.tif242144TIFF2026514377000015.tif82144

[0090] (Table 2) Examples of compounds of formula I (A: IC 50 <1μM;B:IC 50 >1μM) TIFF2026514377000016.tif198144

[0091] Pharmaceutical composition The disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts, stereoisomers, and / or tautomers thereof in combination with a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, and flavoring agents, in accordance with conventional pharmaceutically acceptable formulations.

[0092] In one embodiment, the pharmaceutical composition comprises a compound selected from those shown in Table 1 or Table 2 or a pharmaceutically acceptable salt, stereoisomer, and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0093] The pharmaceutical compositions of this disclosure are formulated, dose-set, and administered in a manner consistent with appropriate medical practice. Factors to be considered in this context include the specific disorder being treated, the specific subject being treated, the clinical condition of the subject, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to healthcare professionals.

[0094] The “therapeutic effective dose” of the compound administered (or its pharmaceutically acceptable salts, stereoisomers, and / or tautomers) shall be adjusted in accordance with such considerations and shall be the minimum amount required to induce dose-dependent lymphopenia and a moderate decrease in plasma S1P, or to inhibit SPNS2 activity, or both. Such a dose may be less than the amount toxic to normal cells or the overall subject. Generally, the initial therapeutic effective dose of the compound of the Disclosure administered (or its pharmaceutically acceptable salts, stereoisomers, or tautomers) is in the range of about 0.01 to about 200 mg or about 0.1 to about 20 mg per kg of patient body weight per day, with a typical initial range of about 0.3 to about 15 mg / kg / day. Oral unit dosage forms such as tablets and capsules are available for the compound of the Disclosure (or its The dosage form may contain approximately 1 mg to approximately 1000 mg of the compound disclosed (or its pharmaceutically acceptable salt, stereoisomer, or tautomer). In another embodiment, such a dosage form contains approximately 50 mg to approximately 500 mg of the compound disclosed (or its pharmaceutically acceptable salt, stereoisomer, or tautomer). In yet another embodiment, such a dosage form contains approximately 25 mg to approximately 200 mg of the compound disclosed (or its pharmaceutically acceptable salt, stereoisomer, or tautomer). In yet another embodiment, such a dosage form contains approximately 10 mg to approximately 100 mg of the compound disclosed (or its pharmaceutically acceptable salt, stereoisomer, or tautomer). In yet another embodiment, such a dosage form contains approximately 5 mg to approximately 50 mg of the compound disclosed (or its pharmaceutically acceptable salt, stereoisomer, or tautomer).

[0095] The compositions of this disclosure may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage units. As used herein, the term "parenteral" includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion.

[0096] Suitable oral compositions described herein include, but are not limited to, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0097] Pharmaceutical compositions suitable for single-unit dose administration, comprising the compounds of this disclosure or their pharmaceutically acceptable stereoisomers, salts, or tautomers, and a pharmaceutically acceptable carrier, are also included in this disclosure.

[0098] Compositions suitable for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. For example, a liquid formulation of the compound of the invention contains one or more agents selected from the group consisting of sweeteners, flavorings, colorings, and preservatives in order to provide a pharmaceutically palatable formulation of an SPNS2 inhibitor.

[0099] The tablet compositions are used in the manufacture of tablets by mixing the compounds of this disclosure with non-toxic, pharmaceutically acceptable excipients. Examples of such excipients include, but are not limited to, inert diluents, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., corn starch or alginic acid; binders, e.g., starch, gelatin, or acacia; and lubricants, e.g., magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained therapeutic effect over a desired period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be utilized.

[0100] Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0101] In aqueous suspensions, the compounds of this disclosure are mixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydro(hydro)propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum.

[0102] The oral suspension may also contain a dispersing or wetting agent, such as a naturally occurring phosphatide, e.g., lecithin, or a condensation product of an alkylene oxide and a fatty acid, e.g., polyoxyethylene stearate, or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol, e.g., heptadecaethyleneoxycetanol, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol, e.g., polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol anhydride, e.g., polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, e.g., ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavorings, and one or more sweeteners, e.g., sucrose or saccharin.

[0103] The oily suspension may be formulated by suspending the compounds of this disclosure in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickener, such as beeswax, hard paraffin, or cetyl alcohol.

[0104] Sweeteners and flavorings such as those mentioned above may be added to provide an oral preparation with a pleasant mouthfeel. These compositions may be preserved by adding antioxidants such as ascorbic acid.

[0105] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the compounds of this disclosure in combination with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already described above. Additional excipients, such as sweeteners, flavoring agents, and colorants, may also be present.

[0106] The pharmaceutical compositions of this disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, e.g., olive oil or peanut oil, or a mineral oil, e.g., liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, e.g., acacia gum or tragacanth gum, naturally occurring phosphatides, e.g., soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, e.g., sorbitan monooleate, and condensation reaction products of the partial ester with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. The suspension may also contain sweeteners and flavorings.

[0107] Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, and flavorings and colorings. Pharmaceutical compositions may be in the form of sterile injections, aqueous suspensions, or oily suspensions. These suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents described above. Sterile injection formulations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a 1,3-butanediol solution. In particular, acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils have conventionally been employed as solvents or suspension media. For this purpose, any low-irritation non-volatile oil, including synthetic mono or diglycerides, may be employed. In addition, fatty acids such as oleic acid are used in the preparation of injections.

[0108] Compounds of formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0109] Compositions intended for parenteral administration are administered in a sterile medium. Depending on the vehicle used and the concentration of the drug in the formulation, the parenteral formulation may be either a suspension or a solution containing the dissolved drug. Adjuvants such as local anesthetics, preservatives, and buffers may also be added to the parenteral composition.

[0110] How to use The S1P gradient is a chemotactic property that allows for the correct placement of immune cells and helps maintain the integrity of the endothelial barrier. Therefore, the S1P gradient is utilized for therapeutic benefits because compounds of formula I target SPNS2, the endothelial S1P efflux protein.

[0111] Therefore, in one embodiment, the present disclosure provides a method for inhibiting spinster homolog 2 (SPNS2). This method comprises contacting SPNS2 with an effective amount of a compound described herein. In some embodiments, the contact is carried out in vitro. In other embodiments, the contact is carried out ex vivo or in vivo.

[0112] Another embodiment is a method for treating a patient suffering from a neoplastic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein. In some embodiments, the neoplastic disease is a metastatic tumor.

[0113] An additional embodiment is a method for treating a patient suffering from an allergic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound described herein. An exemplary allergic disease is asthma.

[0114] Compounds of formula I are also useful in methods for treating patients with autoimmune diseases, comprising the step of administering a therapeutically effective amount of the compound to the patient. In various embodiments, the autoimmune disease is selected from multiple sclerosis, type 1 diabetes, inflammatory bowel disease including Crohn's disease and ulcerative colitis, Graves' disease, Addison's disease, dermatomyositis, myasthenia gravis, systemic lupus erythematosus, scleroderma, psoriasis, and atopic dermatitis. An exemplary autoimmune disease is multiple sclerosis. In some embodiments, multiple sclerosis includes one or more progressive forms of multiple sclerosis and relapsing-remitting forms of the disease.

[0115] An additional embodiment includes a method for treating a patient suffering from atherosclerosis or pulmonary hypertension. This method includes administering a therapeutically effective amount of the compound described herein to the patient.

[0116] In additional embodiments, the present disclosure provides a method for treating a patient suffering from a fibrotic disease. The method comprises the step of administering a therapeutically effective amount of a compound described herein to the patient. In some embodiments, the fibrotic disease is renal fibrosis, such as chronic kidney disease. 10,11

[0117] References cited in this disclosure The numbered references in this disclosure are as follows, and are incorporated by reference as if they were all contained herein: TIFF2026514377000017.tif71150TIFF2026514377000018.tif245153TIFF2026514377000019.tif141152 [Examples]

[0118] This disclosure will be better understood by referring to the following examples, which should not be construed as limiting the scope of this disclosure.

[0119] Basic procedure 1: Nucleophilic substitution A A nucleophile (1.0 equivalent), K2CO3 (2.0 equivalents), and alkyl halide (1.2 equivalents) were added to a 6-drum vial containing MeCN at room temperature. The resulting solution was stirred at 80°C for 16 hours or on a TLC until complete consumption of the starting materials was observed. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The organic extracts were combined, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to obtain the desired compound.

[0120] Basic Procedure 2: Urea Synthesis A 1-iodo-4-isocyanatobenzene (1.0 equivalent) was added to an oven-dried 6-drum vial containing a stirring rod, and the mixture was purged with nitrogen. Anhydrous DCM was added to the vial, and the solution was cooled to 0°C in an ice bath. Mono-N-Boc-piperazine (1.05 equivalents) was dissolved in the DCM and added dropwise to the 1-iodo-4-isocyanatobenzene solution. The reaction mixture was then slowly warmed to room temperature over 16 hours. After complete consumption of the starting materials was observed by TLC, the crude reaction mixture was concentrated under reduced pressure and subjected to flash chromatography with appropriate ethyl acetate and hexane mobile phases to obtain the purified product.

[0121] Basic Procedure 3: Suzuki Cross Coupling The required alkene (1.0 equivalent) and 0.5 M 9-BBN in THF (1.5 equivalents) were added to a nitrogen-purged sealed tube. The resulting mixture was stirred at 70°C for 2 hours. At the completion of the hydroboration step, aryl iodide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.05 equivalents), and 3 M KOH (3.0 equivalents) were added sequentially. The resulting mixture was stirred at 70°C for 16 hours, or until complete consumption of the starting material was observed on TLC. The resulting mixture was concentrated under vacuum to obtain a brown oil, which was subjected to flash chromatography with a suitable ethyl acetate and hexane solvent system to obtain the purified product.

[0122] Basic Procedure 4: HCl Boc Deprotection Hydrogen chloride (30-100 equivalents, 4 M in dioxane) was added to a 6-drum vial containing Boc-protected amine (1.0 equivalent). The resulting mixture was stirred (0.5-6 hours) until the starting material was consumed, as monitored by TLC. A thick white precipitate formed during the reaction. The pure product as an HCl salt was obtained by vacuum filtration through filter frit and washing with diethyl ether, or by trituration with diethyl ether and / or ethyl acetate.

[0123] Basic Step 5: TFA Boc Deprotection TFA (30 equivalents) was added to a 6-drum vial containing Boc-protecting amine (1.0 equivalent) dissolved in DCM. The resulting solution was stirred (1–6 hours) until the starting material was consumed, as monitored by TLC. After vacuum concentration and filtration of the resulting off-white solid, it was washed with diethyl ether to obtain the corresponding TFA salt.

[0124] Basic Procedure 6: HCTU Coupling 4-iodobenzoic acid (1.1 equivalents) was added to a 6-drum vial, to which DCM (0.2 M), DIEA (1.8 equivalents), and HCTU (1.1 equivalents) were added. The resulting mixture was stirred at room temperature for 5 minutes, and then mono-N-Boc-piperazine was added. The resulting mixture was stirred at room temperature for 18 hours or on TLC until complete consumption of the starting materials was observed. The resulting mixture was concentrated under vacuum to obtain a yellow oil, which was then subjected to flash chromatography with an ethyl acetate solvent system in suitable hexane to obtain the pure product.

[0125] Basic Procedure 7: Nucleophilic Substitution B A nucleophile (1.0 equivalent), TEA (2.0 equivalents), and alkyl halide (1.2 equivalents) were added to a 6-drum vial containing MeCN (0.2 M) at room temperature. The resulting solution was stirred at 80°C for 16 hours or on a TLC until complete consumption of the starting materials was observed. The resulting mixture was filtered under vacuum, and the filtrate was concentrated under vacuum to obtain a crude yellow oil, which was then subjected to flash chromatography with a suitable ethyl acetate and hexane solvent system to obtain the purified product.

[0126] Basic Procedure 8: DCC Coupling To a 6-drum vial containing a suitable carboxylic acid (1.0 equivalent), DCM (0.2 M), a suitable aniline (1.0 equivalent), and DMAP (10 mol%) were added. The resulting mixture was cooled to 0°C, and then DCC (1.1 equivalents) was added. The resulting mixture was warmed to room temperature and stirred for 18 hours or until complete consumption of the starting material was observed on TLC. The resulting mixture was concentrated under vacuum to obtain a yellow solid, which was then subjected to flash chromatography with an ethyl acetate solvent system in suitable hexane to obtain the pure product.

[0127] Basic Procedure 9: Benzimidazole Amide Synthesis To a solution of 6-bromo-2-(trichloromethyl)-1H-benzo[d]imidazole (1.0 equivalent) in a 1:2 mixture of water and THF (0.2 M), N-Boc-piperazine (1.1 equivalents) was added, followed by sodium bicarbonate (10.0 equivalents). The reaction mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was cooled and concentrated. DCM was added, and the organic layer was washed three times with water. The organic layer was then dried over anhydrous sodium sulfate, filtered, and purified by silica chromatography to obtain the desired compound.

[0128] Basic Procedure 10: Benzimidazole Boc Protection To a solution of 1.0 equivalent of tert-butyl 4-(6-bromo-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate in 0.2 M DCM, 0.1 equivalent of 4-dimethylaminopyridine was added. 1.1 equivalents of Boc anhydride were added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated and purified by silica chromatography to obtain the desired compound.

[0129] Basic Procedure 11: Urea Synthesis B Under an argon atmosphere, triphosgene (0.5 equivalents) was dissolved in anhydrous DCM (0.1 M), and an appropriate amount of aniline (1.0 equivalent) in DCM (0.3 M) was added dropwise. This mixture was stirred at room temperature for 30 minutes, and then treated with triethylamine (2.3 equivalents) in DCM (0.6 M). After 30 minutes, N-Boc protecting amine (1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours, evaporated to dryness, treated with water (10 mL), and extracted with DCM (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and purified by silica chromatography.

[0130] Basic Procedure 12: Suzuki Cross Coupling B The required alkene (2.0 equivalents) and 0.5 M 9-BBN in THF (2.2 equivalents) were added to a nitrogen-purged sealed tube. The resulting mixture was stirred at 70°C for 2 hours. At the completion of the hydroboration step, aryl bromide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.075 equivalents), and 3 M KOH (3.0 equivalents) were added sequentially. The resulting mixture was stirred at 70°C for 16 hours, or until complete consumption of the starting material was observed on TLC. The resulting mixture was concentrated under vacuum to obtain a brown oil, which was subjected to flash chromatography with a suitable ethyl acetate and hexane solvent system to obtain the purified product.

[0131] Basic Procedure 13: Methoxy Ether Synthesis A bromo-1-alkene (1.0 equivalent) was added to a stirred solution of sodium methoxide in methanol (25% wt, 3.5 equivalents). The reaction mixture was stirred at 25°C while monitoring by TLC, then concentrated under vacuum and redissolved in diethyl ether and water. The aqueous phase was washed with diethyl ether (3 times), the organic extracts were combined, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired compound.

[0132] Basic Procedure 14: Miyaura Boronization Bis(pinacolato)diborone (1.1 equivalents), potassium acetate (3.0 equivalents), aryl halide (1.0 equivalent), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)dichloromethane complex (3 mol%) were dissolved in DMSO (0.33 M) with stirring under a nitrogen atmosphere. The reaction mixture was heated to 80°C while monitoring by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (3 times), washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum. The brown residue was purified by flash column chromatography to obtain the desired compound.

[0133] Basic Procedure 15: Wittigolefinization When potassium tert-butoxide (2.0 equivalents) was added to a stirred suspension of methyltriphenylphosphonium bromide (2.0 equivalents) in tetrahydrofuran (0.25 M) under a nitrogen atmosphere at 0°C, a yellow solution was immediately formed. The reaction mixture was stirred for 30 minutes, then ketone (1.0 equivalent) was added, and the reaction mixture was heated to 25°C and stirred while monitoring by TLC. The reaction mixture was quenched with water, extracted with ethyl acetate (3 times), the organic extracts were combined, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to obtain the desired compound.

[0134] Basic Procedure 16: Tosylation In a stirred solution of alcohol (1.0 equivalent) in dichloromethane (0.77 M), triethylamine (1.5 equivalents), DMAP (0.10 equivalents), and 4-methylbenzenesulfonyl chloride (0.97 equivalents) were sequentially added at 0°C under a nitrogen atmosphere. The reaction mixture was heated to room temperature and stirred while monitoring by TLC. The reaction mixture was diluted with diethyl ether and washed with water and aqueous HCl (1 M). The combined aqueous extract was washed with diethyl ether (3 times), the organic extract was added, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired compound.

[0135] Basic Procedure 17: Nucleophilic Substitution C To a stirred solution of alcohol (1.0 equivalent) and potassium carbonate (2.0 equivalents) in acetonitrile (0.20 M), tosylated alcohol (1.2 equivalents) was added. The reaction mixture was heated to 80°C while monitoring by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The organic extracts were combined, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to obtain the desired compound.

[0136] Basic Procedure 18: Carbonyl Reduction A stirred solution of carbonyl (1.0 eq) in THF (0.25 M) was added to lithium aluminum hydride (1.0 M, 0.60 eq) in THF under a nitrogen atmosphere at 0°C. The reaction mixture was heated to 25°C and stirred while monitoring by TLC. The reaction mixture was cooled to 0°C, quenched with water, and then extracted with ethyl acetate (three times). The organic extracts were combined, washed with brine (twice), dried over MgSO4, filtered, and concentrated under vacuum to obtain the desired compound.

[0137] Basic procedure 19: Circulation closure of benzimidazole Phenyldiamine (1.0 equivalent) was added to a heat-dried vial containing a stirring rod, followed by acetic acid (0.2 M). This was cooled to 0°C for 15 minutes. Next, methyl 2,2,2-trichloromethylacetimide (1.1 equivalents) was added dropwise. The reaction mixture was warmed to room temperature and allowed to react for 3 hours or until complete. After completion, the reaction mixture was diluted with cold water and stirred for 10 minutes. The resulting precipitate was then filtered and washed with cold water to obtain the desired pure product.

[0138] Basic Procedure 20: SEM Protection In a heat-dried vial purged with argon, benzimidazole (1.0 equivalent) was added, followed by dry THF (0.2 M). The mixture was cooled to 0°C and stirred for 10 minutes. Sodium hydride (1.1 equivalents) was added, and the reaction mixture was stirred for another 10 minutes. Then, SEM-Cl (1.1 equivalents) was added dropwise, and the reaction mixture was warmed to room temperature for 2 hours. After completion, the reaction mixture was concentrated, and water was added. This was stirred for 10 minutes to quench all residual SEM-Cl. Ethyl acetate was then added, the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the pure final product.

[0139] Basic Procedure 21: TBAF SEM Deprotection A vial containing SEM-protected benzimidazole (1.0 equivalent) was mixed with THF (0.2 M) followed by TBAF (3.0 equivalents). This mixture was refluxed for 16 hours until complete. After completion, saturated ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was washed twice more with water, dried over anhydrous sodium sulfate, and concentrated. The resulting mixture was then purified by silica gel chromatography using a suitable ethyl acetate / hexane solvent system to obtain the pure product.

[0140] Basic Procedure 22: Nucleophilic Permutation D A nucleophile (1.0 equivalent) and an alkyl halide (1.2 equivalents) were added to a heated and dried 6-drum vial containing dry THF at 0°C, followed by the addition of sodium hydride (60% wt, dispersion in liquid paraffin, 1.0 equivalent). The resulting solution was stirred and heated to room temperature for 16 hours or until complete consumption of the starting materials was observed on TLC. The reaction mixture was diluted with water and extracted with ethyl acetate (3 times). The organic extracts were combined, washed with brine (2 times), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography to obtain the desired compound.

[0141] Scheme 1: Exemplary synthesis for (hexa-5-en-1-yloxy)benzene TIFF2026514377000020.tif12128(a) Alkenyl halide (1.1 equivalents), K2CO3 (2.0 equivalents), MeCH, 80℃, 16h.

[0142] (penta-4-en-1-yloxy)benzene(1a): TIFF2026514377000021.tif11128 Synthesized according to Procedure 1, clear oil, 122 mg, yield 71%. TIFF2026514377000022.tif41159

[0143] (Hexa-5-en-1-yloxy)benzene(1b): TIFF2026514377000023.tif12128 Synthesized according to Procedure 1, clear oil, 283 mg, yield 76%. TIFF2026514377000024.tif41159

[0144] (hepta-6-en-1-yloxy)benzene(1c): TIFF2026514377000025.tif11128 Synthesized according to Procedure 1, clear oil, 190 mg, yield 94%. TIFF2026514377000026.tif42156

[0145] 1-Methyl-4-(penta-4-en-1-yloxy)benzene(1d): TIFF2026514377000027.tif11128 Synthesized according to Procedure 1, clear oil, 110 mg, yield 68%. TIFF2026514377000028.tif41156

[0146] 1-(Hexa-5-en-1-yloxy)-3-methylbenzene(1e): Synthesized according to procedure 1 of TIFF2026514377000029.tif12128, clear oil, 170 mg, yield 97%. TIFF2026514377000030.tif49158

[0147] 1-Methyl-3-(penta-4-en-1-yloxy)benzene(1f): Synthesized according to procedure 1 of TIFF2026514377000031.tif12128, clear oil, 127 mg, yield 78%. TIFF2026514377000032.tif42158

[0148] 1,3-Dimethyl-3-(penta-4-en-1-yloxy)benzene (1g): TIFF2026514377000033.tif16128 Synthesized according to Procedure 1, clear oil, 230 mg, yield 74%. TIFF2026514377000034.tif41159

[0149] 1-Methyl-2-(penta-4-en-1-yloxy)benzene(1h): TIFF2026514377000035.tif11128 Synthesized according to Procedure 1, clear oil, 213 mg, yield 65%. TIFF2026514377000036.tif41159

[0150] 1-(allyloxy)-4-ethylbenzene(1i): Synthesized according to procedure 1 of TIFF2026514377000037.tif11128, clear oil, 54 mg, yield 25%. TIFF2026514377000038.tif41159

[0151] 1-(buta-3-en-1-yloxy)-3-ethylbenzene(1j): Synthesized according to procedure 1 of TIFF2026514377000039.tif12128, clear oil, 60 mg, yield 42%. TIFF2026514377000040.tif49157

[0152] 1-(allyloxy)-3-propylbenzene (1k): TIFF2026514377000041.tif11128 Synthesized according to Procedure 1, clear oil, 250 mg, yield 97%. TIFF2026514377000042.tif41157

[0153] 1-(buta-3-en-1-yloxy)-3-isopropylbenzene (1 liter): Synthesized according to procedure 1 of TIFF2026514377000043.tif16128, clear oil, 103 mg, yield 37%. TIFF2026514377000044.tif49157

[0154] 1-(buta-3-en-1-yloxy)-3-cyclopropylbenzene(1m): TIFF2026514377000045.tif15128 Synthesized according to Procedure 1, clear oil, 140 mg, yield 40%. TIFF2026514377000046.tif41159

[0155] 1-(buta-3-en-1-yloxy)-3-(tert-butyl)benzene(1n): TIFF2026514377000047.tif16128 Synthesized according to Procedure 1, clear oil, 127 mg, yield 47%. TIFF2026514377000048.tif48157

[0156] 1-(penta-4-en-1-yloxy)-4-(trifluoromethyl)benzene(1o): Synthesized according to procedure 1 of TIFF2026514377000049.tif13128, clear oil, 83 mg, yield 58%. TIFF2026514377000050.tif49159

[0157] 1-(penta-4-en-1-yloxy)-3-(trifluoromethyl)benzene(1p): Synthesized according to procedure 1 of TIFF2026514377000051.tif12128, clear oil, 104 mg, yield 73%. TIFF2026514377000052.tif56158

[0158] 1-(buta-3-en-1-yloxy)-3-methoxybenzene(1q): Synthesized according to procedure 1 of TIFF2026514377000053.tif12128, clear oil, 94 mg, yield 33%. TIFF2026514377000054.tif41157

[0159] 1-(buta-3-en-1-yloxy)-3-(trifluoromethoxy)benzene(1r): Synthesized according to procedure 1 of TIFF2026514377000055.tif12128, clear oil, 70 mg, yield 27%. TIFF2026514377000056.tif49159

[0160] 3-(buta-3-en-1-yloxy)benzonitrile(1s): TIFF2026514377000057.tif13128 Synthesized according to Procedure 1, clear oil, 128 mg, yield 44%. TIFF2026514377000058.tif41155

[0161] 2-(buta-3-en-1-yloxy)naphthalene (1 t): TIFF2026514377000059.tif11128 Synthesized according to Procedure 1, clear oil, 150 mg, yield 55%. TIFF2026514377000060.tif48160

[0162] 1-(buta-3-en-1-yloxy)-3-methoxy-5-methylbenzene(1u): Synthesized according to procedure 1 of TIFF2026514377000061.tif17128, clear oil, 94 mg, yield 34%. TIFF2026514377000062.tif41159

[0163] 1-Fluoro-4-(hexa-5-en-1-yloxy)benzene(1v): Synthesized according to Procedure 1 of TIFF2026514377000063.tif13128, clear oil, 303 mg, yield 87%. TIFF2026514377000064.tif49158

[0164] 1-Fluoro-3-(hexa-5-en-1-yloxy)benzene (1w): Synthesized according to Procedure 1 of TIFF2026514377000065.tif18128, clear oil, 291 mg, yield 84%. TIFF2026514377000066.tif56159

[0165] 1-Fluoro-2-(hexa-5-en-1-yloxy)benzene (1x): Synthesized according to Procedure 1 of TIFF2026514377000067.tif13128, clear oil, 340 mg, yield 98%. TIFF2026514377000068.tif56159

[0166] 1,3-Difluoro-5-(hexa-5-en-1-yloxy)benzene(1y): Synthesized according to Procedure 1 of TIFF2026514377000069.tif18128, clear oil, 317 mg, yield 97%. TIFF2026514377000070.tif49160

[0167] 1,2-Difluoro-3-(hexa-5-en-1-yloxy)benzene(1z): TIFF2026514377000071.tif18128 Synthesized according to Procedure 1, clear oil, 340 mg, yield 98%. TIFF2026514377000072.tif56158

[0168] 1,3-Difluoro-2-(hexa-5-en-1-yloxy)benzene(1aa): Synthesized according to procedure 1 of TIFF2026514377000073.tif18128, clear oil, 293 mg, yield 90%. TIFF2026514377000074.tif49158

[0169] 1,3,5-Trifluoro-2-(hexa-5-en-1-yloxy)benzene(1ab): TIFF2026514377000075.tif18128 Synthesized according to Procedure 1, clear oil, 123 mg, yield 40%. TIFF2026514377000076.tif56159

[0170] 3-(hexa-5-en-1-yloxy)pyridine(1ac): TIFF2026514377000077.tif12128 Synthesized according to Procedure 1, clear oil, 106 mg, yield 28%. TIFF2026514377000078.tif34159

[0171] 1-(allyloxy)-4-cyclopropylbenzene(1ad): TIFF2026514377000079.tif16128 Synthesized according to Procedure 1, clear oil, 320 mg, yield 99%. TIFF2026514377000080.tif41159

[0172] 1-Ethyl-2-(hexa-5-en-1-yloxy)benzene(1ae): Synthesized according to procedure 1 of TIFF2026514377000081.tif12128, clear oil, 232 mg, yield 69%. TIFF2026514377000082.tif41159

[0173] 1-(Hexa-5-en-1-yloxy)-2-(trifluoromethyl)benzene(1af): TIFF2026514377000083.tif13128 Synthesized according to Procedure 1, clear oil, 281 mg, yield 93%. TIFF2026514377000084.tif49159

[0174] 1-Ethyl-2-(penta-4-en-1-yloxy)benzene (1 ag): TIFF2026514377000085.tif12128 Synthesized according to Procedure 1, clear oil, 158 mg, yield 51%. TIFF2026514377000086.tif49159

[0175] 1-(buta-3-en-1-yloxy)-3-cyclopropyl-2-fluorobenzene(1ah): Synthesized according to Procedure 1 of TIFF2026514377000087.tif16128, clear oil, 182 mg, yield 54%. TIFF2026514377000088.tif56159

[0176] 1-(buta-3-en-1-yloxy)-3-cyclopropyl-5-fluorobenzene(1ai): TIFF2026514377000089.tif23128 Synthesized according to Procedure 1, clear oil, 150 mg, yield 44%. TIFF2026514377000090.tif63156

[0177] 1-(allyloxy)-3-cyclobutylbenzene (1aj): TIFF2026514377000091.tif Synthesized according to procedure 1, clear oil, 120 mg, yield 38%. TIFF2026514377000092.tif49159

[0178] 1-chloro-3-(penta-4-en-1-yloxy)benzene (1aq): TIFF2026514377000093.tif Synthesized according to procedure 1, clear oil, 160 mg, yield 52%. TIFF2026514377000094.tif41158

[0179] (allyloxy)benzene (1at): TIFF2026514377000095.tif Synthesized according to procedure 1, clear oil, 204 mg, yield 95%. TIFF2026514377000096.tif27159

[0180] 1-(buta-3-en-1-yloxy)naphthalene (1au): TIFF2026514377000097.tif Synthesized according to procedure 1, clear oil, 176 mg, yield 51%. TIFF2026514377000098.tif48157

[0181] (hexa-5-en-1-yloxy)cyclopentane (1av): TIFF2026514377000099.tif Synthesized according to procedure 21, clear oil, 42 mg, yield 11%. TIFF2026514377000100.tif41159

[0182] ((penta-4-en-1-yloxy)methyl)benzene (1aw): Synthesized according to procedure 21 of TIFF2026514377000101.tif12128, white solid, 61 mg, yield 86%. TIFF2026514377000102.tif34158

[0183] (3-(allyloxy)propyl)benzene(1ax): Synthesized according to procedure 21 of TIFF2026514377000103.tif12128, clear oil, 34 mg, yield 13%. TIFF2026514377000104.tif41157

[0184] (Hexa-5-en-1-yloxy)cyclobutene(1ay): Synthesized according to procedure 21 of TIFF2026514377000105.tif10128, clear oil, 188 mg, yield 35%. TIFF2026514377000106.tif41157

[0185] N-(penta-4-en-1-yl)-benzamide, 1az TIFF2026514377000107.tif121281,2-Dichloroethane (8.0 mL) was mixed with hexa-5-en-1-ol (0.20 g, 0.24 mL, 1.0 eq, 2.0 mmol), triethylsilane (0.47 g, 0.64 mL, 2.0 eq, 4.0 mmol), and ytterbium(III) trifluoromethanesulfonate hydrate (51 mg, 0.04 eq, 80 μmol). Cyclohexanone (0.39 g, 0.41 mL, 2.0 eq, 4.0 mmol) was added to the mixed solution under a nitrogen atmosphere. The reaction mixture was heated under reflux for 24 hours, cooled to room temperature, diluted with water (15 mL), and then extracted with diethyl ether (3 × 5 mL). The organic extracts were combined, washed with brine (2 × 15 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 10 g silica, Φ=2.5 cm, hexane / ethyl acetate 0 → 10%) to obtain (hexa-5-en-1-yloxy)cyclohexane (161 mg, 44%) as a colorless oil. TIFF2026514377000108.tif34158

[0186] 5-(buta-3-en-1-yloxy)-1,2,3,4-tetrahydronaphthalene, 1ba Synthesized according to Procedure 1 of TIFF2026514377000109.tif19128. 57 mg, 28%, colorless oil. TIFF2026514377000110.tif41155

[0187] 4-(buta-3-en-1-yloxy)-2,3-dihydro-1H-indene, 1bb Synthesized according to Procedure 1. 166 mg, 44%, colorless oil. TIFF2026514377000112.tif41159

[0188] 7-Methoxyhepta-1-ene, 1bc TIFF2026514377000113.tif Synthesized according to procedure 13. 491 mg, 44%, 57% in Et2O, colorless solution. TIFF2026514377000114.tif 27159

[0189] (4 - Oxocyclohexyl)methyl 4 - methylbenzenesulfonate, XXbd TIFF2026514377000115.tif A solution of 4 - (hydroxymethyl)cyclohexan - 1 - one (0.26 g, 1 eq, 2.0 mmol) in pyridine (2.0 mL) was slowly added with 4 - methylbenzenesulfonyl chloride (0.43 g, 1.12 eq, 2.2 mmol) at 0 °C. The reaction mixture was left for 3 days. The reaction mixture was diluted with water (40 mL) and extracted with diethyl ether (3 × 40 mL). The combined organic extracts were washed with saturated aqueous CuSO4 until the washing solution maintained a light blue color, then washed with water (80 mL), brine (3 × 80 mL), dried over MgSO4, filtered, and concentrated in vacuo to give (4 - oxocyclohexyl)methyl 4 - methylbenzenesulfonate 4m (0.30 g, 1.1 mmol, 53%) as an orange oil, which was used without further purification. TIFF2026514377000116.tif 20156

[0190] 4 - (Phenoxymethyl)cyclohexan - 1 - one, XXbd TIFF2026514377000117.tif Synthesized according to procedure 17 and proceeded to the next step without purification. 96 mg, 47%, colorless oil.

[0191] ((4 - Methylenecyclohexyl)methoxy)benzene, 1bd TIFF20265143​​​​​​​Synthesized according to procedure 13 of TIFF2026514377000120.tif5128. 260 mg, 91%, colorless oil. TIFF2026514377000121.tif34157

[0193] 3-Methylenecyclohexane-1-carboxylate methyl, XXbf Synthesized according to procedure 15 of TIFF2026514377000122.tif18128, and proceeded without purification. 59 mg, 38%, colorless oil.

[0194] (3-methylenecyclohexyl)methanol, XXbf Synthesized according to procedure 18 of TIFF2026514377000123.tif11128. 48 mg, 99%, colorless oil. TIFF2026514377000124.tif34156

[0195] 4-Methylbenzenesulfonic acid (3-methylenecyclohexyl)methyl, XXbf Synthesized according to procedure 16 of TIFF2026514377000125.tif17128. 103 mg, 97%, colorless oil. TIFF2026514377000126.tif41159

[0196] ((3-methylenecyclohexyl)methoxy)benzene, 1bf Synthesized according to procedure 17 of TIFF2026514377000127.tif18128. 32 mg, 47%, colorless oil. TIFF2026514377000128.tif34159

[0197] 3-Methylenecyclopentane-1-carboxylate ethyl, XXbg Synthesized according to procedure 15 of TIFF2026514377000129.tif22128, and proceeded without purification. 0.46g, 99%, colorless oil.

[0198] (3-Methylenecyclopentyl)methanol, XXbg Synthesized according to procedure 18 of TIFF2026514377000130.tif9128. 0.31g, 93%, colorless oil. TIFF2026514377000131.tif34159

[0199] 4-Methylbenzenesulfonic acid (3-methylenecyclopentyl)methyl, XXbg Synthesized according to procedure 16 of TIFF2026514377000132.tif19128. 0.397g, 54%, colorless oil. TIFF2026514377000133.tif34159

[0200] ((3-methylenecyclopentyl)methoxy)benzene, 1bg Synthesized according to procedure 17 of TIFF2026514377000134.tif16128. 85 mg, 31%, colorless oil. TIFF2026514377000135.tif41158

[0201] 4-(phenoxymethyl)methyl benzoate, XXbh TIFF2026514377000136.tif26128 Methyl 4-(bromomethyl)benzoate (0.55 g, 1.0 eq, 2.4 mmol) was added to a stirred solution of phenol (0.23 g, 1 eq, 2.4 mmol) and potassium carbonate (1.0 g, 3.0 eq, 7.2 mmol) in acetone (12 mL). The reaction mixture was heated to 56 °C while monitoring by TLC. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic extracts were combined, washed with brine (2 × 30 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 40 g silica, Φ=5 cm, hexane / ethyl acetate 0 → 30%) to obtain 8 t of methyl 4-(phenoxymethyl)benzoate (0.542 g, 2.24 mmol, 93%) as a white, amorphous solid. TIFF2026514377000137.tif26155

[0202] (4-(phenoxymethyl)phenyl)methanol, XXbh Synthesized according to procedure 18 of TIFF2026514377000138.tif18128. 0.436g, 93%, colorless oil. TIFF2026514377000139.tif27156

[0203] 1-(bromomethyl)-4-(phenoxymethyl)benzene, XXbh Triphenylphosphine (0.26 g, 1.1 eq, 0.99 mmol) was slowly added at 0°C to a stirred solution of carbon tetrabromide (0.33 g, 1.1 eq, 0.99 mmol) and (4-(phenoxymethyl)phenyl)methanol (0.19 g, 1.0 eq, 0.90 mmol) in dichloromethane (0.90 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with hexane (5 mL), filtered through Celite, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 25g silica, Φ=2.5cm, hexane / ethyl acetate 0→3%) to obtain 2t (0.155g, 0.559 mmol, 62%) of 1-(bromomethyl)-4-(phenoxymethyl)benzene as a white, amorphous solid. TIFF2026514377000141.tif19157

[0204] Scheme 2: Exemplary synthesis for N-(4-(6-phenoxyhexyl)phenyl)piperazine-1-carboxamide hydrochloride TIFF2026514377000142.tif92128 (a) Mono-N-Boc-diamine (1.05 equivalents), DCM, 0-25℃, 18h; (b) (i) 9-BBN (1.5 equivalents), alkene (1.1 equivalents), THF, 70℃, 2h; (ii) aryl iodide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.05 equivalents), 3M KOH (3.0 equivalents), THF, 70℃, 4h; (c) 4M HCl / dioxane (10 equivalents), DCM, 25℃, 2h.

[0205] 4-((4-iodophenyl)carbamoyl)piperazine-1-carboxylate tert-butyl: Synthesized according to procedure 2 of TIFF2026514377000143.tif25128, white solid, 865 mg, yield 98%. TIFF2026514377000144.tif20158

[0206] 4-((4-(5-phenoxypentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2a): Synthesized according to procedure 3 of TIFF2026514377000145.tif33128, white solid, 82 mg, yield 76%. TIFF2026514377000146.tif49156

[0207] 4-((4-(6-phenoxyhexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2b): Synthesized according to procedure 3 of TIFF2026514377000147.tif26128, white solid, 466 mg, yield 64%. TIFF2026514377000148.tif41158

[0208] 4-((4-(7-phenoxyheptyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2c): Synthesized according to procedure 3 of TIFF2026514377000149.tif33128, white solid, 186 mg, yield 81%. TIFF2026514377000150.tif48158

[0209] 4-((4-(5-(p-tolyloxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2d): Synthesized according to procedure 3 of TIFF2026514377000151.tif33128, white solid, 112 mg, yield 67%. TIFF2026514377000152.tif41158

[0210] 4-((4-(6-(m-tolyloxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2e): Synthesized according to procedure 3 of TIFF2026514377000153.tif26128, white solid, 205 mg, yield 89%. TIFF2026514377000154.tif48164

[0211] 4-((4-(5-(m-tolyloxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2f): Synthesized according to procedure 3 of TIFF2026514377000155.tif33128, white solid, 191 mg, yield 86%. TIFF2026514377000156.tif41161

[0212] 4-((4-(5-(m-tolyloxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (2g): Synthesized according to procedure 3 of TIFF2026514377000157.tif38128, white solid, 144 mg, yield 63%. TIFF2026514377000158.tif41158

[0213] 4-((4-(5-(o-tolyloxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2h): Synthesized according to procedure 3 of TIFF2026514377000159.tif33128, white solid, 73 mg, yield 65%. TIFF2026514377000160.tif49156

[0214] 4-((4-(3-(4-ethylphenoxy)propyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2i): Synthesized according to procedure 3 of TIFF2026514377000161.tif33128, white solid, 73 mg, yield 65%. TIFF2026514377000162.tif49158

[0215] 4-((4-(4-(3-ethylphenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2j): Synthesized according to procedure 3 of TIFF2026514377000163.tif26128, white solid, 71 mg, yield 64%. TIFF2026514377000164.tif49159

[0216] 4-((4-(3-(3-propylphenoxy)propyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2k): Synthesized according to procedure 3 of TIFF2026514377000165.tif33128, white solid, 121 mg, yield 36%. TIFF2026514377000166.tif49164

[0217] 4-((4-(4-(3-isopropylphenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (2L): Synthesized according to procedure 3 of TIFF2026514377000167.tif30128, white solid, 158 mg, yield 92%. TIFF2026514377000168.tif48164

[0218] 4-((4-(4-(3-cyclopropylphenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2m): Synthesized according to procedure 3 of TIFF2026514377000169.tif29128, white solid, 124 mg, yield 54%. TIFF2026514377000170.tif42160

[0219] 4-((4-(4-(3-(tert-butyl)phenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2n): Synthesized according to procedure 3 of TIFF2026514377000171.tif30128, white solid, 188 mg, yield 80%. TIFF2026514377000172.tif34164

[0220] 4-((4-(5-(4-(trifluoromethyl)phenoxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2o): Synthesized according to procedure 3 of TIFF2026514377000173.tif35128, white solid, 98 mg, yield 53%. TIFF2026514377000174.tif56158

[0221] 4-((4-(5-(3-(trifluoromethyl)phenoxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2p): Synthesized according to procedure 3 of TIFF2026514377000175.tif33128, white solid, 85 mg, yield 46%. TIFF2026514377000176.tif56160

[0222] 4-((4-(4-(3-methoxyphenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2q): Synthesized according to procedure 3 of TIFF2026514377000177.tif26128, white solid, 116 mg, yield 69%. TIFF2026514377000178.tif41158

[0223] 4-((4-(4-(3-(trifluoromethoxy)phenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2r): Synthesized according to procedure 3 of TIFF2026514377000179.tif26128, white solid, 75 mg, yield 40%. TIFF2026514377000180.tif49159

[0224] 4-((4-(4-(3-cyanophenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2s): Synthesized according to procedure 3 of TIFF2026514377000181.tif28128, a white solid, 160 mg, yield 72%. TIFF2026514377000182.tif41164

[0225] 4-((4-(4-(naphthalene-2-yloxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2t): Synthesized according to procedure 3 of TIFF2026514377000183.tif26128, white solid, 193 mg, yield 83%. TIFF2026514377000184.tif41158

[0226] 4-((4-(4-(3-methoxy-5-methylphenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2u): Synthesized according to procedure 3 of TIFF2026514377000185.tif26128, white solid, 104 mg, yield 60%. TIFF2026514377000186.tif41160

[0227] 4-((4-(6-(4-fluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2v): Synthesized according to procedure 3 of TIFF2026514377000187.tif27128, white solid, 183 mg, yield 53%. TIFF2026514377000188.tif49159

[0228] 4-((4-(6-(3-fluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (2w): Synthesized according to procedure 3 of TIFF2026514377000189.tif27128, white solid, 256 mg, yield 74%. TIFF2026514377000190.tif56158

[0229] 4-((4-(6-(2-fluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2x): Synthesized according to procedure 3 of TIFF2026514377000191.tif27128, white solid, 205 mg, yield 59%. TIFF2026514377000192.tif56160

[0230] 4-((4-(6-(3,5-difluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2y): Synthesized according to procedure 3 of TIFF2026514377000193.tif27128, a white solid, 250 mg, yield 69%. TIFF2026514377000194.tif49158

[0231] 4-((4-(6-(2,3-difluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2z): Synthesized according to procedure 3 of TIFF2026514377000195.tif27128, white solid, 287 mg, yield 80%. TIFF2026514377000196.tif56160

[0232] 4-((4-(6-(2,6-difluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2aa): Synthesized according to procedure 3 of TIFF2026514377000197.tif31128, white solid, 202 mg, yield 56%. TIFF2026514377000198.tif56160

[0233] 4-((4-(6-(2,4,6-trifluorophenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ab): Synthesized according to procedure 3 of TIFF2026514377000199.tif31128, white solid, 239 mg, yield 64%. TIFF2026514377000200.tif56164

[0234] 4-((4-(6-(pyridine-3-yloxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ac): Synthesized according to procedure 3 of TIFF2026514377000201.tif26128, white solid, 176 mg, yield 63%. TIFF2026514377000202.tif41159

[0235] 4-((4-(3-(4-cyclopropylphenoxy)propyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ad): Synthesized according to procedure 3 of TIFF2026514377000203.tif38128, a white solid, 250 mg, yield 75%. TIFF2026514377000204.tif41163

[0236] 4-((4-(6-(2-ethylphenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ae): Synthesized according to procedure 3 of TIFF2026514377000205.tif26128, white solid, 158 mg, yield 67%. TIFF2026514377000206.tif49160

[0237] 4-((4-(6-(2-(trifluoromethyl)phenoxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2af): Synthesized according to procedure 3 of TIFF2026514377000207.tif26128, white solid, 126 mg, yield 49%. TIFF2026514377000208.tif56163

[0238] 4-((4-(5-(2-ethylphenoxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (2ag): Synthesized according to procedure 3 of TIFF2026514377000209.tif33128, white solid, 158 mg, yield 69%. TIFF2026514377000210.tif48162

[0239] 4-((4-(4-(3-cyclopropyl-2-fluorophenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ah): Synthesized according to procedure 3 of TIFF2026514377000211.tif31128, white solid, 124 mg, yield 54%. TIFF2026514377000212.tif56159

[0240] 4-((4-(4-(3-cyclopropyl-5-fluorophenoxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ai): Synthesized according to procedure 3 of TIFF2026514377000213.tif30128, white solid, 185 mg, yield 62%. TIFF2026514377000214.tif56160

[0241] 4-((4-(3-(3-cyclobutylphenoxy)propyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2aj): Synthesized according to procedure 3 of TIFF2026514377000215.tif33128, white solid, 70 mg, yield 41%. TIFF2026514377000216.tif56159

[0242] 4-((4-(5-(3-chlorophenoxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (2aq): Synthesized according to procedure 3 of TIFF2026514377000217.tif40128, white solid, 152 mg, yield 65%. TIFF2026514377000218.tif48162

[0243] 4-((4-(4-(naphthalene-1-yloxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2au): Synthesized according to procedure 3 of TIFF2026514377000219.tif34128, white solid, 111 mg, yield 38%. TIFF2026514377000220.tif49158

[0244] 4-((4-(6-(cyclopentyloxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2av): Synthesized according to procedure 3 of TIFF2026514377000221.tif34128, white solid, 69 mg, yield 79%. TIFF2026514377000222.tif41159

[0245] 4-((4-(5-(benzyloxy)pentyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2aw): Synthesized according to procedure 3 of TIFF2026514377000223.tif33128, white solid, 82 mg, yield 73%. TIFF2026514377000224.tif48158

[0246] 4-((4-(3-(3-phenylpropoxy)propyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ax): Synthesized according to procedure 3 of TIFF2026514377000225.tif33128, white solid, 87 mg, yield 78%. TIFF2026514377000226.tif48160

[0247] 4-((4-(6-cyclobutoxyhexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ay): Synthesized according to procedure 3 of TIFF2026514377000227.tif34128, white solid, 89 mg, yield 42%. TIFF2026514377000228.tif49159

[0248] 4-((4-(6-(cyclohexyloxy)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2az Synthesized according to procedure 3 of TIFF2026514377000229.tif26128. 0.133 g, 84%, amorphous, white solid. TIFF2026514377000230.tif49157

[0249] 4-((4-(4-((5,6,7,8-tetrahydronaphthalene-1-yl)oxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2ba Synthesized according to procedure 3 of TIFF2026514377000231.tif25128. 0.093 g, 66%, amorphous, white solid. TIFF2026514377000232.tif41158

[0250] 4-((4-(4-((2,3-dihydro-1H-inden-4-yl)oxy)butyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bb Synthesized according to procedure 3 of TIFF2026514377000233.tif26128. 0.123g, 83%, amorphous, white solid. TIFF2026514377000234.tif49158

[0251] 4-((4-(7-methoxyheptyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bc Synthesized according to procedure 3 of TIFF2026514377000235.tif25128. 93 mg, 56%, amorphous, white solid. TIFF2026514377000236.tif33159

[0252] 4-((4-((4-((phenoxymethyl)cyclohexyl)methyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bd Synthesized according to procedure 3 of TIFF2026514377000237.tif25128. 21 mg, 25%, dr80:20, amorphous white solid. TIFF2026514377000238.tif27157

[0253] 4-((4-(8-methoxyoctyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2be Synthesized according to procedure 3 of TIFF2026514377000239.tif19128. 0.11 g, 71%, amorphous, white solid. TIFF2026514377000240.tif33158

[0254] 4-((4-((3-(phenoxymethyl)cyclohexyl)methyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bf Synthesized according to procedure 3 of TIFF2026514377000241.tif32128. 16 mg, 24%, dr68:32, white, amorphous solid. TIFF2026514377000242.tif63158

[0255] 4-((4-((3-(phenoxymethyl)cyclopentyl)methyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bg Synthesized according to step 3. 0.086 g, 54%, dr60:40, white, amorphous solid. TIFF2026514377000243.tif63159

[0256] Scheme 3: Exemplary synthesis of 4-((4-(4-(phenoxymethyl)benzyl)phenyl)carbamoyl)piperazine-1-ium chloride TIFF2026514377000244.tif59150a) Boc-piperazine (1.05 equivalents), 0~25℃, 16h;b) B2pin2 (1.1 equivalents), KOAc (3.0 equivalents) ), Pd(dppf)Cl2·CH2Cl2 (0.003 equivalent), DMSO, 80℃, 16h;c) (i) NaIO4 (2.4 equivalent), THF, H2O, 25℃, 30min, (ii) 1M HCl aq (0.70 equivalents), 25°C, 24h; d) Benzyl bromide (1.2 equivalents), Pd(PPh3)4 (0.08 equivalents), 1M NaOH (3.0 equivalents), toluene, EtOH, 110°C, 16h; e) 4M HCl / dioxane (10 equivalents), DCM, 25°C, 16h.

[0257] 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl Synthesized according to procedure 14 of TIFF2026514377000245.tif36128. 0.276 g, 71%, off-white, amorphous solid. TIFF2026514377000246.tif27159

[0258] (4-(4-(tert-butoxycarbonyl)piperazine-1-carboxamide)phenyl)boronic acid TIFF2026514377000247.tif30128 A two-phase solution of 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl (0.35 g, 1.0 eq, 0.81 mmol) in THF (2.6 mL) and water (0.65 mL) was stirred, and sodium periodate (0.52 g, 3.0 eq, 2.4 mmol) was added. The reaction mixture was stirred at 25°C for 30 minutes, then aqueous hydrogen chloride solution (21 mg, 0.57 mL, 1.0 molar concentration, 0.70 eq, 0.57 mmol) was added, and the reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 × 25 mL). The organic extracts were combined, washed with brine (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 25 g silica, Φ=2.5 cm, dichloromethane / methanol 0 → 5%) to obtain (4-(4-(tert-butoxycarbonyl)piperazine-1-carboxamide)phenyl)boronic acid (0.129 g, 369 μmol, 46%). TIFF2026514377000248.tif27152

[0259] 4-((4-(4-phenoxymethyl)benzyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl, 2bh TIFF2026514377000249.tif25128 1-(bromomethyl)-4-(phenoxymethyl)benzene (83 mg, 1.2 eq, 0.30 mmol), (4-(4-(tert-butoxycarbonyl)piperazine-1-carboxamide)phenyl)boronic acid (87 mg, 1.0 eq, 0.25 mmol), and tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.08 eq, 20 μmol) were stirred together in toluene (4.5 mL) and ethanol (0.39 mL). Sodium hydroxide in water (10 mg, 0.25 mL, 1 molar concentration, 1 eq, 0.25 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 25g silica, Φ=2.5cm, hexane / ethyl acetate 0→35%), and then triturated with ethyl acetate to obtain 4-((4-(4-(phenoxymethyl)benzyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl 16t (0.013g, 10%) as a white, amorphous solid. TIFF2026514377000250.tif41158

[0260] N-(4-(5-phenoxypentyl)phenyl)piperazine-1-carboxamide hydrochloride (3a): Synthesized according to procedure 4 of TIFF2026514377000251.tif27128, purified by trituration with diethyl ether, white solid, 66 mg, yield 93%. TIFF2026514377000252.tif41160

[0261] N-(4-(6-phenoxyhexyl)phenyl)piperazine-1-carboxamide hydrochloride (3b): Synthesized according to procedure 4 of TIFF2026514377000253.tif19128, purified by trituration with diethyl ether, white solid, 367 mg, yield 75%. TIFF2026514377000254.tif41160

[0262] N-(4-(7-phenoxyheptyl)phenyl)piperazine-1-carboxamide hydrochloride (3c): Synthesized according to procedure 4 of TIFF2026514377000255.tif27128, purified by trituration with diethyl ether, white solid, 122 mg, yield 88%. TIFF2026514377000256.tif41159

[0263] TIFF2026514377000257.tif27128N-(4-(5-(p-tolyloxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3d): Synthesized according to procedure 4, purified by trituration with diethyl ether, white solid, 69 mg, yield 84%. TIFF2026514377000258.tif41159

[0264] N-(4-(6-(m-tolyloxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3e): Synthesized according to procedure 4 of TIFF2026514377000259.tif19128, purified by trituration with diethyl ether, white solid, 151 mg, yield 87%. TIFF2026514377000260.tif49160

[0265] N-(4-(5-(m-tolyloxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3f): Synthesized according to procedure 4 of TIFF2026514377000261.tif27128, purified by trituration with diethyl ether, white solid, 149 mg, yield 90%. TIFF2026514377000262.tif49159

[0266] N-(4-(5-(3,5-dimethylphenoxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3g): Synthesized according to procedure 4 of TIFF2026514377000263.tif30128, white solid, 79 mg, yield 91%. TIFF2026514377000264.tif41158

[0267] N-(4-(5-(o-tolyloxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3h): Synthesized according to procedure 4 of TIFF2026514377000265.tif27128, white solid, 99 mg, yield 91%. TIFF2026514377000266.tif41160

[0268] N-(4-(3-(4-ethylphenoxy)propyl)phenyl)piperazine-1-carboxamide hydrochloride (3i): Synthesized according to procedure 4 of TIFF2026514377000267.tif27128, white solid, 119 mg, yield 92%. TIFF2026514377000268.tif41160

[0269] N-(4-(3-(3-ethylphenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3j): Synthesized according to procedure 4 of TIFF2026514377000269.tif19128, purified by trituration with diethyl ether, white solid, 55 mg, yield 89%. TIFF2026514377000270.tif48158

[0270] N-(4-(3-(3-propylphenoxy)propyl)phenyl)piperazine-1-carboxamide hydrochloride (3k): Synthesized according to procedure 4 of TIFF2026514377000271.tif27128, purified by trituration with diethyl ether, white solid, 22 mg, yield 85%. TIFF2026514377000272.tif49159

[0271] N-(4-(4-(3-isopropylphenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3L): Synthesized according to procedure 4 of TIFF2026514377000273.tif23128, white solid, 122 mg, yield 93%. TIFF2026514377000274.tif41161

[0272] N-(4-(4-(3-cyclopropylphenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3m): Synthesized according to procedure 4 of TIFF2026514377000275.tif22128, white solid, 79 mg, yield 91%. TIFF2026514377000276.tif48159

[0273] N-(4-(4-(3-(tert-butyl)phenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3n): Synthesized according to procedure 4 of TIFF2026514377000277.tif23128, white solid, 144 mg, yield 88%. TIFF2026514377000278.tif41158

[0274] N-(4-(4-(4-(trifluoromethoxy)phenoxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (30): Synthesized according to procedure 4 of TIFF2026514377000279.tif27128, white solid, 88 mg, yield 89%. TIFF2026514377000280.tif56158

[0275] N-(4-(4-(3-(trifluoromethoxy)phenoxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3p): Synthesized according to procedure 4 of TIFF2026514377000281.tif27128, a white solid, 190 mg, yield 95%. TIFF2026514377000282.tif49158

[0276] N-(4-(4-(3-(methoxy)phenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3q): Synthesized according to procedure 4 of TIFF2026514377000283.tif19128, white solid, 81 mg, yield 93%. TIFF2026514377000284.tif41159

[0277] N-(4-(4-(3-(trifluoromethoxy)phenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3r): Synthesized according to procedure 4 of TIFF2026514377000285.tif19128, white solid, 55 mg, yield 83%. TIFF2026514377000286.tif56160

[0278] N-(4-(4-(3-cyanophenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3s): Synthesized according to procedure 4 of TIFF2026514377000287.tif21128, white solid, 112 mg, yield 86%. TIFF2026514377000288.tif34158

[0279] N-(4-(4-(naphthalene-2-yloxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3t): Synthesized according to procedure 4 of TIFF2026514377000289.tif19128, purified by trituration with diethyl ether, white solid, 125 mg, yield 95%. TIFF2026514377000290.tif41159

[0280] N-(4-(4-(3-methoxy-5-methylphenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3u): Synthesized according to procedure 4 of TIFF2026514377000291.tif19128, white solid, 79 mg, yield 91%. TIFF2026514377000292.tif41159

[0281] N-(4-(6-(4-fluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3v): Synthesized according to procedure 4 of TIFF2026514377000293.tif19128, white solid, 138 mg, yield 90%. TIFF2026514377000294.tif49160

[0282] N-(4-(6-(3-fluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3w): Synthesized according to procedure 4 of TIFF2026514377000295.tif19128, white solid, 169 mg, yield 97%. TIFF2026514377000296.tif56160

[0283] N-(4-(6-(2-fluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3x): Synthesized according to procedure 4 of TIFF2026514377000297.tif24128, white solid, 133 mg, yield 87%. TIFF2026514377000298.tif56160

[0284] N-(4-(6-(3,5-difluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3y): Synthesized according to procedure 4 of TIFF2026514377000299.tif19128, white solid, 197 mg, yield 90%. TIFF2026514377000300.tif49160

[0285] N-(4-(6-(2,3-difluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3z): Synthesized according to procedure 4 of TIFF2026514377000301.tif24128, white solid, 201 mg, yield 92%. TIFF2026514377000302.tif62160

[0286] N-(4-(6-(2,6-difluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3aa): Synthesized according to procedure 4 of TIFF2026514377000303.tif24128, purified by trituration with diethyl ether, white solid, 98 mg, yield 89%. TIFF2026514377000304.tif56160

[0287] N-(4-(6-(2,4,6-trifluorophenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3ab): Synthesized according to procedure 4 of TIFF2026514377000305.tif24128, white solid, 80 mg, yield 91%. TIFF2026514377000306.tif56160

[0288] N-(4-(6-(pyridine-3-yloxy)hexyl)phenyl)piperazine-1-carboxamidobis-trifluoroacetic acid (3AC): Synthesized according to procedure 4 of TIFF2026514377000307.tif19128, yellow oil, 26 mg, yield 60%. TIFF2026514377000308.tif56158

[0289] N-(4-(3-(4-cyclopropylphenoxy)propyl)phenyl)piperazine-1-carboxamide hydrochloride (3ad): Synthesized according to procedure 4 of TIFF2026514377000309.tif31128, white solid, 172 mg, yield 90%. TIFF2026514377000310.tif41164

[0290] N-(4-(6-(2-ethylphenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3ae): Synthesized according to procedure 4 of TIFF2026514377000311.tif27128, white solid, 112 mg, yield 85%. TIFF2026514377000312.tif42157

[0291] N-(4-(6-(2-trifluoromethylphenoxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3af): Synthesized according to procedure 4 of TIFF2026514377000313.tif27128, white solid, 112 mg, yield 85%. TIFF2026514377000314.tif49159

[0292] N-(4-(5-(2-ethylphenoxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3 ag): Synthesized according to procedure 4 of TIFF2026514377000315.tif27128, white solid, 115 mg, yield 88%. TIFF2026514377000316.tif42158

[0293] N-(4-(4-(3-cyclopropyl-2-fluorophenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3ah): Synthesized according to procedure 4 of TIFF2026514377000317.tif26128, white solid, 121 mg, yield 86%. TIFF2026514377000318.tif56160

[0294] N-(4-(4-(3-cyclopropyl-5-fluorophenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3ai): Synthesized according to procedure 4 of TIFF2026514377000319.tif24128, white solid, 155 mg, yield 96%. TIFF2026514377000320.tif56159

[0295] N-(4-(4-(3-cyclobutylphenoxy)propyl)-2-fluorophenyl)piperazine-1-carboxamide hydrochloride (3aj): Synthesized according to procedure 4 of TIFF2026514377000321.tif27128, white solid, 51 mg, yield 84%. TIFF2026514377000322.tif49158

[0296] N-(4-(5-(3-chlorophenoxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3aq): Synthesized according to procedure 4 of TIFF2026514377000323.tif26128, white solid, 32 mg, yield 81%. TIFF2026514377000324.tif49159

[0297] N-(4-(4-(naphthalene-1-yloxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride (3 au): Synthesized according to procedure 4 of TIFF2026514377000325.tif20128, white solid, 86 mg, yield 89%. TIFF2026514377000326.tif55160

[0298] N-(4-(6-(cyclopentyloxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3av): Synthesized according to procedure 4 of TIFF2026514377000327.tif20128, white solid, 49 mg, yield 82%. TIFF2026514377000328.tif48156

[0299] N-(4-(5-(benzyloxy)pentyl)phenyl)piperazine-1-carboxamide hydrochloride (3aw): Synthesized according to procedure 4 of TIFF2026514377000329.tif20128, white solid, 61 mg, yield 86%. TIFF2026514377000330.tif41157

[0300] N-(4-(3-(3-phenylpropoxy)propyl)phenyl)piperazine-1-carboxamide hydrochloride (3ax): Synthesized according to procedure 4 of TIFF2026514377000331.tif20128, white solid, 66 mg, yield 87%. TIFF2026514377000332.tif41156

[0301] N-(4-(6-(cyclobutyloxy)hexyl)phenyl)piperazine-1-carboxamide hydrochloride (3ay): Synthesized according to procedure 4 of TIFF2026514377000333.tif20128, white solid, 66 mg, yield 86%. TIFF2026514377000334.tif49159

[0302] 4-((4-(6-(cyclohexyloxy)hexyl)phenyl)carbamoyl)piperazine-1-ium chloride, (3az): Synthesized according to procedure 4 of TIFF2026514377000335.tif19128, off-white solid, 82 mg, 71%. TIFF2026514377000336.tif49158

[0303] 4-((4-(4-((5,6,7,8-tetrahydronaphthalene-1-yl)oxy)butyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3ba: Synthesized according to procedure 4 of TIFF2026514377000337.tif19128, off-white solid, 58 mg, 77%. TIFF2026514377000338.tif48159

[0304] 4-((4-(4-((5,6,7,8-tetrahydronaphthalene-1-yl)oxy)butyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bb Synthesized according to procedure 4 of TIFF2026514377000339.tif19128, off-white solid, 73 mg, 84%. TIFF2026514377000340.tif56160

[0305] 4-((4-(7-methoxyheptyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bc Synthesized according to procedure 4 of TIFF2026514377000341.tif18128, off-white solid, 59 mg, 82%. TIFF2026514377000342.tif41157

[0306] 4-((4-((4-(phenoxymethyl)cyclohexyl)methyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bd Synthesized according to procedure 4 of TIFF2026514377000343.tif18128, off-white solid, 5 mg, 30%, dr88:12. TIFF2026514377000344.tif41158

[0307] 4-((4-(8-methoxyoctyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3be Synthesized according to procedure 4 of TIFF2026514377000345.tif19128, off-white solid, 50 mg, 63%. TIFF2026514377000346.tif41154

[0308] 4-((4-((3-(phenoxymethyl)cyclohexyl)methyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bf Synthesized according to procedure 4 of TIFF2026514377000347.tif26128, off-white solid, 9 mg, 78%, dr70:30. TIFF2026514377000348.tif71167

[0309] 4-((4-((3-(phenoxymethyl)cyclopentyl)methyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bg Synthesized according to procedure 4 of TIFF2026514377000349.tif18128, off-white solid, 11 mg, 97%, dr60:40. TIFF2026514377000350.tif71165

[0310] 4-((4-(4-phenoxymethyl)benzyl)phenyl)carbamoyl)piperazine-1-ium chloride, 3bh Synthesized according to procedure 4 of TIFF2026514377000351.tif18128, off-white solid, 11 mg, 97%. TIFF2026514377000352.tif49158

[0311] N-(4-(4-(3-(trifluoromethyl)phenoxy)butyl)phenyl)piperazine-1-carboxamide hydrochloride, 3bi Synthesized according to procedure 4 of TIFF2026514377000353.tif19128, white solid, 47 mg, yield 38%. TIFF2026514377000354.tif41159

[0312] Scheme 4: Exemplary synthesis for (4-(6-phenoxyhexyl)phenyl)(piperazin-1-yl)methanone hydrochloride TIFF2026514377000355.tif89128(a)4-iodobenzoic acid (1.1 equivalents), HCl (1.1 equivalents), DIEA (1.8 equivalents), mono-N-Boc-protected diamine (1.0 equivalent), DCM, rt, 18h;(b)(i)9-BBN (1.5 equivalents), alkene (1.1 equivalents), THF, 70℃, 2h;(ii)aryl iodide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.05 equivalents), 3M KOH (3.0 equivalents), THF, 70℃, 4h;(c)4M HCl / dioxane (10 equivalents), DCM, 25℃, 2h.

[0313] 4-(4-iodobenzoyl)piperazine-1-carboxylate tert-butyl: Synthesized according to procedure 6 of TIFF2026514377000356.tif24128, a white solid, 780 mg, 93%. TIFF2026514377000357.tif33157

[0314] TIFF2026514377000358.tif241284-(4-(6-phenoxyhexyl)benzoyl)piperazine-1-carboxylate tert-butyl(4a): Synthesized according to step 3, a white solid, 182 mg, 91%. TIFF2026514377000359.tif49159

[0315] 4-(4-(3-(3-propylphenoxy)propyl)benzoyl)piperazine-1-carboxylate tert-butyl(4b): Synthesized according to procedure 3 of TIFF2026514377000360.tif25128, white solid, 214 mg, 96%. TIFF2026514377000361.tif49159

[0316] 4-(4-(4-(3-(tert-butyl)phenoxy)butyl)benzoyl)piperazine-1-carboxylate tert-butyl(4c): Synthesized according to procedure 3 of TIFF2026514377000362.tif24128, white solid, 74 mg, 62%. TIFF2026514377000363.tif49156

[0317] (4-(6-phenoxyhexyl)phenyl)(piperazine-1-yl)methanone hydrochloride (5a): Synthesized according to procedure 4 of TIFF2026514377000364.tif18128, white solid, 145 mg, yield 92%. TIFF2026514377000365.tif41158

[0318] Piperazine-1-yl(4-(3-(3-propylphenoxy)propyl)phenyl)methanone hydrochloride (5b): Synthesized according to procedure 4 of TIFF2026514377000366.tif25128, a white solid, 170 mg, yield 92%. TIFF2026514377000367.tif47163

[0319] (4-(4-(3-(tert-butyl)phenoxy)butyl)phenyl)(piperazine-1-yl)methanone hydrochloride (5c): Synthesized according to procedure 4 of TIFF2026514377000368.tif22128, white solid, 28 mg, yield 92%. TIFF2026514377000369.tif41163

[0320] Scheme 5: Exemplary synthesis of N-(4-decylphenyl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxamide hydrochloride: TIFF2026514377000370.tif67128(a)(i)9-BBN (1.5 equivalents), alkene (1.1 equivalents), THF, 70℃, 2h; (ii) aryl iodide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.05 equivalents), 3M KOH (3.0 equivalents), THF, 70℃, 4h; (b) triphosgene (0.5 equivalents), TEA (2.3 equivalents), mono-N-Boc-amine (1.5 equivalents), 25℃, 16h; (c) 4M HCl / dioxane (10 equivalents), DCM, 25℃, 2h.

[0321] 5-((4-decylphenyl)carbamoyl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tert-butyl(6a): Synthesized according to the basic procedure described herein. 112 mg, 52%, clear oil. TIFF2026514377000372.tif56157

[0322] 7-((4-decylphenyl)carbamoyl)-4,7-diazaspiro[2.5]octane-4-carboxylate tert-butyl(6b): Synthesized according to the basic procedure described herein. 48 mg, 24%, clear oil. TIFF2026514377000374.tif56157

[0323] 6-((4-decylphenyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl(6c): Synthesized according to the basic procedure described herein. 59 mg, 27%, clear oil. TIFF2026514377000376.tif41159

[0324] 1-((4-decylphenyl)carbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate tert-butyl(6d): Synthesized according to the basic procedure described herein. 53 mg, 22%, clear oil. TIFF2026514377000378.tif49158

[0325] 3-((4-decylphenyl)carbamoyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate tert-butyl(6e): Synthesized according to the basic procedure described herein. 125 mg, 34%, clear oil. TIFF2026514377000380.tif48159

[0326] N-(4-decylphenyl)-2,5-diazabicyclo[4.1.0]heptan-2-carboxamide hydrochloride (7a): Synthesized according to the basic procedure described herein, a white solid, 20 mg, yield 77%. TIFF2026514377000381.tif23128 TIFF2026514377000382.tif41158

[0327] N-(4-decylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide hydrochloride (7b): Synthesized according to the basic procedure described herein, a white solid, 33 mg, yield 83%. TIFF2026514377000383.tif24128 TIFF2026514377000384.tif41158

[0328] N-(4-decylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide 2,2,2-trifluoroacetate (7c): Synthesized according to the basic procedure described herein. 25 mg, 97%, white solid. TIFF2026514377000386.tif41158

[0329] N-(4-decylphenyl)-1,6-diazaspiro[3.3]heptane-1-carboxamide 2,2,2-trifluoroacetate (7d): Synthesized according to the basic procedure described herein. 25 mg, 97%, yellow oil. TIFF2026514377000388.tif41159

[0330] N-(4-decylphenyl)-3,6-diazabicyclo[3.1.1]heptan-3-carboxamide hydrochloride (7e): Synthesized according to the basic procedure described herein. 55 mg, 50%, brown solid. TIFF2026514377000390.tif41158

[0331] 3-(4-iodobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: Purified via column chromatography (35% ethyl acetate / hexane). White solid (90%, 482 mg). TIFF2026514377000392.tif27159 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 18 H 24 The calculated value for IN2O3 was 443.0826, and the measured value was 443.0832.

[0332] 3-(4-decylbenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl(8a): Purified via column chromatography (30-40% ethyl acetate / hexane). Clear oil (74%, 367 mg). TIFF2026514377000394.tif40158 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [2M+H] + C 56 H 89 The calculated value for N4O6 was 913.6777, and the measured value was 913.6774.

[0333] (2,5-Diazabicyclo[2.2.1]heptan-2-yl)(4-decylphenyl)methanone hydrochloride (9a): Purified by trituration with ethyl acetate and diethyl ether. White solid (65%, 56 mg). TIFF2026514377000396.tif41158 is a substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 22 H 35 The calculated value for N2O was 343.2744, and the measured value was 343.2738.

[0334] (3,8-Diazabicyclo[3.2.1]octan-3-yl)(4-decylphenyl)methanone hydrochloride (9b): Purified via trituration with ethyl acetate and diethyl ether. White solid (93%, 80 mg). TIFF2026514377000398.tif34159 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 23 H 37 The calculated value for N2O was 357.2900, and the measured value was 357.2911.

[0335] 3-((4-iodophenyl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl Purified via column chromatography (30-40% ethyl acetate / hexane). White solid (99%, 745 mg). TIFF2026514377000400.tif34154

[0336] 3-((4-decylphenyl)carbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl(6f): Purified via column chromatography (30-40% ethyl acetate / hexane). White solid (60%, 483 mg). TIFF2026514377000402.tif49159

[0337] N-(4-decylphenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxamide hydrochloride (7f) Purified by trituration with ethyl acetate and diethyl ether. White solid (87%, 75 mg). TIFF2026514377000404.tif41159

[0338] N-(hexa-5-en-1-yl)aniline: Synthesized according to procedure 7 of TIFF2026514377000405.tif15128, yellow oil, 180 mg, yield 64%. TIFF2026514377000406.tif34164

[0339] 4-((4-(6-(phenylamino)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ak): Synthesized according to procedure 3 of TIFF2026514377000407.tif28128, yellow solid, 140 mg, yield 63%. HRMS:(ESI) [M+H] + C 12 H 18The calculated value for N is 176.1434, and the measured value is 176.1438. TIFF2026514377000408.tif49158

[0340] N-(4-(6-(phenylamino)hexyl)phenyl)piperazine-1-carboxamide hydrogen chloride (3ak): Synthesized according to procedure 4 of TIFF2026514377000409.tif22128, yellow solid, 55 mg, yield 91%. TIFF2026514377000410.tif41160

[0341] N-phenylhexa-5-enamide: Synthesized according to procedure 8 of TIFF2026514377000411.tif15128, yellow solid, 320 mg, yield 97%. TIFF2026514377000412.tif34159

[0342] 4-((4-(6-oxo-6-(phenylamino)hexyl)phenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2al): Synthesized according to procedure 3 of TIFF2026514377000413.tif29128, a white solid, 130 mg, yield 38%. TIFF2026514377000414.tif41159

[0343] N-(4-(6-oxo-6-(phenylamino)hexyl)phenyl)piperazine-1-carboxamide hydrogen chloride (3al): Synthesized according to procedure 4 of TIFF2026514377000415.tif22128, white solid, 44 mg, yield 84%. TIFF2026514377000416.tif55157

[0344] 4-((6-iodopyridine-3-yl)carbamoyl)piperazine-1-carboxylate tert-butyl: Synthesized according to procedure 11 of TIFF2026514377000417.tif25128, yellow solid, 244 mg, yield 41%. TIFF2026514377000418.tif27163

[0345] 4-((2-bromopyrimidine-5-yl)carbamoyl)piperazine-1-carboxylate tert-butyl: Synthesized according to procedure 11 of TIFF2026514377000419.tif25128 (in THF instead of DCM), yellow solid, 310 mg, yield 56%. TIFF2026514377000420.tif27154

[0346] 4-((2-fluoro-4-iodophenyl)carbamoyl)piperazine-1-carboxylate tert-butyl: Synthesized according to procedure 11 of TIFF2026514377000421.tif25128, white solid, 277 mg, yield 49%. TIFF2026514377000422.tif34164

[0347] 4-((6-bromonaphthalene-2-yl)carbamoyl)piperazine-1-carboxylate tert-butyl Synthesized according to procedure 11 of TIFF2026514377000423.tif34128, yellow solid, 610 mg, yield 78%. TIFF2026514377000424.tif34160

[0348] 4-((7-bromonaphthalene-2-yl)carbamoyl)piperazine-1-carboxylate tert-butyl Synthesized according to procedure 11 of TIFF2026514377000425.tif33128, yellow solid, 427 mg, yield 96%. TIFF2026514377000426.tif34163

[0349] 4-((6-(3-(4-cyclopropylphenoxy)propyl)pyridine-3-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2am): Synthesized according to procedure 3 of TIFF2026514377000427.tif31128, white solid, 60 mg, yield 39%. TIFF2026514377000428.tif48159

[0350] 4-((6-(4-(3-cyclopropylphenoxy)butyl)132-iridin-3-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2an): Synthesized according to procedure 3 of TIFF2026514377000429.tif24128, white solid, 30 mg, yield 22%. TIFF2026514377000430.tif55159

[0351] 4-((4-(4-(3-cyclopropylphenoxy)butyl)-2-fluorophenyl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ao): Synthesized according to procedure 3 of TIFF2026514377000431.tif24128, white solid, 64 mg, yield 40%. TIFF2026514377000432.tif70157

[0352] 4-((2-decylpyrimidine-5-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ap): Synthesized according to procedure 3 of TIFF2026514377000433.tif21128, white solid, 90 mg, yield 52%. TIFF2026514377000434.tif41156

[0353] 4-((6-octylnaphthalen-2-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2ar): Synthesized according to procedure 3 of TIFF2026514377000435.tif33128, white solid, 155 mg, yield 72%. TIFF2026514377000436.tif48163

[0354] 4-((7-heptylnaphthalen-2-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2as): Synthesized according to procedure 3 of TIFF2026514377000437.tif33128, white solid, 121 mg, yield 58%. TIFF2026514377000438.tif41158

[0355] 4-((7-(3-phenoxypropyl)naphthalene-2-yl)carbamoyl)piperazine-1-carboxylate tert-butyl(2at) Synthesized according to procedure 3 of TIFF2026514377000439.tif33128, white solid, 146 mg, yield 52%. TIFF2026514377000440.tif48160

[0356] N-(6-(3-(4-cyclopropylphenoxy)propyl)pyridine-3-yl)piperazine-1-carboxamide bis-hydrochloride (3am): Synthesized according to procedure 4 of TIFF2026514377000441.tif31128, yellow solid, 20 mg, yield 72%. TIFF2026514377000442.tif41164

[0357] N-(6-(4-(3-cyclopropylphenoxy)butyl)pyridine-3-yl)piperazine-1-carboxamide bis-hydrochloride (3an): Synthesized according to procedure 4 of TIFF2026514377000443.tif25128, white solid, 20 mg, yield 71%. TIFF2026514377000444.tif56158

[0358] N-(4-(4-(3-cyclopropylphenoxy)butyl)-2-fluorophenyl)piperazine-1-carboxamide hydrochloride (3ao): Synthesized according to procedure 4 of TIFF2026514377000445.tif24128, white solid, 52 mg, yield 93%. TIFF2026514377000446.tif63157

[0359] N-(2-decylpyrimidine-5-yl)piperazine-1-carboxamide bis-hydrochloride (3ap): Synthesized according to procedure 4 of TIFF2026514377000447.tif20128, yellow solid, 32 mg, yield 76%. TIFF2026514377000448.tif34161

[0360] N-(6-octylnaphthalen-2-yl)piperazine-1-carboxamide hydrochloride (3ar): Synthesized according to procedure 4 of TIFF2026514377000449.tif19128, white solid, 111 mg, yield 86%. TIFF2026514377000450.tif41159

[0361] N-(7-heptylnaphthalen-2-yl)piperazine-1-carboxamide hydrochloride (3as): Synthesized according to procedure 4 of TIFF2026514377000451.tif19128, white solid, 87 mg, yield 84%. TIFF2026514377000452.tif34159

[0362] N-(7-(3-phenoxypropyl)naphthalene-2-yl)piperazine-1-carboxamide hydrochloride (3at): Synthesized according to procedure 4 of TIFF2026514377000453.tif19128, white solid, 66 mg, yield 84%. TIFF2026514377000454.tif56159

[0363] Scheme 6: Exemplary synthesis of (6-(6-phenoxyhexyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride TIFF2026514377000455.tif841632,2,2-Methyl trichloroacetimide (1.1 equivalent), AcOH, 0℃~25℃, 2h; (b) Mono-N-Boc-piperazine (1.1 equivalent), NaHCO3 (10.0 equivalent), 1:2 water:THF, 50℃, 16h; (c) Boc anhydrous (1.1 equivalent), DMAP (0.1 equivalent), DCM, 25℃, 16h; (d) (i) 9-BBN (1.5 equivalent), Alkene (1.1 equivalent), THF, 70℃, 2h, (ii) Aryl iodide (1.0 equivalent), Pd(dppf)Cl2*CH2Cl2 (0.05 equivalent), 3M KOH (3.0 eq), THF, 70°C, 4 h; (e) 4M HCl / dioxane (10 eq), DCM, 25°C, 2 h

[0364] Scheme 7: Synthesis example of piperazine-1-yl(6-(4-(3-(trifluoromethyl)phenoxy)butyl)-1H-benzo[d]imidazole-2-yl)methanone hydrochloride TIFF2026514377000456.tif84164 (a) 2,2,2-Methyl trichloroacetimide (1.1 equivalents), AcOH, 0℃~20℃, 3h, 92%; (b) N-Boc-piperazine (1.2 equivalents), NaHCO3 (10.0 equivalents), 1:2 water:THF, 50℃, 2h, 84%; (c) NaH (1.1 equivalents), SEM-Cl (1.1 equivalents), THF, 0℃~20℃, 2h, 98%; (d) (i) Alkene (2.0 equivalents), 9-BBN (2.3 equivalents), THF, 70℃, 1h. (ii) Aryl bromide (1.0 eq.), PdCl2(dppf)·CH2Cl2 (0.15 eq.), 3M aqueous K2CO3 (3.0 eq.), THF, 70°C, 16 h, 61-86%; (e) TBAF (3.0 eq.), THF, 70°C, 3 h, 38-93% (f) 4M in dioxane. HCl (10.0 eq.), DCM, 20 °C, 1 h, 85–95%.

[0365] 4-(6-bromo-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl (15a): Synthesized according to basic procedure 9 of TIFF2026514377000457.tif20128. Purified via column chromatography (30-50% ethyl acetate / hexane). White solid (79%, 410 mg). TIFF2026514377000458.tif33158 is a substance isolated as an isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 17 H 22 BrN4O3 + The calculated value for this is 409.0870, and the measured value is 409.0884.

[0366] 6-Bromo-2-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-1H-benzo[d]imidazole-1-carboxylate tert-butyl: Synthesized according to basic procedure 10 of TIFF2026514377000459.tif20128. 452 mg, 89%, white solid. TIFF2026514377000460.tif56158

[0367] 4-(6-(6-phenoxyhexyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl (17a): Synthesized according to basic procedure 3 of TIFF2026514377000461.tif23128. Purified via column chromatography (30-40% ethyl acetate / hexane). Clear oil (60%, 60 mg). TIFF2026514377000462.tif49156

[0368] 4-(6-(4-(3-cyclopropylphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17b): Synthesized according to basic procedure 3 of TIFF2026514377000463.tif23128. Purified via column chromatography (20-40% ethyl acetate / hexane). White solid (64%, 52 mg). TIFF2026514377000464.tif63158 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 30 H 39 N4O4 + The calculated value for this is 519.2966, and the measured value is 519.2987.

[0369] (6-(6-phenoxyhexyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18a): Synthesized according to basic procedure 4 of TIFF2026514377000465.tif27128. 39 mg, 89%, off-white solid. TIFF2026514377000466.tif49159

[0370] (6-(4-(3-cyclopropylphenoxy)butyl)-1H-benzo[d]142-midazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18b): Synthesized according to basic procedure 4 of TIFF2026514377000467.tif27128. Purified by trituration with diethyl ether. White solid (73%, 51 mg). TIFF2026514377000468.tif49159

[0371] 6-Bromo-2-(trichloromethyl)-1H-benzo[d]imidazole Synthesized according to basic procedure 18 of TIFF2026514377000469.tif13128. Purified by precipitation. White solid (92%, 15.49g). TIFF2026514377000470.tif27156

[0372] 4-(6-bromo-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl Synthesized according to basic procedure 9 of TIFF2026514377000471.tif20128. Purified via column chromatography (30-50% ethyl acetate / hexane). White solid (79%, 410 mg). TIFF2026514377000472.tif34158 A substance isolated as an isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 17 H 22 BrN4O3 + The calculated value for this is 409.0870, and the measured value is 409.0884.

[0373] 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl Synthesized according to basic procedure 19. Purified by extraction. Yellow oil (98%, 1280 mg). TIFF2026514377000474.tif34157

[0374] 4-(6-(4-(2-ethylphenoxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl Synthesized according to basic procedure 20 of TIFF2026514377000475.tif23128. Purified via column chromatography (40-50% ethyl acetate / hexane). Yellow oil (61%, 145 mg). TIFF2026514377000476.tif78160 A substance isolated as a positional isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 35 H 53 N4O5Si + The calculated value for this is 637.3780, and the measured value is...

[0375] 4-(6-(4-(3-isopropylphenoxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17h) Synthesized according to basic procedure 20 of TIFF2026514377000477.tif23128. Purified via column chromatography (20-30% ethyl acetate / hexane). Yellow oil (82%, 198 mg). TIFF2026514377000478.tif63159 A substance isolated as an approximately 1:1 mixture of positional isomers. A substance isolated as positional isomers in an approximately 1:1 ratio. HRMS: (ESI) [M+H] + C 36 H 55 N4O5Si + The calculated value for this is 651.3936, and the measured value is 651.3916.

[0376] 4-(6-(4-(3-(dimethylamino)phenoxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17i) Synthesized according to basic procedure 20 of TIFF2026514377000479.tif23128. Purified via column chromatography (20-40% ethyl acetate / hexane). Yellow oil (86%, 187 mg). TIFF2026514377000480.tif70160 A substance isolated as a positional isomer with a ratio of approximately 1:1. A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + The calculated value for C35H54N5O5Si+ is 652.3889, and the measured value is 652.3871.

[0377] 4-(6-(4-(3-methoxyphenoxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(18j) Synthesized according to basic procedure 20 of TIFF2026514377000481.tif23128. Purified via column chromatography (20-30% ethyl acetate / hexane). Yellow oil (86%, 213 mg). A substance isolated as a positional isomer with a ratio of approximately 1:1 (TIFF2026514377000482.tif70156). HRMS: (ESI) [M+H] + C 34 H 51 N4O6Si + The calculated value for this is 639.3572, and the measured value is 639.3560.

[0378] 4-(6-(4-(3-(trifluoromethyl)phenoxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(18k) Synthesized according to basic procedure 20 of TIFF2026514377000483.tif23128. Purified via column chromatography (10-30% ethyl acetate / hexane). Yellow oil (70%, 158 mg). A substance isolated as a positional isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 34 H 48 F3N4O5Si + The calculated value for this is 677.3341, and the measured value is 677.3320.

[0379] 4-(6-(6-phenoxyhexyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl (17a) Synthesized according to basic procedure 20 of TIFF2026514377000485.tif23128. Purified via column chromatography (30-40% ethyl acetate / hexane). Clear oil (60%, 60 mg). TIFF2026514377000486.tif49157

[0380] 4-(6-(4-(m-tolyloxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17e) Synthesized according to basic procedure 20 of TIFF2026514377000487.tif23128. Purified via column chromatography (35-50% ethyl acetate / hexane). Clear oil (93%, 287 mg). TIFF2026514377000488.tif49158 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 28 H 37 N4O4 + The calculated value for this is 493.2809, and the measured value is 493.2824.

[0381] 4-(6-(4-(2-ethylphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17f) Synthesized according to basic procedure 20 of TIFF2026514377000489.tif23128. Purified via column chromatography (40-50% ethyl acetate / hexane). White solid (72%, 83 mg). TIFF2026514377000490.tif63160 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 29 H 39 N4O4 + The calculated value for this is 507.2966, and the measured value is...

[0382] 4-(6-(4-(3-ethylphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl (18g) Synthesized according to basic procedure 20 of TIFF2026514377000491.tif23128. Purified via column chromatography (40-50% ethyl acetate / hexane). Clear oil (93%, 258 mg). TIFF2026514377000492.tif63158 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 29 H 39 N4O4 + The calculated value for this is 507.2966, and the measured value is 507.2960.

[0383] 4-(6-(4-(3-isopropylphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17h) Synthesized according to basic procedure 20 of TIFF2026514377000493.tif23128. Purified via column chromatography (40-50% ethyl acetate / hexane). White solid (98%, 155 mg). TIFF2026514377000494.tif49159 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 30 H 41 N4O4 + The calculated value for this is 521.3122, and the measured value is 521.3111.

[0384] 4-(6-(4-(3-cyclopropylphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17b) Synthesized according to basic procedure 20 of TIFF2026514377000495.tif23128. Purified via column chromatography (20-40% ethyl acetate / hexane). White solid (64%, 52 mg). TIFF2026514377000496.tif63158 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 30 H 39 N4O4 + The calculated value for this is 519.2966, and the measured value is 519.2987.

[0385] 4-(6-(3-(3-cyclopropylphenoxy)propyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl (17L) Synthesized according to basic procedure 20 of TIFF2026514377000497.tif38128. Purified via column chromatography (30-50% ethyl acetate / hexane). Orange oil (53%, 224 mg). TIFF2026514377000498.tif70159: A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 29 H 37 N4O4 + The calculated value for this is 505.2809, and the measured value is 505.2819.

[0386] 4-(6-(4-(3-(dimethylamino)phenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(18i) Synthesized according to basic procedure 20 of TIFF2026514377000499.tif23128. Purified via column chromatography (40-60% ethyl acetate / hexane). White solid (89%, 113 mg). A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 29 H 40 N5O4 + The calculated value for this is 522.3075, and the measured value is 522.3098.

[0387] 4-(6-(4-(3-methoxyphenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17j) Synthesized according to basic procedure 20 of TIFF2026514377000501.tif23128. Purified via column chromatography (30-50% ethyl acetate / hexane). White solid (93%, 132 mg). TIFF2026514377000502.tif56160 A substance isolated as a rotational isomer with a ratio of approximately 1:1. HRMS: (ESI) [M+H] + C 28 H 37 N4O5 + The calculated value for this is 509.2758, and the measured value is 509.2784.

[0388] 4-(6-(4-(3-(trifluoromethyl)phenoxy)butyl)-1H-benzo[d]imidazole-2-carbonyl)piperazine-1-carboxylate tert-butyl(17k) Synthesized according to basic procedure 20 of TIFF2026514377000503.tif23128. Purified via column chromatography (30-50% ethyl acetate / hexane). White solid (70%, 158 mg). TIFF2026514377000504.tif70159

[0389] (6-(6-phenoxyhexyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18a) Synthesized according to basic procedure 4 of TIFF2026514377000505.tif27128. Purified by trituration with diethyl ether. White solid (89%, 39 mg). TIFF2026514377000506.tif49159

[0390] Piperazine-1-yl(6-(4-(m-tolyloxy)butyl)-1H-benzo[d]imidazole-2-yl)methanone hydrochloride (18m) Synthesized according to basic procedure 4 of TIFF2026514377000507.tif24128. Purified by trituration with diethyl ether. White solid (89%, 222 mg). TIFF2026514377000508.tif49159

[0391] (6-(4-(2-ethylphenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18f) Synthesized according to basic procedure 4 of TIFF2026514377000509.tif28128. Purified by trituration with diethyl ether. White solid (72%, 52 mg). TIFF2026514377000510.tif49157

[0392] (6-(4-(3-ethylphenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18g) Synthesized according to basic procedure 4 of TIFF2026514377000511.tif23128. Purified by trituration with diethyl ether. White solid (85%, 36 mg). TIFF2026514377000512.tif41156

[0393] (6-(4-(3-isopropylphenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18h) Synthesized according to basic procedure 4 of TIFF2026514377000513.tif30128. Purified by trituration with diethyl ether. White solid (79%, 115 mg). TIFF2026514377000514.tif56159

[0394] (6-(4-(3-cyclopropylphenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18b) Synthesized according to basic procedure 4 of TIFF2026514377000515.tif27128. Purified by trituration with diethyl ether. White solid (73%, 51 mg). TIFF2026514377000516.tif49159

[0395] (6-(3-(3-cyclopropylphenoxy)propyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone (18l) Synthesized according to basic procedure 4 of TIFF2026514377000517.tif26128. Purified by trituration with diethyl ether. White solid (88%, 100 mg). TIFF2026514377000518.tif41159

[0396] (6-(4-(3-(dimethylamino)phenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18i) Synthesized according to basic procedure 4 of TIFF2026514377000519.tif29128. Purified via trituration with diethyl ether. TIFF2026514377000520.tif49159

[0397] (6-(4-(3-methoxyphenoxy)butyl)-1H-benzo[d]imidazole-2-yl)(piperazine-1-yl)methanone hydrochloride (18j) Synthesized according to basic procedure 4 of TIFF2026514377000521.tif29128. Purified by trituration with diethyl ether. White solid (98%, 113 mg). TIFF2026514377000522.tif49158

[0398] Piperazine-1-yl(6-(4-(3-(trifluoromethyl)phenoxy)butyl)-1H-benzo[d]imidazole-2-yl)methanone hydrochloride (18k) Synthesized according to basic procedure 4 of TIFF2026514377000523.tif27128. Purified by trituration with diethyl ether. White solid (98%, 136 mg). TIFF2026514377000524.tif49157

[0399] Scheme 7: Exemplary synthesis for (R)-3-(((6-(4-(3-(tert-butyl)phenoxy)butyl)benzo[d]oxazol-2-yl)amino)methyl)pyrrolidine hydrochloride TIFF2026514377000525.tif45158 a) K2CO3 (1.2 equivalents), CS2 (1.2 equivalents), 5:1 EtOH:water, 80℃, 16h; b) SOCl2 (2.5 equivalents), DMF (0.04 equivalents), DCM, 25℃, 3h; c) (R)-3-(aminomethyl)pyrrolidine-1-carboxylate tert-butyl (1.2 equivalents), K2CO3 (2.0 equivalents), DMF, 120℃, 16h; d) (i) 9-BBN (2.2 equivalents), alkene (2.0 equivalents), THF, 70℃, 1h, (ii) Pd(dppf)Cl2·CH2Cl2 (0.075 equivalents), 3M KOH (3.0 equivalents), THF, 70°C, 16h; e) 4M HCl / Dioxane (10 equivalents), DCM, 25°C, 16h.

[0400] 6-bromobenzo[d]oxazole-2-thiol, 9 TIFF2026514377000526.tif13128 To a stirred solution of potassium carbonate (2.7 g, 1.2 eq, 19 mmol) and 2-amino-5-bromophenol (3.0 g, 1.0 eq, 16 mmol) in ethanol (44 mL) and water (8.9 mL), carbon disulfide (1.5 g, 1.2 mL, 1.2 eq, 19 mmol) was added. The reaction mixture was heated under reflux for 16 hours while monitoring by TLC. The reaction mixture was diluted with water, and acetic acid was added dropwise to precipitate a white solid. The reaction mixture was filtered, the precipitate was redissolved in ethyl acetate, and then concentrated under vacuum to obtain 6-bromobenzo[d]oxazole-2-thiol (3.31 g, 14.4 mmol, 90%) as an amorphous, off-white solid. TIFF2026514377000527.tif19160

[0401] 6-bromo-2-chlorobenzo[d]oxazole, 10 TIFF2026514377000528.tif13128 In a stirred solution of 6-bromobenzo[d]oxazole-2-thiol 9 (0.45 g, 1 Eq, 2.0 mmol) in dichloromethane (6 mL), thionyl chloride (sulfurous dichloride) (0.58 g, 0.36 mL, 2.5 Eq, 4.9 mmol) and N,N-dimethylformamide (5.7 mg, 6.1 μL, 0.04 Eq, 78 μmol) were sequentially added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours while monitoring by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate (3 × 5 mL). The organic extracts were combined, washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 10 g silica, Φ=2.5 cm, hexane / ethyl acetate 0 → 30%) to obtain 6-bromo-2-chlorobenzo[d]oxazole (0.682 g, 2.93 mmol, 75%) as a yellow amorphous solid. TIFF2026514377000529.tif19158

[0402] (R)-3-(((6-bromobenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl TIFF2026514377000530.tif29128 Potassium carbonate (0.78 g, 2.0 Eq, 5.7 mmol) and (R)-3-(aminomethyl)pyrrolidine-1-carboxylate tert-butyl (0.68 g, 1.2 Eq, 3.4 mmol) were added to a stirred solution of 6-bromo-2-chlorobenzo[d]oxazole 10 (0.66 g, 1.0 Eq, 2.8 mmol) in N,N-dimethylformamide (9.5 mL). The reaction mixture was heated to 120 °C for 16 hours while monitoring by TLC. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated lithium bromide solution (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The brown residue was purified by flash column chromatography (Teledyne ISCO, 25g silica, Φ=2.5cm, hexane / ethyl acetate 0→100%) to obtain (R)-3-(((6-bromobenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl (0.68g, 1.7 mmol, 60%) as a pale yellow amorphous solid. TIFF2026514377000531.tif41158

[0403] (S)-3-(((tert-butoxycarbonyl)(6-hydroxybenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate (S)-3-(((tert-butoxycarbonyl)(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl (0.31 g, 1.0 eq, 0.57 mmol) was stirred in THF (0.50 M), to which sodium perborate monohydrate (0.17 g, 3.0 eq, 1.7 mmol) and water (0.57 mL) were added. The reaction mixture was stirred at room temperature while monitoring by TLC, then diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic extracts were combined, washed with brine (2 × 15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (Teledyne ISCO, 25g silica, Φ=2.5cm, hexane / ethyl acetate 0→100%) to obtain (S)-3-(((tert-butoxycarbonyl)(6-hydroxybenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl (0.212g, 0.489 mmol, 86%) as an orange oil. TIFF2026514377000533.tif49158

[0404] (R)-3-(((6-(4-(3-(tert-butyl)phenoxy)butyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl(20a): Synthesized according to basic procedure 12. 0.100g, 64%, yellow oil. TIFF2026514377000535.tif63160

[0405] (R)-3-(((6-(6-(2,6-difluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl(20b): Synthesized according to basic procedure 12. 0.118g, 80%, yellow oil. TIFF2026514377000537.tif63159

[0406] (R)-3-(((6-(6-(3,5-difluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl(20c): Synthesized according to basic procedure 12. 0.12g, 82%, yellow oil. TIFF2026514377000539.tif56159

[0407] (R)-3-(((6-(6-phenoxyhexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20e Synthesized according to basic procedure 12. 0.060g, 41%, yellow oil. TIFF2026514377000541.tif41160

[0408] (R)-3-(((6-(6-(2-oxobenzo[d]oxazole-3(2H)-yl)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20f Synthesized according to basic procedure 12. 0.103g, 80%, yellow oil. TIFF2026514377000543.tif64159

[0409] (R)-3-(((6-(5-benzamidopentyl)benzo[d]oxazol-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20g Synthesized according to basic procedure 12. 0.052g, 49%, yellow oil. TIFF2026514377000545.tif56159

[0410] (R)-3-(((6-(6-(2-fluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20h Synthesized according to basic procedure 12. 0.065g, 46%, yellow oil. TIFF2026514377000547.tif71160

[0411] Scheme 8: Exemplary synthesis for (R)-3-(((6-((5-(2,6-difluorophenoxy)pentyl)oxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride TIFF2026514377000548.tif70159 a) K2CO3 (1.2 equivalents), CS2 (1.2 equivalents), 5:1 EtOH:water, 80℃, 16h; b) SOCl2 (2.5 equivalents), DMF (0.04 equivalents), DCM, 25℃, 3h; c) (R)-3-(aminomethyl)pyrrolidine-1-carboxylate tert-butyl (1.2 equivalents), K2CO3 (2.0 equivalents), DMF, 120℃, 16h; d) Boc2O (1.2 equivalents), DMAP (0.1 equivalent), DCM ;e)B2pin2 (1.1 equivalent), KOAc (3.0 equivalent), Pd(dppf)Cl2·CH2Cl2 (0.03 equivalent), DMSO, 80℃, 16h;f)NaBO3· H2O (3.0 eq.), THF, H2O, 25°C, 16h; g) Tosylated alcohol (1.2 eq.), K2CO3, (2.0 eq.), MeCN, 80°C, 16h; h) 4M HCl / dioxane (10 eq), DCM, 25°C, 16h.

[0412] (S)-3-(((6-bromobenzo[d]oxazole-2-yl)(tert-butoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl TIFF2026514377000549.tif37128 To a stirred solution of (R)-3-(((6-bromobenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl 5 (1.19 g, 1.0 eq, 3.00 mmol) in dichloromethane (7.51 mL), Boc2O (786 mg, 0.828 mL, 1.2 eq, 3.60 mmol) and DMAP (36.7 mg, 0.1 eq, 300 μmol) were added as a solution in dichloromethane (7.51 mL). The reaction mixture was stirred overnight at 25°C, then quenched with water, extracted with ethyl acetate (3 × 20 mL), washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (TeledyneISCO, 40g SiO2, Φ=5cm, hexane / ethyl acetate 0→50%) to obtain (S)-3-(((6-bromobenzo[d]oxazole-2-yl)(tert-butoxycarbonyl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl (1.255g, 2.528 mmol, 84%) as an orange oil. TIFF2026514377000550.tif49159

[0413] (S)-3-(((tert-butoxycarbonyl)(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl Synthesized according to basic procedure 14 of TIFF2026514377000551.tif37128. 0.107g, 65%, off-white, amorphous solid. TIFF2026514377000552.tif27158

[0414] (S)-3-(((tert-butoxycarbonyl)(6-((5-(2,6-difluorophenoxy)pentyl)oxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20i Synthesized according to basic procedure 17 of TIFF2026514377000553.tif36128. 18 mg, 49%. TIFF2026514377000554.tif71159

[0415] (S)-3-(((tert-butoxycarbonyl)(6-(3-(3-cyclopropylphenoxy)propoxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20j Synthesized according to basic procedure 17. 30 mg, 53%, colorless oil. TIFF2026514377000556.tif63162

[0416] (S)-3-(((tert-butoxycarbonyl)(6-((4-((2,6-difluorophenoxy)methyl)cyclohexyl)oxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20k Synthesized according to basic procedure 17. 22 mg, 36%, colorless oil. TIFF2026514377000558.tif63159

[0417] Scheme 9: Exemplary synthesis for (R)-3-(((6-(4-(3-cyclopropylphenoxy)butyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride TIFF2026514377000559.tif47159a) K2CO3 (1.2 equivalents), CS2 (1.2 equivalents), 5:1 EtOH: Water, 80°C, 16h; b) SOCl2 (2.5 equivalents), DMF (0.04 equivalents), DCM, 25°C, 3h; c) (R)-3-(aminomethyl)pyrrolidine-1-carboxylate tert-butyl (1.2 equivalents), K2CO3 (2.0 equivalents), DMF, 120°C, 16h; d) Boc2O (1.2 equivalents), DMAP (0.1 equivalent), DCM; e) (i) 9-BBN (2.2 equivalents), alkene (2.0 equivalents), THF, 70°C, 1h, (ii) Pd(dppf)Cl2·CH2Cl2 (0.075 equivalents), 3M KOH (3.0 equivalents), THF, 70°C, 16h; f) 4M HCl / dioxane (10 equivalents), DCM, 25°C, 16h.

[0418] (S)-3-(((tert-butoxycarbonyl)(6-(4-(3-cyclopropylphenoxy)butyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl, 20l Synthesized according to basic procedure 12. 75 mg, 47%, yellow oil. TIFF2026514377000561.tif56163

[0419] (R)-3-(((6-(4-(3-(tert-butyl)phenoxy)butyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine hydrochloride (21a): Synthesized according to basic procedure 4 of TIFF2026514377000562.tif16128. 70 mg, 89%, off-white, amorphous solid. TIFF2026514377000563.tif63158

[0420] Chloride (R)-3-(((6-(6-(2,6-difluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium(21b): Synthesized according to basic procedure 4 of TIFF2026514377000564.tif18128. 70 mg, 89%, off-white, amorphous solid. TIFF2026514377000565.tif78160

[0421] Chloride (R)-3-(((6-(6-(3,5-difluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium(21c): Synthesized according to basic procedure 4 of TIFF2026514377000566.tif21128. 59 mg, 61%, off-white, amorphous solid. TIFF2026514377000567.tif71159

[0422] (R)-3-(((6-bromobenzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 1u Synthesized according to basic procedure 4 of TIFF2026514377000568.tif15128. 40 mg, 0.12 mmol, 95%, off-white, amorphous solid. TIFF2026514377000569.tif41159

[0423] (R)-3-(((6-(6-phenoxyhexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 21e Synthesized according to basic procedure 4 of TIFF2026514377000570.tif15128. 9 mg, 20%, yellow, amorphous solid. TIFF2026514377000571.tif56158

[0424] Chloride (R)-3-(((6-(6-(2-oxobenzo[d]oxazole-3(2H)-yl)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium, 21f Synthesized according to basic procedure 4 of TIFF2026514377000572.tif20128. 59 mg, 61%, off-white, amorphous solid. TIFF2026514377000573.tif56159

[0425] (R)-3-(((6-(5-benzamidopentyl)benzo[d]oxazol-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 21g Synthesized according to basic procedure 4 of TIFF2026514377000574.tif17128. 38 mg, 84%, off-white, amorphous solid. TIFF2026514377000575.tif63158

[0426] (R)-3-(((6-(6-(2-fluorophenoxy)hexyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 21h Synthesized according to basic procedure 4 of TIFF2026514377000576.tif15128. 12 mg, 21%, off-white, amorphous solid. TIFF2026514377000577.tif71159

[0427] (R)-3-(((6-((5-(2,6-difluorophenoxy)pentyl)oxy)benzo[d]oxazol-2-yl)amino)methyl)pyrrolidine-1-ium, 21i Synthesized according to basic procedure 4 of TIFF2026514377000578.tif18128. 7 mg, 50%, off-white, amorphous solid. TIFF2026514377000579.tif63161

[0428] Chloride (R)-3-(((6-(3-(3-cyclopropylphenoxy)propoxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium, 21j Synthesized according to basic procedure 4 of TIFF2026514377000580.tif19128. 50 mg, 63%, off-white, amorphous solid. TIFF2026514377000581.tif63158

[0429] (R)-3-(((6-((4-((2,6-difluorophenoxy)methyl)cyclohexyl)oxy)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 21k Synthesized according to procedure 4 of TIFF2026514377000582.tif21128. 15 mg, 91%, dr86:14, off-white, amorphous solid. TIFF2026514377000583.tif86160

[0430] (R)-3-(((6-(4-(3-cyclopropylphenoxy)butyl)benzo[d]oxazole-2-yl)amino)methyl)pyrrolidine-1-ium chloride, 21l Synthesized according to basic procedure 4 of TIFF2026514377000584.tif19128. 40 mg, 0.090 mmol, 78%, off-white, amorphous solid. TIFF2026514377000585.tif63159

[0431] Treatment of Autoimmune Diseases: Sphingosine 1-phosphate (S1P) is crucial for the proper alignment of immune cells. Furthermore, drugs that inhibit S1P signaling modulate the immune response at the lymphocyte transport level. Such drugs are approved for the treatment of autoimmune diseases such as multiple sclerosis and ulcerative colitis. The novel chemicals claimed herein modulate lymphocyte transport by blocking different nodes in the S1P signaling pathway. Therefore, these molecules are expected to be effective in treating patients with autoimmune diseases and conditions requiring immunosuppression, such as organ transplantation. Among the many autoimmune diseases are multiple sclerosis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, scleroderma, Sjögren's syndrome, atopic dermatitis, uveitis, and vasculitis. Transplanted organs include kidneys, hearts, livers, lungs, intestines, stomachs, pancreatic beta cells, and stem cells. Complications that may arise from organ or stem cell transplantation, such as graft-versus-host disease, are also included. Figure 1 shows representative datasets for each Spns2-dependent S1P transport blocker (STB) in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Mice (female, C57BL / 6 strain, 11 weeks old) were vaccinated with MOG33-35 peptide and treated with pertussis toxin on day 0. When symptoms appeared in the animals, they were randomly assigned to the treatment group (N=12), and clinical scores were measured until day 35. The treatment agent was administered once daily via enteral nutrition. The dose of the positive control (FTY720, known as fingolimod) was 3 mg / kg / day. Both STB compounds A and B, as disclosed herein, were administered at doses of 30 and 10 mg / kg / day, respectively.

Claims

1. Compounds of formula I or pharmaceutically acceptable salts thereof: During the ceremony X is C 6 ~C 10 They are aryl or 5- to 10-membered heteroaryl rings (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S); R 1 and R 2 each independently is selected from the group consisting of H, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkoxy, C 3 to C 8 cycloalkyl, C 1 to C 6 haloalkyl, CN, and halo; W is a bond, O, NH, -NHC(O)-, or -O-(N=)C(R)- (where R is H or C). 1 ~C 6 Alkyl) is; U is (A) A 6- to 8-membered heterocycloalkyl group having two ring atoms that are nitrogen, which may be condensed, crosslinked, or spirocondensed, where V is H, C 1 ~C 14 Alkyl, C 2 ~C 12 Alkenil, (C 6 ~C 10 )Aaryl, (C 6 ~C 10 ) Heteroaryl, -C 1 ~C 10 Alkyl-(C 6 ~C 10 ) Ariel, -C 2 ~C 12 Alkenil-(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-(C 3 ~C 8 )cycloalkyl, -(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), -(C 1 ~C 10 Selected from the group consisting of alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), or (B) Monocyclic 4-7 member heterocycloalkyl (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), where V is H, -C 1 ~C 14 Alkyl, -C 1 ~C 10 Alkyl-O-(C 3 ~C 14 ) Cycloalkyl, -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-NR x -(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-NR x C(O)(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-C(O)NR x (C 6 ~C 10 ) Ariel, -C 2 ~C 12 Alkenyl-O-(C) 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 )heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S), and -C 2 ~C 12 Alkenyl-O-(C) 6 ~C 10 ) Selected from the group consisting of heteroaryls (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S). It is either one of the following; T is -C(O)- or -NR x It is C(O)-; R x is H or C 1 ~C 6 It is alkyl; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Here, each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is independently selected from the group consisting of hydroxy, halo, C 1 to C 6 alkyl, C 1 to C 6 haloalkoxy, C 1 to C 6 haloalkyl, -NR' 2 , -NHC(O)(OC 1 to C 6 alkyl), -NO 2 , -CN, oxo, -C(O)OH, -C(O)O(C 1 to C 6 alkyl), -C 1 to C 6 alkyl(C 1 to C<000009                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            &emsp​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Here, each R' is independent of C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 6 ~C 10 Aryl, 3-14 member heterocycloalkyl and -(C 1 ~C 6 The group is selected from alkyl)-(3-14 member heterocycloalkyl) (where 1-4 ring members are independently selected from N, O, and S) and 5-10 member heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S).

2. U is a 6- to 8-membered heterocycloalkyl group in which (A) two ring atoms are N, and which may be substituted and may be condensed, crosslinked, or spirocondensed. V is H, C 1 ~C 14 Alkyl, C 2 ~C 12 Alkenil, (C 6 ~C 10 )Aaryl, (C 6 ~C 10 ) Heteroaryl, -C 1 ~C 10 Alkyl-(C 6 ~C 10 ) Ariel, -C 2 ~C 12 Alkenil-(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-(C 3 ~C 8 )cycloalkyl, -(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), -(C 1 ~C 10 Selected from the group consisting of alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. V is C 1 ~C 14 A compound according to claim 2, wherein the compound is alkyl, or a pharmaceutically acceptable salt thereof.

4. V is C 8 ~C 12 A compound according to claim 2 or 3, which is alkyl, or a pharmaceutically acceptable salt thereof.

5. Even if U is substituted A compound according to any one of claims 2 to 4, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

6. U is a (B) optionally substituted monocyclic 4- to 7-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl members are independently selected from N, O, and S), V, -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-NR x -(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-NR x C(O)(C 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-C(O)NR x (C 6 ~C 10 ) Ariel, -C 2 ~C 12 Alkenyl-O-(C) 6 ~C 10 ) Ariel, -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 )heteroaryl (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S), and -C 2 ~C 12 Alkenyl-O-(C) 6 ~C 10 ) Selected from the group consisting of heteroaryls (where 1 to 4 heteroaryl ring members are independently selected from N, O, and S), The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein U is a monocyclic 5- to 7-membered heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O).

8. The compound according to claim 6 or 7 or a pharmaceutically acceptable salt thereof, wherein U is selected from pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl, which may be substituted.

9. A compound according to any one of claims 6 to 8, wherein U is piperazinyl, or a pharmaceutically acceptable salt thereof.

10. V is -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 A compound according to any one of claims 6 to 9 or a pharmaceutically acceptable salt thereof, wherein the compound is an aryl compound.

11. V is -C 3 ~C 8 A compound according to any one of claims 6 to 10, which is an alkyl-O-phenyl, or a pharmaceutically acceptable salt thereof.

12. X is C 6 ~C 10 A compound according to any one of claims 1 to 11, wherein the compound is an aryl compound or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 12, wherein X is phenyl, or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 13, wherein W is bonded or O, or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of claims 1 to 14, wherein W is a bond, or a pharmaceutically acceptable salt thereof.

16. T is -NR x A compound according to any one of claims 1 to 15, which is C(O)-, or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 15, wherein T is -C(O)-, or a pharmaceutically acceptable salt thereof.

18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein m is 0.

19. U is a 6-8 member heterocycloalkyl group, (A) having two ring atoms that are N, which may be substituted, condensed, crosslinked, or spirocondensed. X is C 6 ~C 10 It is Ariel, T, R x H is -NR x C(O)-, V is C 8 ~C 12 It is alkyl, W is a bond, m is 0. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

20. U is a (B) optionally substituted 5- to 7-membered heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O), X is C 6 ~C 10 It is Ariel, T, R x H is -NR x C(O)-, V is -C 1 ~C 10 Alkyl-O-(C 6 ~C 10 ) is an aryl, W is a bond, m is 0. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

21. The aforementioned compounds are shown in the following table A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is more selected.

22. The aforementioned compounds are shown in the following table A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is more selected.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

24. A method for inhibiting spinster homolog 2 (SPNS2), comprising the step of contacting SPNS2 with an effective amount of a compound according to any one of claims 1 to 22.

25. The method according to claim 24, wherein the contact step is performed in vivo.

26. A method for treating a patient suffering from a neoplastic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 22.

27. The method according to claim 26, wherein the neoplastic disease is a metastatic tumor.

28. A method for treating a patient suffering from an allergic disease, comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 22.

29. The method according to claim 28, wherein the allergic disease is asthma.

30. A method for treating a patient suffering from an autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 22.

31. The method according to claim 30, wherein the autoimmune disease is multiple sclerosis, type 1 diabetes, Crohn's disease and inflammatory bowel disease including ulcerative colitis, Graves' disease, Addison's disease, dermatomyositis, myasthenia gravis, systemic lupus erythematosus, scleroderma, psoriasis, or atopic dermatitis.

32. The method according to claim 30 or 31, wherein the autoimmune disease is multiple sclerosis.

33. The method according to claim 32, wherein the autoimmune disease includes one or more progressive multiple sclerosis.

34. A method for treating a patient suffering from a fibrous disease, comprising the step of administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 22.

35. The method according to claim 34, wherein the fibrous disease is renal fibrosis.

36. The method according to claim 35, wherein renal fibrosis is a chronic kidney disease.

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