Piperidine compounds having Lp (a) reducing activity

Abstract

The present disclosure provides compounds of the formula: and pharmaceutically acceptable salts thereof, and compounds of the formula: and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising these compounds, and their use in the treatment of cardiovascular disease and elevated Lp (a) plasma levels.

Description

Technical Field

[0001] This invention relates to piperidine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions and the therapeutic use of said compounds, particularly their use in reducing lipoprotein(a) (Lp(a)) plasma levels. Background Technology

[0002] Significant progress has been made in the treatment of cardiovascular disease (CVD). Despite these advancements, patients still experience cardiovascular events such as angina, myocardial infarction, and stroke, which can lead to death if left untreated. Dyslipidemia, or abnormal lipid levels, remains a major risk factor for CVD. Dyslipidemia can be categorized into four general risk factors: elevated low-density lipoprotein cholesterol (LDL-c), low high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated Lp(a). Various treatment options exist for elevated LDL-c, low HDL-c, and elevated triglycerides. For patients with elevated Lp(a) levels, approved treatment options are limited. In some cases, apheresis can be used to filter blood to remove LDL and Lp(a); however, the effects are temporary and usually need to be repeated every two weeks. Currently, there are no approved drug therapies specifically for lowering Lp(a) levels.

[0003] Lp(a) is a genetically determined, independent cardiovascular risk factor. Elevated serum Lp(a) levels greater than 50 mg / dL or 125 nmol / L, found in ~20% of the population, are associated with at least a 1.6-fold increased risk of first cardiovascular events (Kronenberg, F. Clin. Res. Cardiol. Suppl. 14, 5-12 (2019)) and a >1.42-fold increased risk of secondary events (Madsen, CM et al., Arterioscler. Thromb. Vasc. Biol. 40, 255-266 (2020)). Lp(a) may exhibit both prothrombotic and antithrombotic properties, as well as atherogenic and atherosclerotic thrombotic properties. Lp(a) may inhibit fibrinolysis and accumulate in the vessel wall to induce thrombosis and atherosclerotic lesions. Plasma Lp(a) levels vary considerably among individuals. Unlike other risk factors, Lp(a) plasma levels do not change significantly with diet and exercise.

[0004] Lp(a) is similar to LDL-c in that it includes an LDL lipid core and an attached apolipoprotein B (apoB), but unlike LDL-c, Lp(a) also contains a unique apolipoprotein (a) (apo(a)) that is bound to apoB via disulfide bonds. Apo(a) is synthesized in the liver. The assembly of Lp(a) from apo(a) and LDL particles can occur in hepatocytes, on the cell wall, or in plasma. Inhibition of the assembly of LDL particles with apo(a) reduces Lp(a) levels.

[0005] WO2020 / 247429 discloses a compound that inhibits Lp(a) formation by blocking the interaction between Apo(a) and ApoB.

[0006] Patients with cardiovascular disease, particularly those with dyslipidemia or abnormal lipid levels, require additional treatment options. Patients whose cardiovascular risk cannot be adequately managed using current standard of care therapies (such as diet, exercise, and / or the use of one or more medications, such as statins, fibrates, and niacin) require alternative treatment options. More specifically, there is a need for additional, pharmaceutically acceptable alternative compounds that inhibit Lp(a) formation and thus lower plasma Lp(a) levels. Summary of the Invention

[0007] Therefore, in the first aspect, compounds of formula I or pharmaceutically acceptable salts thereof are provided: in R 1 It is H or CH3; Q 1 It is -(CH2) n NR 15 (CH2) n R 10 -B(OR) 10 2. Ethylene glycol borate, pinacol borate, 1,3-propanediol borate, 2,2-dimethyl-1,3-propanediol borate, -(CH2) n NR 15 CONR 15 (CH2) n R 10 -(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 -(CH2) n NR 15 SO2(CH2) n R 10 -(CH2)n O(CH2) p O(CH2) n R 10 -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 NH2, -NHCONH2, or ; Q 2 It is H, C 1-4 Alkyl, cyclopropyl, CF3, OH, C 1-4 Alkoxy, O-cyclopropyl, OCF3, halogen, or CN; n is 0, 1, 2 or 3 independently each time it appears; R 10 Selected from: halogen; C can be optionally replaced by one to four OH or OCH3 groups. 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C can be optionally replaced by OCH3 1-4 Halogenated alkyl groups; C 2-6 alkynyl group; NH2; Naphthyl; 3,4-dihydro-2H-1λ optionally substituted with CF3 2 - Quinoline; Phenoxy groups optionally substituted with methoxy groups; 4-, 5-, or 6-membered heterocycles, optionally separated by OCH3, C 1-4 Alkyl, (CH2)pyridine, O(CH2)phenyl, or (CH2) m Phenyl substitution, wherein the phenyl group is optionally substituted by one or two substituents selected from the following: halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, optionally substituted by one or two substituents selected from the following: C 1-4 Alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a halogen; and Phenyl, optionally substituted by one to three independent substituents selected from the following: halogen, C 1-4 Alkoxy, C 1-4 Alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)n Phenyl, wherein the phenyl group is optionally substituted with one or two halogens; m is 0 or 1; p is 1, 2, 3, 4, or 5; and R 15 Is it H or C? 1-3 alkyl.

[0008] In the second aspect, compounds of formula II or salts thereof are provided: in R 1a It is H, CH3 or a protecting group; X is OH or C. 1-4 Alkoxy; Q 1 It is -(CH2) n NR 15 (CH2) n R 10 -B(OR) 10 2. Ethylene glycol borate, pinacol borate, 1,3-propanediol borate, 2,2-dimethyl-1,3-propanediol borate, -(CH2) n NR 15 CONR 15 (CH2) n R 10 -(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 -(CH2) n NR 15 SO2(CH2) n R 10 -(CH2) n O(CH2) p O(CH2) n R 10 -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 NH2, -NHCONH2, or ; Q 2 It is H, C 1-4 Alkyl, cyclopropyl, CF3, OH, C 1-4Alkoxy, O-cyclopropyl, OCF3, halogen, or CN; n is 0, 1, 2 or 3 independently each time it appears; R 10 Selected from: halogen; C can be optionally replaced by one to four OH or OCH3 groups. 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C can be optionally replaced by OCH3 1-4 Halogenated alkyl groups; C 2-6 alkynyl group; NH2; Naphthyl; 3,4-dihydro-2H-1λ optionally substituted with CF3 2 - Quinoline; Phenoxy groups optionally substituted with methoxy groups; 4-, 5-, or 6-membered heterocycles, optionally separated by OCH3, C 1-4 Alkyl, (CH2)pyridine, O(CH2)phenyl, or (CH2) m Phenyl substitution, wherein the phenyl group is optionally substituted by one or two substituents selected from the following: halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, optionally substituted by one or two substituents selected from the following: C 1-4 Alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a halogen; and Phenyl, optionally substituted by one to three independent substituents selected from the following: halogen, C 1-4 Alkoxy, C 1-4 Alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n Phenyl, wherein the phenyl group is optionally substituted with one or two halogens; m is 0 or 1; p is 1, 2, 3, 4, or 5; and R 15 Is it H or C? 1-3 alkyl, Where X is OH, then R 1a It must be a protecting group.

[0009] In a third aspect, the use of compounds of formula II or salts thereof in the preparation of oligomers is provided.

[0010] In a fourth aspect, oligomers prepared from compounds of formula II or salts thereof are provided. In one embodiment, the oligomer comprises at least two piperidine moieties. In another embodiment, the oligomer comprises at least three piperidine moieties.

[0011] In the fifth aspect, compounds of formula III or pharmaceutically acceptable salts thereof are provided: R 1 Each time it appears, it is independently either H or CH3; L stands for -(CH2). p NHC(O)NH(CH2) p -、-(CH2) p NH(CH2) p -、 or ; p is 0 or 1 independently each time it appears; Q 3 Each time it appears, it is independently H or C. 1-4 Alkyl, cyclopropyl, CF3, OH, C 1-4 Alkoxy, O-cyclopropyl, OCF3, halogen, or CN; L 2 It is a C1-3 alkylene group or bond.

[0012] In a sixth aspect, a pharmaceutical composition is provided comprising a compound of formula I or III or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

[0013] In a seventh aspect, a method for treating a patient’s cardiovascular disease is provided, comprising administering to the patient an effective amount of a compound of formula I or III or a pharmaceutically acceptable salt thereof.

[0014] In an eighth aspect, a method for treating elevated Lp(a) plasma levels in a patient is provided, comprising administering to the patient an effective amount of a compound of formula I or III or a pharmaceutically acceptable salt thereof.

[0015] In the ninth aspect, compounds of formula I or III or pharmaceutically acceptable salts thereof are provided for use in therapy.

[0016] In the tenth aspect, compounds of formula I or III or pharmaceutically acceptable salts thereof are provided for the treatment of cardiovascular diseases.

[0017] In the eleventh aspect, compounds of formula I or III or pharmaceutically acceptable salts thereof are provided for the treatment of elevated Lp(a) plasma levels. Detailed Implementation

[0018] In one embodiment of the compound of formula I, R 1 It's H.

[0019] In one embodiment of the compound of formula I, Q 2 It's H.

[0020] In one embodiment, a compound of formula Ia is provided: Or a pharmaceutically acceptable salt thereof. Formula I encompasses Formula Ia, and references to Formula I below, such as in treatment methods and therapeutic uses, are also interpreted as references to Formula Ia.

[0021] In one embodiment of the compound of formula I, Q 1 It is -(CH2) n NR 15 (CH2) n R 10 -(CH2) n NR 15 CONR 15 (CH2) n R 10 -(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 -(CH2) n NR 15 SO2(CH2) n R 10 -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 NH2 or In one particular implementation, Q 1 It is NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10 -NHCONH(CH2)2R 10 -N(CH3)CON(CH3)R 10 -NHCOR 10 -NHCOCH2R 10 -NHCO(CH2)2R 10 CH2NHSO2R 10-NHSO2R 10 -O(CH2)2R 10 -NHSO2(CH2)3R 10 -N(CH3)SO2(CH2)2R 10 -CH2O(CH2)2O(CH2)2OCH2R 10 NH2 or In a more specific implementation, Q 1 It is NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10 -NHCONH(CH2)2R 10 -NHCOR 10 -NHCO(CH2)2R 10 , or .

[0022] In one embodiment of the compound of formula I, Q 1 It is -(CH2) n NR 15 (CH2) n R 10 -(CH2) n NR 15 CONR 15 (CH2) n R 10 -(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 -(CH2) n NR 15 SO2(CH2) n R 10 -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 , or And R 10 Selected from: C can be optionally replaced by one to four OH groups 1-4 alkyl; C 3-6 cycloalkyl; C can be optionally replaced by OCH3 1-4Halogenated alkyl groups; C 2-6 alkynyl group; Naphthyl; 3,4-dihydro-2H-1λ optionally substituted with CF3 2 - Quinoline; phenoxy; A 4- or 6-membered heterocycle, optionally composed of OCH3 or (CH2). m Phenyl substitution, wherein the phenyl group is optionally substituted by one or two substituents selected from the following: halogen and CH3; 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl, optionally substituted by one or two substituents selected from the following: C 1-4 Alkyl, halogen, pyrrolidine, or benzyl, wherein the benzyl group is optionally substituted with a halogen; and Phenyl, optionally substituted by one to three independent substituents selected from the following: halogen, C 1-4 Alkoxy, C 1-4 Alkyl, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or -(CH2) n Phenyl. Preferably, R 10 Selected from: CH3; CH2OH; cyclopropyl; CH2CH(CH2Cl)CH2OCH3; ethynyl; naphthyl; CF3-substituted 3,4-dihydro-2H-1λ2-quinoline; phenoxy; Piperazine, piperidine, or aziridine, wherein the pipeazine, piperidine, or aziridine is optionally substituted with OCH3 or a phenyl group, wherein the phenyl group is optionally substituted with one or two substituents selected from Cl and CH3; Indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein the indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is optionally substituted with one or two substituents selected from: CH3, Cl, pyrrolidine, or benzyl, wherein the benzyl group is substituted with Cl; and Phenyl, optionally substituted by one or two substituents independently selected from: Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or phenyl. More preferably, R 10 Selected from: Cyclopropyl, ethynyl, phenoxy Phenyl-substituted piperazines, wherein the phenyl group is substituted by Cl and CH3. Phenyl-substituted piperidine, OCH3-substituted nitrogen-containing heterocyclic butanes Indole Thiophene, CH3-substituted pyrazoles Phenyl groups substituted with OCH3, Cl, or CH3.

[0023] In one embodiment, a compound of formula Ia or a pharmaceutically acceptable salt thereof is provided, wherein Q 1 It is NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10 -NHCONH(CH2)2R 10 -N(CH3)CON(CH3)R 10 -NHCOR 10 -NHCOCH2R 10 -NHCO(CH2)2R 10 CH2NHSO2R 10 -NHSO2R 10 -O(CH2)2R 10 -NHSO2(CH2)3R 10 -N(CH3)SO2(CH2)2R 10 -CH2O(CH2)2O(CH2)2OCH2R 10 NH2 or And R 10 Selected from: CH3; CH2OH; cyclopropyl; CH2CH(CH2Cl)CH2OCH3; ethynyl; naphthyl; CF3-substituted 3,4-dihydro-2H-1λ2-quinoline; phenoxy; Piperazine, piperidine, or aziridine, wherein the pipeazine, piperidine, or aziridine is optionally substituted with OCH3 or a phenyl group, wherein the phenyl group is optionally substituted with one or two substituents selected from Cl and CH3; Indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein the indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is optionally substituted with one or two substituents selected from: CH3, Cl, pyrrolidine, or benzyl, wherein the benzyl group is substituted with Cl; and Phenyl, which is optionally substituted by one or two independent substituents selected from the following: Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl or phenyl.

[0024] In one embodiment, the compound of formula I is selected from: Or its pharmaceutically acceptable salt.

[0025] In one embodiment of the compound of formula II, R 1a It is a protecting group, and the protecting group is selected from: tert-butoxycarbonyl, carboxybenzyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide. In a particular embodiment, R 1a It is a tert-butoxycarbonyl group.

[0026] In one embodiment of the compound of formula III, Q 3 It's H.

[0027] In one embodiment, a compound of formula IIIa is provided: Or a pharmaceutically acceptable salt thereof. Formula III encompasses Formula IIIa, and references to Formula III below, such as in treatment methods and therapeutic uses, are also interpreted as references to Formula IIIa.

[0028] In one embodiment of the compound of formula III, L is -(CH2). p NHC(O)NH(CH2) p -or-(CH2) p NH(CH2) p - In one particular embodiment, L is -NHC(O)-. In an alternative embodiment, L is -NH-.

[0029] In one embodiment, the compound of formula III is selected from: Or its pharmaceutically acceptable salt.

[0030] In one embodiment, a method of treating a patient requiring treatment of cardiovascular disease is provided, comprising administering an effective amount of a compound of formula I or III or a pharmaceutically acceptable salt thereof. In another embodiment, a method of treating a patient requiring treatment of elevated Lp(a) plasma levels is provided, comprising administering an effective amount of a compound of formula I or III or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, a compound of formula I or III or a pharmaceutically acceptable salt thereof is provided for use in a therapeutic manner.

[0032] In one embodiment, a compound of formula I or III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of cardiovascular disease. In another embodiment, a compound of formula I or III, or a pharmaceutically acceptable salt thereof, is provided for the treatment of elevated Lp(a) plasma levels.

[0033] In one embodiment, the use of a compound of formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical agent for treating cardiovascular diseases is provided. In another embodiment, the use of a compound of formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical agent for treating elevated Lp(a) plasma levels is provided.

[0034] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0035] Term "C" 1-n "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to n carbon atoms. C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. 1-3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, and propyl.

[0036] Term "C" 1-3 "alkylene" refers to a divalent straight-chain or branched carbon atom. 1-3 alkyl.

[0037] Term "C" 1-4 "Halogenated alkyl" refers to C as defined herein. 1-4 Alkyl groups, which are substituted with one or more halogens. C 1-4 Examples of alkyl halogens include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0038] Term "C" 1-4 "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 4 carbon atoms with a terminal "O", i.e., -O (alkyl). C 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0039] Term "C" 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon containing 2 to 6 carbon atoms and at least one triple bond.

[0040] Term "C" 3-6 "Cycloalkyl" refers to a monocyclic saturated carbon ring containing 3 to 6 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0041] The term "heteroaryl" refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from N, S, and O. Examples of 5-membered heteroaryl groups include, but are not limited to, pyrazoles, triazoles, and thiazoles. Examples of 6-membered heteroaryl groups include, but are not limited to, pyridines and pyridazines.

[0042] The term "bicyclic heteroaryl" refers to a bicyclic aromatic ring containing one or more heteroatoms, preferably selected from N, S, and O. Examples of 9-membered bicyclic heteroaryl groups include, but are not limited to, indole, isoindole, indazole, and pyrazolopyridine. Examples of 10-membered bicyclic heteroaryl groups include, but are not limited to, quinoline and chromene.

[0043] The term "4-, 5- or 6-membered heterocycle" refers to a 4-, 5- or 6-membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine and piperidine.

[0044] As used herein, the term "elevated Lp(a) plasma level" refers to an Lp(a) plasma level equal to or higher than approximately 50 mg / dL. The compounds described herein may be used for the treatment of lowering Lp(a) plasma levels.

[0045] As used herein, the term "oligomer" refers to a compound having at least two piperidine moieties as shown in Formula I or II. As used herein, "piperidine moieties" refers to optionally substituted piperidines. The piperidine moieties in oligomers may be the same or different.

[0046] As used in this article, the term "pharmaceuticalally acceptable salt" refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," P. Stahl et al., 2nd revised edition, Wiley-VCH, 2011, and SM Berge et al., "Pharmaceutical Salts." Journal of Pharmaceutical Sciences , 1977, 66(1), 1-19. In particular, compounds of formula I or III can be zwitterions, monoacids, diacids or triacids addition salts.

[0047] The pharmaceutical compositions of the present invention can be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable" means one or more carriers, diluents, and / or excipients that are compatible with the other components of the composition and are pharmaceutically harmless to the patient. Examples of pharmaceutical compositions and methods of their preparation are well known to those skilled in the art and can be found, for example, in "Remington: The Science and Practice of Pharmacy," edited by Loyd, V. et al., 22nd edition, Mack Publishing Co., 2012.

[0048] As used herein, the term "effective dose" refers to a dose that is effective in treating the disorder. The effective dose for a particular patient can be determined by an experienced healthcare professional.

[0049] As used herein, the terms “treating,” “to treat,” or “treatment” include slowing, alleviating, preventing, or reversing the progression or severity of existing symptoms, disorders, conditions, or diseases. As used herein, “treating cardiovascular disease” refers to slowing, alleviating, preventing, or reversing the progression of heart or vascular disease.

[0050] As used herein, the term "patient" refers to a mammal. Preferably, the patient is a human.

[0051] The pharmaceutical composition may be formulated as tablets or capsules for oral administration, solutions for oral administration, or injectable solutions. In one embodiment, the composition is suitable for oral administration.

[0052] Some abbreviations can refer to the following: "ACN" refers to acetonitrile; "Apo" refers to apolipoprotein; "BOC" refers to tert-butoxycarbonyl; "DCC" refers to N,N'-dicyclohexylcarbodiimide; "DCM" refers to dichloromethane; "DMA" refers to dimethylacetamide; "DMAP" refers to 4-dimethylaminopyridine; "DMEA" refers to dimethylethanolamine; "DMEM" refers to Dulbecco's modified Eagle's medium; "DMF" refers to dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "EACA" refers to ε-aminohexanoic acid or 6-aminohexanoic acid; "ELISA" refers to enzyme-linked immunosorbent assay; "EtOAc" refers to ethyl acetate; "FBS" refers to fetal bovine serum; "HEC" refers to hydroxyethyl cellulose; "HEK" refers to human embryonic kidney; "HepG2" refers to human hepatocellular carcinoma cell line; "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; "HLB" refers to hydrophilic-lipophilic balance; "h" refers to hour; "HRP" refers to horseradish peroxidase; "IC 50"IPA" refers to the concentration of the reagent that produces 50% of the maximum possible inhibitory response; "MeCN" refers to isopropyl alcohol; "min" refers to minutes; "MTBE" refers to methyl tert-butyl ether; "RT" refers to room temperature; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TMB" refers to 3,3',5,5'-tetramethylbenzidine.

[0053] Those skilled in the art can separate or resolve independent isomers, enantiomers and diastereomers at any convenient point in the synthesis of the following compounds by methods known to the art, such as selective crystallization or chiral chromatography.

[0054] Compounds of Formula I or III are readily converted into pharmaceutically acceptable salts and can be isolated as such. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form an acid addition salt or upon the addition of a pharmaceutically acceptable base to form a base addition salt. Salt formation can also occur simultaneously with the deprotection of nitrogen or oxygen, i.e., the removal of the protecting group. Examples, reactions, and conditions for salt formation are known to those skilled in the art.

[0055] Compounds of Formula I or III, or any of the described formulas, or salts thereof, can be prepared by various procedures, some of which are illustrated in the preparations and examples below. The specific synthetic steps of each route can be combined in different ways, or combined with steps from different routes, to prepare the compounds or salts of the present invention. The products of the steps in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, preparation, and crystallization.

[0056] In the following figures, unless otherwise specified, all substituents are as defined above. Reagents and starting materials are readily available to those skilled in the art. The following figures, preparations, and examples are provided to further illustrate the invention without limiting its scope. Compounds of the above formulas or salts thereof can be prepared using starting materials or intermediates having the corresponding desired stereochemical configuration.

[0057] Diagram 1 Figure 1 illustrates the preparation of key intermediates 6 and 7, used to prepare the compounds of this invention. Compound 1 is reacted with NaH in N,N-dimethylacetamide in step A, followed by the addition of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride at 40°C, or alternatively with TEA and trifluoromethylsulfonyl trifluoromethanesulfonate at -78°C, followed by heating to room temperature to give sulfonate compound 2. Compound 2 then undergoes a cross-coupling reaction with boric acid (3a) or borate ester (3b) in step B, reacting at high temperature using a palladium catalyst and a carbonate base to give coupling product 4. Subsequently, in step C, the ring is reduced using hydrogen and a palladium catalyst to give compound 5, exhibiting a cis-related stereochemistry. Then, in step D, compound 5 is epimerized to the trans form by heating with an alkoxide base (such as sodium methoxide in ethanol) to give compound 6. Water is added to the reaction and heating time is extended to hydrolyze the ester to give compound 7. Q 2 As defined in Equation I or II, Q 3 As defined in Formula III.

[0058] Diagram 2 Figure 2 illustrates the preparation of further intermediates used to prepare the compounds of this invention. In step A, aniline compound 8 is converted to halide 9 using tert-butyl nitrite, sulfonic acid (methanesulfonic acid or p-toluenesulfonic acid), copper bromide, and tetrabutylammonium iodide or tetrabutylammonium bromide. In step B, compound 9 is carbonylated at high temperature using a CO / H2 gas mixture at 100 psi, a palladium catalyst, and N,N,N',N'-tetramethylethylenediamine to give aldehyde 10. In step C, the aldehyde is reduced at 0°C using sodium borohydride in ethanol to give alcohol compound 42, which is then treated with NaH in step D and reacted with alkyl halides 11a or 11b to give compounds 12a or 12b, respectively.

[0059] In the presence of trimethylsilane azide and tert-butyl nitrite, aniline compound 8 can also be converted into an azide, which then undergoes a click chemistry reaction with nitrile 15 in step F to give 1,2,3-triazole compound 16. This step can be carried out using a flow reactor.

[0060] In step E, halide 9 can also be coupled with imidazolium-2-one compound 13 by heating in 1,4-dioxane using a palladium catalyst and an alkoxide base to give compound 14. 2 As defined in Equation I or II, Q 3 As defined in Equation III. R 10 , n, p and X are as defined in Equation II.

[0061] Diagram 3 Figure 3 illustrates the preparation of primary amine compound 18, wherein nitrile compound 17 is reduced using hydrogen, an amine base, a palladium catalyst, and a mixture of THF and EtOH. 2 As defined in Equation I or II, Q 3 As defined in Equation III. X is defined in Equation II.

[0062] Diagram 4 Figure 4 illustrates the reaction on amino intermediate 19. Reaction with acyl chloride 20 and an amine base, or coupling with acid 21 using a coupling agent such as DCC, yields amide 27. Amino intermediate 19 reacts with isocyanate 22, or alternatively with triphosgene and an amine base, followed by reaction with amine 23, to yield urea compound 28. Amino intermediate 19 undergoes alkylation with alkyl halide 24 and a carbonate base to yield compound 29, and intermediate 19 undergoes reductive amination with aldehyde 25 and sodium triacetoxyborohydride to yield compound 30. Finally, amino intermediate 19 reacts with sulfonyl chloride 26 using pyridine and a catalytic amount of DMAP to yield compound 31. Optionally, R... 15 Compounds 28 and 31 with H can be methylated, first by treatment with NaH, followed by the addition of iodomethane. 2 As defined in Equation I or II, Q 3 As defined in Equation III. R 10 R 15 , n and X are as defined in Equation II.

[0063] Diagram 5 Figure 5 illustrates the preparation of polymers 32 and 33. Amino compound 19 was reacted with 1,1'-carbonyldiimidazole in THF at high temperature to give symmetrical urea compound 32. Aniline compound 8 was coupled with aryl bromide 9 using a palladium catalyst and a carbonate base to give dimer compound 33. 3 As defined in Equation III. n and X are defined as defined in Equation II.

[0064] Diagram 6 Figure 6 illustrates the final deprotection and optional methylation steps to obtain the compounds of the present invention. Compound 34 first undergoes ester hydrolysis in step A in the presence of a strongly alkaline aqueous solution to give acid compound 35, and then in step B, the BOC group is removed using HCl in an organic solvent (such as diethyl ether or 1,4-dioxane) to give compound 36, which can be separated as an HCl salt by concentrating the reaction solution to dryness. Alternatively, in step C, the piperidine nitrogen of compound 34 is first deprotected using HCl in an organic solvent (such as diethyl ether or 1,4-dioxane), purified by ion exchange (SCX) to give a free amine, and then in step D, the product undergoes reductive amination with paraformaldehyde and sodium triacetoxyborohydride under heating to give compound 37. Subsequently, ester hydrolysis is carried out in step E using a strongly alkaline aqueous solution to give compound 38.

[0065] These same deprotection steps are used to obtain the polymeric compounds. Compound 39 undergoes de-BOC and ester hydrolysis steps (steps A and B, respectively) to give compound 40, and alternatively, BOC deprotection (step C), methylation (step D), and ester hydrolysis (step E) to give compound 41. 1 and Q 2 As defined in formula I or II. Q 3 And L as defined in Formula III.

[0066] Preparation 1 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester A solution of 4-ethyl 1-tert-butyl 3-oxopiperidinium-1,4-dicarboxylic acid (CAS No. 71233-25-5, 100 g, 350 mmol) in N,N-dimethylacetamide was slowly added to a suspension of sodium hydride (60% by mass in mineral oil, 420 mmol) in N,N-dimethylacetamide (300 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. Finally, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (CAS No. 375-72-4, 116 g, 69.2 mL, 385 mmol) was added dropwise. The mixture was stirred at room temperature and then stirred overnight at 40 °C. The reaction was diluted with MTBE and quenched with a saturated aqueous solution of NH4Cl. The phases were separated, and the aqueous layer was extracted with MTBE. The combined organic phases were washed twice with water and then with a saturated aqueous solution of NaCl. The organic phase was dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using a 0–50% gradient of EtOAc / hexane to give 87 g (45%) of the title compound. ES / MS m / z 498 (M- Uncle Butyl + H).

[0067] Preparation 2 5-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid O1-tert-butyl ester O4-ethyl ester Trifluoromethanesulfonyl trifluoromethanesulfonate (132 g, 470 mmol, 77 mL, 1.5 eq) was added dropwise to a solution of 1-tert-butyl 4-ethyl 3-oxopiperidinium-1,4-dicarboxylic acid (85 g, 313 mmol, 1.0 eq) and TEA (95 g, 94 mmol, 130 mL, 3.0 eq) in DCM (850 mL) at -78 °C for 30 min under N2, while the temperature was maintained at -78 °C and the mixture was stirred for 1 h. The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction was quenched with water (1 L) and extracted with DCM (1 L x 2). All organic phases were combined, washed with brine (2.5 L), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the title compound (586 g, 95% yield, 82% purity) as a dark brown liquid, which was ready for use without further purification. TLC (petroleum ether: EtOAc = 3:1, Rf = 0.24).

[0068] Preparation 3 1-tert-butyl 4-ethyl ester of 5-(3-aminophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid A solution of (3-aminophenyl)boronic acid (CAS No. 30418-59-8, 25.9 g, 189 mmol) in 1,4-dioxane (609 mL) was added to a suspension of K₂CO₃ (86.9 g, 628.8 mmol). The mixture was heated to 75 °C under nitrogen and maintained for 15 minutes. A solution of 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (87 g, 157.2 mmol) in 1,4-dioxane (174 mL) was then added to the mixture, followed by the addition of Pd(dppf)Cl₂ (2.30 g, 3.144 mmol). The mixture was then heated to 95 °C and maintained for 45 minutes. The mixture was cooled to room temperature and diluted with EtOAc (500 mL). The mixture was filtered through a diatomaceous earth mat, which was washed with EtOAc. The filtrate was concentrated, dissolved in EtOAc, and washed twice with water and a saturated aqueous NaCl solution. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0–100% EtOAc / hexane gradient to give a pale yellow solid, which was ground and sonicated with MTBE / hexane (1:1, 200 mL). The solid was filtered, washed with hexane, and dried under vacuum at 45 °C to give the title compound (47 g, 86%) as a white solid. ES-MS m / z 347 (M+H).

[0069] The title compound was alternatively prepared in 37% yield using 5-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid O1-tert-butyl ester O4-ethyl ester, KF as base and Pd(PPh3)4 as catalyst, and purified by silica gel chromatography using a 17-25% EtOAc / petroleum ether gradient.

[0070] Preparation 4 1-tert-butyl 4-ethyl cis-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (racemic mixture, isomer 1 and isomer 2) Palladium (10% on activated carbon, charcoal, 121.2 mmol, 12.90 g) was added to a solution of 1-tert-butyl 4-ethyl 5-(3-aminophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid (42 g, 121.2 mmol) in MeOH (606 mL). The mixture was then stirred at 110 psi hydrogen pressure and room temperature for 18 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the filter cake was further washed with MeOH and EtOH plug. The filtrate was concentrated under vacuum, and the residue was purified by filtration through a silica plug (EtOAc as eluent) and vacuum dried at room temperature for several days to give a racemic mixture of the title compound (40.69 g, 96.32%) as a light pink solid. ES-MS m / z 293 (M-Boc).

[0071] 3.0 g of the racemic mixture was purified by chiral chromatography (column: Chiralpak IC 5 × 25 cm, 5 µm; mobile phase: solvent A - CO2, solvent B - 0.2% dimethyl ethylamine in IPA, isocratic elution, 20% solvent B in solvent A; flow rate: 250 g / min) to obtain isomer 1 (first eluted isomer, 1.15 g) and isomer 2 (second eluted isomer, 1.15 g).

[0072] Preparation 5 trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, isomer 1 and isomer 2) A solution of cis-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (racemic mixture, 10 g, 28.70 mmol) in EtOH (5.74 mL) was stirred at room temperature. Sodium ethoxide (2 equivalents, 57.41 mmol, 21% by mass, 18.60 g) in EtOH was added, and the mixture was heated at 80 °C for about 48 hours. The mixture was then cooled to room temperature, water (29 mL) was added, and the mixture was refluxed for an additional 2 hours. The reaction mixture was concentrated to dryness, dissolved in EtOAc, and quenched with 5% citric acid aqueous solution until pH=4. The layers were separated, the organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reversed-phase chromatography using a gradient of 0 to 60% ACN / NH4CO3 aqueous solution (pH 9) to give the title compound (3.1 g, 87%) as a pale yellow solid. ES / MS 265 [M+H-tBu].

[0073] Optically pure enantiomers (isomers 1 and 2) were prepared substantially as described above, using isomers 1 and 2 of cis-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester, respectively, as starting materials.

[0074] Preparation of 6 trans-1-tert-butoxycarbonyl-3-[3-(prop-2-acetylamido)phenyl]piperidine-4-carboxylic acid (racemic mixture) DCC (0.2376 g, 1.140 mmol) was added to a solution of propargyl acid (75 µL, 85 mg, 1.12 mmol) in DCM (4.75 mL), and the mixture was stirred for 10 min. Then, a solution of trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, 308 mg, 961.3 µmol) in DCM (4.75 mL) was added dropwise, and the mixture was stirred at room temperature for 1.5 h. After 10 min, a solution of propargyl acid (75 µL, 85 mg, 1.12 mmol) and DCC (0.2376 g, 1.140 mmol) in DCM (4.75 mL) was slowly added, and the mixture was allowed to react for approximately 1 h. The mixture was extracted with acidic water (H₂O with a few drops of 1M HCl until pH = 4) to give a white solid. The solid was filtered. The organic layer was then separated, dried over Na₂SO₄, and the solvent was evaporated by flushing with N₂. The crude product was dissolved in DMSO and purified using an HLB column, followed by reversed-phase chromatography to give the title product (0.152 g, 41%) as a pale yellow solid. ES / MS m / z : 317 (M- Uncle Butyl + H).

[0075] Preparation 7 trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methylphenyl)piperazin-1-yl]methyl]triazol-1-yl]phenyl]piperidin-4-carboxylic acid (isomer 2) The title compound was prepared using a flow reactor apparatus. Three solutions were prepared: • Solution A: Add azidotrimethylsilane (0.62 g, 0.72 mL, 5.2 mmol) to a solution of trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2, 1.4 g, 4.4 mmol) and DMF (17 mL) at room temperature. Solution B: Add tert-butyl nitrite (0.54 g, 0.63 mL, 5.2 mmol) to DMF (17 mL). • Solution C: Add 1-(3-chloro-4-methylphenyl)-4-(prop-2-yn-1-yl)piperazine (1.3 g, 5.2 mmol) to DMF (17 mL). Approximately one-fifth of the total volume of solutions A and B was pumped together into a 2 mL PTFE reactor (flow rate A: 0.074 mL / min, flow rate B: 0.088 mL / min, residence time 12 min) at 80 °C. Then, approximately one-fifth of the total volume of solution C was added to the eluent in a 10 mL copper reactor (residence time 40 min) at a flow rate of 0.088 mL / min at 120 °C. The eluent pool was diluted with EtOAc and washed with saturated NH4Cl aqueous solution, water, and saturated NaCl. The organic matter was dried over Na2SO4, filtered, and concentrated. The residue was passed through a silica gel column and eluted with 10% MeOH / DCM. The eluent was concentrated and purified by reversed-phase HPLC to give 9.1 mg (2%) of the title compound. ES-MS m / z 595 (M+H).

[0076] Preparation of 8 trans-1-tert-butoxycarbonyl-3-[3-[3-(1H-indol-3-yl)propionylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture) DCC (193 mg, 0.9363 mmol) and DMAP (137 mg, 1.12 mmol) were added to a solution of 3-indolepropionic acid (213 mg, 1.12 mmol) in DCM (4.72 mL). The mixture was stirred at room temperature for 10 min, and then trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, 0.3 g, 0.9363 mmol) was added. The resulting mixture was stirred at room temperature. The crude product was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness. Purification was performed by reversed-phase chromatography using a gradient of 0 to 60% ACN / NH4CO3 aqueous solution (pH 9) to give the title compound (0.242 g, 46%) as a colorless oil. ES / MS m / z : 436 [M+H-tBu].

[0077] Preparation 9 1-(3-Methoxyphenyl)imidazolidine-2-one A mixture of cuprous iodide (I) (81 mg, 0.427 mmol), potassium phosphate tribasic (1.81 g, 8.546 mmol), N,N'-dimethylethylenediamine (0.2 g, 2 mmol), imidazolidine-2-one (3.67 g, 42.73 mmol), and 1-iodo-3-methoxybenzene (1 g, 4.273 mmol) in DMF (0.5 mL) was stirred at 120 °C. The reaction was cooled to room temperature, diluted with EtOAc, and filtered through a 5 g diatomaceous earth column. The resulting solution was washed with aqueous solutions of H₂O, NH₄OH, and saturated NaCl. The organic layer was separated, dried over MgSO₄, and evaporated under vacuum. The crude product was purified by silica gel chromatography (20% to 100% EtOAc / hexane) to give the title compound (0.319 g, 37%) as a white solid. ES-MS m / z 193 (M+H).

[0078] Preparation 10 Trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (racemic mixture, isomer 1, isomer 2) 4-ethyl tert-butyl cis-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (racemic mixture, 100 g, 287 mmol, 1.00 eq) was added in a single dose of sodium methoxide (190 g, 2.8 mol, 9.7 eq) to a solution in ethanol (1.5 L), and stirred at 80 °C for 15 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The crude product was washed with petroleum ether:ethyl acetate = 10:1 (0.8 L) to give a racemic mixture of the title compound as a yellow solid (89 g, 255 mmol, 44% yield). ES-MS m / z 249 (M-BOC+H).

[0079] The racemic mixture (75 g) was subjected to chiral SFC (column: Chiralpak IC 25 × 5 cm, 5 µm; mobile phase: 30% IPA + 0.2% DMEA / CO2) to obtain isomer 1 (first eluting isomer, 34.9 g, >98% ee) and isomer 2 (second eluting isomer, 35.5 g, >98% ee).

[0080] Preparation 11 4-ethyl tert-butyl trans-3-(3-iodophenyl)piperidine-1,4-dicarboxylic acid (tert-butyl ester) A mixture of tetrabutylammonium iodide (4.8 g, 13.0 mmol), 1-tert-butyl 4-ethyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 1.5 g, 4.31 mmol), and p-toluenesulfonic acid (1 g, 5.1 mmol) was dissolved in anhydrous ACN (45 mL). Then, copper bromide (45 mg, 0.20 mmol) and tert-butyl nitrite (600 µL, 520 mg, 5.04 mmol) were added, and the final reaction mixture was stirred at room temperature for 5 minutes. Next, the mixture was heated at 70 °C for 16–18 hours. The reaction mixture was then poured into H₂O and extracted with diethyl ether. The organic matter was washed with H₂O, dried over Na₂SO₄, evaporated, and dried under vacuum. The crude residue was purified by silica gel chromatography using DCM to give the title compound (1.48 g, 72%) as a thick brown oil. ES / MS m / z 404 (M- t Bu+H).

[0081] Preparation 12 trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4-carboxylic acid (isomer 1) 4-ethyl 1-tert-butyl trans-3-(3-iodophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 1.28 g, 2.79 mmol) was purged under N2, and then anhydrous EtOH (15 mL) and H2O were added. Lithium hydroxide (201 mg, 8.39 mmol) was added to the solution, and the final reaction mixture was heated at 70 °C for about 6 hours. The reaction mixture was concentrated to remove EtOH, and the resulting mixture was poured into H2O, 1 M HCl (8.5 mL) was added, and then extracted with DCM (2x). The combined organic matter was washed with water, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (1.14 g, 99%) as a pale yellow foam, which was then ground to give the title compound as a powder. ES / MS m / z 376 (M-tBu+H).

[0082] Preparation 13 trans-1-tert-butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidine-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 1) A solution of trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidin-4-carboxylic acid (isomer 1, 150 mg, 0.3478 mmol), 1-(3-methoxyphenyl)imidazolidine-2-one (73.5 mg, 0.3826 mmol), tBuXPhos-Pd-G3 (28 mg, 0.03478 mmol), and sodium tert-butoxide (100 mg, 1.043 mmol) in 1,4-dioxane (3.5 mL) was stirred under N2 for 16–18 h at 100 °C. The reaction mixture was diluted with water, filtered through a diatomaceous earth column, and the solution was extracted with EtOAc. The compound was separated by acidifying the aqueous layer with HCl 1N, extracting the compound with EtOAc, and then purified using silica gel eluted with EtOAc to give the title compound (0.12 g, 70%) as an off-white solid. ES / MS m / z:396 (M-BOC+H).

[0083] Preparation 14 trans-1-tert-butoxycarbonyl-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid (isomer 2) At room temperature, isocyanate cyclopropane (131 mg, 1.573 mmol) was added to a solution of trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2, 252 mg, 0.7865 mmol) in THF (5.6 mL), and the mixture was stirred at room temperature for about 2 hours. NaOH (1 N) was added, and the crude product was extracted with EtOAc, discarding the organic fraction. The pH was adjusted with HCl (1 N), and the final compound was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.32 g, 99%) as a beige solid. ES / MS m / z : 304 (M-BOC+H).

[0084] Preparation 15 trans-3-[3-(prop-2-ynylamino)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (racemic mixture) 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (racemic mixture, 230 mg, 0.6602 mmol) was dissolved in ACN (2.2 mL) and DMF (0.66 mL). Potassium carbonate (0.66 mmol) and 3-bromoprop-1-yne (80% by mass in toluene, 108.0 mg, 0.7262 mmol) were added. The mixture was stirred at room temperature for 16–18 hours. H₂O was added to the mixture and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using an EtOAc / hexane (10–40%) gradient to give the title compound (0.09 g, 34%) as a yellow oil. ES / MS m / z 331 (M-tBu+H).

[0085] Preparation of 16 trans-1-tert-butoxycarbonyl-3-[3-(prop-2-ynylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture) To a solution of trans-3-[3-(prop-2-ynylamino)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (racemic mixture, 90 mg, 0.2329 mmol) in MeOH (1.4 mL) and THF (3 mL), NaOH / H₂O (0.7 mL, 1 mmol, 2 M) was added. The mixture was stirred at room temperature for about 36 hours. Citric acid (5% in water) was added until pH = 4. The aqueous layer was extracted with EtOAc (3x). The organic layer was separated and dried over Na₂SO₄. The residue was purified by reversed-phase chromatography (H₂O-MeCN 10-40%). The desired fractions were combined, the solvent was removed under vacuum, and the residue was dried under vacuum at 40 °C to give the title compound (70 mg, 84%) as a yellow solid. ES / MS m / z : 303 (M- Uncle Butyl + H).

[0086] Preparation of 17 trans-3-[3-(benzylcarbamoylamino)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (isomer 2) The title compound was prepared essentially as described in Preparation 14 using 4-chlorophenylethyl isocyanate, and purified by reversed-phase rapid chromatography using a gradient of 0–40% ACN / NH4CO3 aqueous solution (pH 9). ES / MS m / z: 402 (M-BOC+H).

[0087] Preparation of 18 trans-1-tert-butoxycarbonyl-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 2) The title compound was prepared essentially as described in Preparation 7 using propan-2-alkynoxybenzene and purified by silica gel chromatography using acetone / hexane as eluent. ES-MS m / z 479 (M+H).

[0088] Preparation of 19 trans-3-[3-[(4-phenylpiperidin-1-carbonyl)amino]phenyl]piperidin-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) Triphosgene (1 equivalent, 0.6228 mmol) and TEA (3 equivalents, 1.869 mmol) were added to a solution of trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 0.217 g, 0.6228 mmol) in CHCl3 (6 mL) at room temperature. The mixture was stirred at room temperature for 15 min. The solvent was evaporated under vacuum and the residue was suspended in THF, followed by the addition of 4-phenylpiperidine (3 equivalents, 1.869 mmol) and stirring continued at room temperature for about 1 h. The solvent was evaporated and the residue was extracted with 1N HCl and DCM. The organic layer was separated, dried and evaporated to give a colorless oil. The crude product was purified by silica gel chromatography eluting with EtOAc / hexane (25% to 100%, 10 CV). The desired fraction was collected and evaporated under vacuum to give the title compound (0.307 g, 92%) as the colorless oil. ES / MS m / z 436 (M-BOC+H).

[0089] Preparation 20 trans-1-tert-butoxycarbonyl-3-[3-[((1-methyltriazol-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) To a solution of trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (racemic mixture, 100 mg, 0.31 mmol) in DCM (2 mL), 1-methyl-1H-1,2,3-triazol-4-carboxaldehyde (34 mg, 0.31 mmol) and sodium sulfate (220 mg, 1.55 mmol) were added. The mixture was stirred at room temperature for 3 hours, and then sodium triacetoxyborohydride (197 mg, 0.93 mmol) was added. The resulting mixture was stirred at room temperature for 16–18 hours. The reaction mixture was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified by reversed-phase rapid chromatography (mobile phase: 10–60% ACN / NH4CO3 aqueous solution (pH 9)). The mixture was further purified by reversed-phase chromatography to give the title compound (34.2 mg, 25%). ES / MS m / z : 416 [M+H].

[0090] Preparation 21 trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (racemic mixture) A catalytic amount of DMAP and 0.28 mmol of 4-(benzyloxy)benzene-1-th-butyl 4-ethyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (racemic mixture, 0.06 g, 0.19 mmol) were added to a solution of pyridine (1 mL, 12.4 mmol). The reaction mixture was stirred at room temperature for about 1 hour. The solvent was evaporated under vacuum, and the residue was extracted with EtOAc and 1N HCl (3 mL each). The organic layer was separated, dried over MgSO4, and evaporated under vacuum. The residue was purified by reversed-phase HPLC to give the title compound (60.5 mg, 56%). ES-MS m / z 511 (M- t Bu+H).

[0091] The following preparations are basically carried out using the corresponding sulfonyl chlorides as described in Preparation 21.

[0092] Table 1 a. Starting material used: trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2).

[0093] Preparation 25 trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) The title compound was prepared substantially as described in Preparation 14 using 3,5-bis(trifluoromethyl)phenyl isocyanate and 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomer 1), and purified by silica gel chromatography using a 0-40% EtOAc / hexane gradient. ES / MS m / z : 564 [M-(CO2Et)+H3O + ].

[0094] Preparation 26 trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (isomer 1) NaOH (0.205 g, 5.12 mmol) and H₂O (1 mL) were added to a solution of trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 0.56 g, 0.92 mmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 80 °C for 2.5 h. The reaction mixture was cooled to room temperature. The mixture was acidified with an aqueous solution of HCl (1 M) and extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under vacuum to give the title compound (0.236 g, 44%) as a white solid. ES / MS m / z: 592 [M+H] + .

[0095] Preparation 27 trans-1-tert-butoxycarbonyl-3-[3-[[4-(phenylphenyl)methyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) The title compound was prepared essentially as described in Preparation 20 using 4-phenylbenzaldehyde. ES / MS m / z : 431 [M+1- t Bu.

[0096] Preparation 28 trans-1-tert-butoxycarbonyl-3-[3-[[2-(2-naphthyl)acetyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) N,N-diisopropylethylamine (78 mg, 0.60 mmol) was added to a solution of trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50 mg, 0.15 mmol) in DCM (0.78 mL). The mixture was stirred at room temperature for 10 min, and then 2-(2-naphthyl)acetyl chloride (34 mg, 0.165 mmol) was added. The resulting mixture was stirred at room temperature for 16–18 h. Additional N,N-diisopropylethylamine and 2-(2-naphthyl)acetyl chloride were added, and the resulting mixture was stirred at room temperature for 16–18 h. The mixture was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified by reversed-phase rapid chromatography using a gradient of 10% to 60% ACN / NH4CO3 aqueous solution (pH 9) to give the title compound (14 mg, 17%) as a pale yellow oil. ES / MS m / z : 433 [M+1- t Bu.

[0097] Preparation 29 1-tert-butyl 4-ethyl ester of 5-(3-cyanophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid Add (3-cyanophenyl)boronic acid (43.17 g, 293.8 mmol) to a suspension of potassium carbonate (136 g, 979 mmol) in 1,4-dioxane (813 mL) and water (41 mL), and heat the mixture under N2 to 50–60 °C for 15 minutes. Add a solution of 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (35.5 g, 244.5 mmol) in 1,4-dioxane (271 mL), followed by Pd(dppf)Cl2 (3.66 g, 4.90 mmol). Then heat the mixture under N2 to 95 °C for 2 hours. The solvent was evaporated to dryness, and water (200 mL) and EtOAc (500 mL) were added. The organic layer was separated. The material was dried over MgSO4, filtered, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography using a 10% to 30% EtOAc / hexane gradient to give the title compound (66 g, 75.63%) as a yellow oil. ES / MS m / z: 301 (M- t Bu+H).

[0098] Preparation 30 cis-3-[3-(aminomethyl)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (racemic mixture, isomer 1 and isomer 2) To a 2 L Parr reactor, add: 4-ethyl 1-tert-butyl 5-(3-cyanophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid (66 g, 185.2 mmol), THF (330 mL), EtOH (330 mL), TEA (741 mmol, 103 mL, 75.0 g), and palladium (10% on activated carbon, 50% H₂O, 185.2 mmol, 19.7 g), and purge the mixture with hydrogen at 300 psi overnight. Filter the mixture to remove the catalyst, and evaporate the reaction solvent to dryness. Purify the crude material by silica gel chromatography using a 0–40% EtOH / EtOAc gradient to give a racemic mixture (41 g, 61%) of the title compound as a yellow oil. ES-MS m / z 363 (M+H).

[0099] The racemic mixture was subjected to chiral SFC (column: Chiralpak IC 4.6 × 150 mm; mobile phase: 30% IPA + 0.5% DMEA / CO2; flow rate 5 mL / min) to obtain isomer 1 (first eluted isomer, 15.64 g, >96% ee) and isomer 2 (second eluted isomer, 13.27 g, >96% ee).

[0100] Preparation 31 trans-3-[3-(aminomethyl)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (racemic mixture) A mixture of cis-3-[3-(aminomethyl)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (racemic mixture, 5 g, 13.8 mmol), sodium methoxide (30 wt% in MeOH, 69.0 mmol), and MeOH (69 mL) was heated at 90 °C for 2 days. The reaction solvent was evaporated, and HCl (1 N) was added until the pH of the mixture reached 7–8. The solid was filtered off and discarded. The pH of the aqueous mixture was adjusted to 5–6 with HCl (1 N) and extracted with EtOAc. The organic phase was washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (2.8 g, 82 wt% purity, 50% yield). ES / MS m / z : 335 [M+H].

[0101] Preparation of 32 trans-1-tert-butoxycarbonyl-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid (racemic mixture) To a mixture of 3-cyanobenzenesulfonyl chloride (43 mg, 0.22 mmol) and trans-3-[3-(aminomethyl)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (racemic mixture, 60 mg, 0.1794 mmol), 0.36 mL of 1 M aqueous solution of NaOH was added. The mixture was stirred at room temperature for 24 hours, and then the reaction solvent was evaporated under a nitrogen atmosphere. The residue was dissolved in a small amount of MeOH and then packed into an SCX column (5 g). The column was eluted with MeOH and the eluent was discarded. The residue was eluted with 2 M NH3 / MeOH, collected, and concentrated. The residue was then purified by reversed-phase HPLC to give the title compound (27 mg, 30%). ES-MS m / z 444 (M- t Bu+H).

[0102] Preparation of 33 trans-1-tert-butoxycarbonyl-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid (racemic mixture) The title compound was prepared essentially as described in Preparation 32 using 3-phenoxybenzenesulfonyl chloride. ES-MS m / z 467(M-BOC+H).

[0103] Preparation of 34 2-[4-[2-(2-bromoethoxy)ethoxymethyl]phenyl]pyridine Sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol) was added to a stirred solution of [4-(2-pyridyl)phenyl]methanol (0.2 g, 1.080 mmol) in DMF (2.5 g) at 0 °C under N2. The mixture was warmed to room temperature and stirred for 30 min. The resulting suspension was added via syringe over 10 min to a solution of 1-bromo-2-(2-bromoethoxy)ethane (0.751 g, 3.239 mmol) in DMF (2.0 g), and reacted at room temperature for 16 h. H2O was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel scrubbing with 0 to 25% EtOAc / hexane to give the title compound (0.14 g, 39%) as a colorless oil. ES-MS m / z 336 (M+H).

[0104] Preparation of 35 4-ethyl 1-tert-butyl trans-3-(3-bromophenyl)piperidine-1,4-dicarboxylic acid (isomer 1) A mixture of 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 1 g, 2.87 mmol) and tetrabutylammonium bromide (6.32 mmol, 2.06 g), along with 4-methylbenzenesulfonic acid monohydrate (3.33 mmol, 0.64 g), was dissolved in anhydrous ACN (30 mL). Copper bromide (0.287 mmol, 0.0648 g) and tert-butyl nitrite (3.73 mmol, 0.385 g) were then added, and the final reaction mixture was stirred at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was further washed with water, dried over Na2SO4, and evaporated under vacuum. The crude residue was purified by silica gel chromatography using a 10% to 50% EtOAc / hexane gradient to give the title compound (0.775 g, 64%) as a yellow viscous oil. ES-MS m / z 356, 358 (M- t Bu+H).

[0105] Preparation of 36 Trans-3-(3-formylphenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) A solution of 1-tert-butyl 4-ethyl trans-3-(3-bromophenyl)piperidine-1,4-dicarboxylic acid (isomeric 1,775 mg, 1.88 mmol), butyl di-1-adamantylphosphine (0.4511 mmol), palladium(II) acetate (0.1880 mmol), and N,N,N',N'-tetramethylethylenediamine (0.328 g, 2.820 mmol) in toluene (12 mL) was placed in a reaction vessel equipped with a stir bar, purged with N2, and pressurized with CO / H2 at a 1:1 ratio. The gas was purged and the pressure was increased to 70 psi, repeated three times. The mixture was stirred at 100 °C for 16–18 hours. The vessel was pressurized again with CO / H2 at a 1:1 ratio, the gas was purged, and the pressure was increased to 70 psi, repeated three times. The reaction mixture was stirred at 100 °C for 24–36 hours. The reactants were cooled to room temperature, the crude product was diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was partitioned between EtOAc and HCl (1 N). The organic layer was separated, washed twice with a saturated aqueous NaCl solution, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc / hexane (5% to 30%) to give the title compound (0.601 g, 88.47%) as a yellow oil. ES / MS m / z :262 (M-BOC+H).

[0106] Preparation of 37 Trans-3-[3-(hydroxymethyl)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) Sodium borohydride (1.2 equivalents, 0.0755 g) was added to a solution of cis-3-(3-formylphenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 0.601 g, 1.66 mmol) in EtOH (10 mL) at 0 °C, and the reaction mixture was stirred for 16 h. The solvent was removed, and the residue was extracted from EtOAc and water. The organic layer was separated, washed with a saturated aqueous solution of NaCl (2x), and evaporated under vacuum to give the title compound (0.3 g, 50%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ 7.28-7.25 (m, 3H), 7.18-7.16 (m, 1H), 4.70 (s, 2H), 4.39-4.23(m, 2H), 3.94 (q, J= 7.1 Hz, 2H), 2.98 (td, J= 11.5, 4.2 Hz, 1H), 2.78 (td, J= 11.6, 3.7 Hz, 3H), 1.99 (dd, J= 2.9, 13.2 Hz, 1H), 1.79 (qd, J= 12.7, 4.4Hz, 1H), 1.49 (s, 9H), 1.01 (t, J= 7.2 Hz, 3H).

[0107] Preparation of 38 trans-3-[3-[2-[2-[[4-(2-pyridyl)phenyl]methoxy]ethoxy]methoxymethyl]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) Sodium hydride (60% in mineral oil, 0.33 mmol, 0.013 g) was added to a stirred solution of trans-3-[3-(hydroxymethyl)phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 0.1 g, 0.275 mmol) in DMF (0.7 mL) at 0 °C under N2. The mixture was warmed to room temperature and stirred for 30 min. The resulting suspension was added via syringe over 10 min to a solution of 2-[4-[2-(2-bromoethoxy)ethoxymethyl]phenyl]pyridine (0.4128 mmol, 0.1388 g) in DMF (0.6 mL), and allowed to react at room temperature for 16 h. H2O was added, and the mixture was extracted with EtOAc. The aqueous phase was acidified to pH 6 with HCl (1N) and then extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The compound was purified twice by silica gel chromatography, first using a 0–8% MeOH / DCM gradient, then using a 0–6% MeOH / DCM gradient, to obtain the title compound. ES / MS m / z : 619 (M+H).

[0108] Preparation 39 trans-1-tert-butoxycarbonyl-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid (isomer 2) Sodium hydride (60% by mass in mineral oil, 0.79 mmol) was added to a solution of trans-1-tert-butoxycarbonyl-3-[3-(2-phenylethylsulfonylamino)phenyl]piperidine-4-carboxylic acid (isomer 2154 mg, 0.32 mmol) in THF (3 mL). The reaction mixture was stirred at 0 °C for 15 min, then iodomethane (0.79 mmol) was added, and the reaction mixture was heated to room temperature overnight. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography using a gradient of 30–60% ACN / NH4HCO3 aqueous solution (pH 9), followed by further purification by reversed-phase HPLC to give 52 mg (33%) of the title compound as a yellow oil. ES-MS m / z 447 (M- t Bu+H).

[0109] Preparation of 40 trans-3-(3-(2-oxooxazolidine-3-yl)phenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) A solution of 1-tert-butyl 4-ethyl trans-3-(3-bromophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 210 mg, 0.5093 mmol), oxazolidin-2-one (0.1331 g, 1.528 mmol), tBuXPhos-Pd-G3 (0.04046 g, 0.05093 mmol), and sodium tert-butoxide (0.1514 g, 1.528 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C under N2 for approximately 16–24 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness under vacuum. The crude product was purified using an HLB column (6 gr loaded) with a gradient of 0–75% ACN / NH4HCO3 (pH 9) to give the title product (170 mg) as a pale yellow solid. ES / MS m / z : 363 [M+H- t Bu.

[0110] Preparation 41 trans-1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidine-1-ylpyridin-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) The title compound was prepared essentially as described in Preparation 8 using 6-pyrrolidine-1-ylpyridin-2-carboxylic acid. ES-MS m / z 495 (M+H).

[0111] Preparation 42 trans-3-[3-[[3-[(4-chlorophenyl)methyl]imidazol-4-carbonyl]amino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) The title compound was prepared essentially as described in Preparation 8 using 1-tert-butyl 4-ethyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomer 1) and (3-[(4-chlorophenyl)methyl]imidazol-4-carboxylic acid), purified using an HLB column with a 10–100% ACN / water gradient, followed by reversed-phase HPLC purification. ES-MS m / z 567 (M+H).

[0112] Preparation of 43 trans-3-[3-[(3-methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) The title compound was prepared substantially as described in Preparation 15 using 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylate (isomer 1) and 1-isocyanate-3-methoxybenzene, and purified by silica gel chromatography using a 0 to 10% DCM / hexane gradient. ES-MS m / z 398 (M-BOC+H).

[0113] Preparation of 44 Trans-3-(3-(3-(3-methoxyphenyl)-1,3-dimethylurea)phenyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) Sodium hydride (60% by weight in mineral oil, 0.663 mmol) was added to a solution of trans-3-[3-[(3-methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 150 mg, 0.301 mmol) in THF (3 mL), and the mixture was stirred at room temperature for 30 min. Iodimethane (1.507 mmol) was then added, and stirring continued for approximately 2 h. The mixture was extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl solution (3x), dried over MgSO4, and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography eluting with 0–100% EtOAc / hexane to give the title product (0.147 g, 89%) as a colorless oil. ES / MS m / z 526 (M+H).

[0114] Preparation of 45 Methyl 2-[3-(2-methoxyethoxy)phenyl]acetate A mixture of methyl 2-(3-hydroxyphenyl)acetate (1.7 g, 10.2 mmol), cesium carbonate (4.3 g, 13.2 mmol), and sodium iodide (80 mg, 0.56 mmol) was purged under nitrogen. Acetone (70 mL) was then added, followed by 1-bromo-2-methoxyethane (2.11 g, 1.45 mL, 15.2 mmol), and the reaction mixture was heated to 60 °C under nitrogen. After 5 hours, 1-bromo-2-methoxyethane (0.37 g, 0.25 mL, 2.62 mmol) was added, and the reaction mixture was heated overnight at 60 °C. After 16 hours, the solvent was evaporated, and the residue was dissolved in ether / water. After separation, the organic matter was further washed with water, dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (2.15 g, 95%) as a pale yellow oil. ES-MS m / z 242 (M+H2O) + .

[0115] Preparation of 46 2-[3-(2-methoxyethoxy)phenyl]ethanol A solution of methyl 2-[3-(2-methoxyethoxy)phenyl]acetate (2.15 g, 9.6 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled in an ice / water bath under a nitrogen atmosphere. Diisobutylaluminum hydride (1 M, 26 mL, 26 mmol) was then added, and the final reaction mixture was continuously stirred in the bath. After 3 hours, the solvent was evaporated, and the residue was slowly poured into 1 M HCl. Once gas was released, EtOAc was added and the mixture was shaken. After separation, the organic phase was washed with water, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by silica gel chromatography using 2% MeOH / DCM to give the title compound (1.29 g, 69%) as a light brown oil. ES-MS m / z 197 (M+H).

[0116] Preparation 47 trans-1-tert-butoxycarbonyl-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid (isomer 1) A mixture of trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidin-4-carboxylic acid (isomer 1, 438 mg, 1.02 mmol), N,N-dimethylglycine hydrochloride (29 mg, 0.20 mmol), cuprous(I) iodide (21 mg, 0.11 mmol), and cesium carbonate (995 mg, 3.05 mmol) was purged under N2. 2-[3-(2-methoxyethoxy)phenyl]ethanol (also used as a solvent) was added, and the reaction mixture was stirred at 105 °C for 22.5 h. The reaction mixture was dissolved in water and EtOAc. Next, 1 M HCl (7 ml) was added, and the mixture was shaken. The layers were separated, the organic matter was further washed with water, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with 25% EtOAc / DCM, followed by a second purification using silica gel chromatography with 0–25% EtOAc / DCM. The product was subsequently purified by reversed-phase chromatography to give the title compound (51 mg, 10%) as a pale yellow oil. ES-MS m / z 444 (M- t Bu+H).

[0117] Preparation of 48 trans-3-[3-[[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3-piperidinyl]phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) A solution of 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomeric 1, 350 mg, 1.01 mmol) and 1,1'-carbonyldiimidazole (0.502 mmol) in THF (10 mL) was stirred at room temperature for 24 hours. The reaction mixture was then heated and stirred at 70 °C for 24 hours. 0.251 mmol of 1,1'-carbonyldiimidazole was added, and the mixture was continued to be heated to reflux temperature for approximately 4 hours. The reaction mixture was then heated again to 70 °C and stirred for 36 hours. HCl (1N) was added, and the compound was extracted with EtOAc. The organic layer was separated, dried over MgSO4, and evaporated under vacuum. The residue was purified by silica gel chromatography eluting with DCM / hexane (gradient from 0 to 50%) to give the title compound (0.144 g, 20%) as a white solid. ES / MS m / z : 623 (M-BOC+H).

[0118] Preparation 49 Ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-1-methyl-3-piperidinyl]anilino]phenyl]-1-methyl-piperidin-4-carboxylic acid (isomer 1) Paraformaldehyde (87 mg, 0.94 mmol) was added to a suspension of trans-3-[3-[3-[trans-4-ethoxycarbonyl-3-piperidinyl]anilino]phenyl]piperidin-4-carboxylate (isomer 1, 90 mg, 0.188 mmol) in MeOH (2 mL), and the resulting mixture was stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (199 mg, 0.938 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Further addition of paraformaldehyde (87 mg, 0.94 mmol) and sodium triacetoxyborohydride (199 mg, 0.938 mmol) was made, and the mixture was heated to 50°C and maintained for 16 hours. The reaction solvent was removed under a nitrogen stream, and the residue was purified by reversed-phase rapid chromatography using a gradient of 0-100% ACN / NH4HCO3 aqueous solution (10 mM, pH 9) to give the title compound (75 mg, 76%) as a pale yellow oil. ES-MS m / z 508 (M+H).

[0119] Preparation of 50 trans-3-[3-[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3-piperidinyl]aniline]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (isomer 1) A solution of 4-ethyl 1-tert-butyl trans-3-(3-bromophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 350 mg, 0.85 mmol), 4-ethyl 1-tert-butyl trans-3-(3-aminophenyl)piperidine-1,4-dicarboxylic acid (isomer 1, 0.355 g, 1.02 mmol), RuPhos Pd G3 (0.217 g, 0.255 mmol), and cesium carbonate (0.831 g, 2.55 mmol) in 1,4-dioxane (5.9 mL) was stirred at 110 °C under N2 for 16–18 hours. The mixture was filtered through diatomaceous earth and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography with a 0–95% EtOAc / hexane gradient to give the title compound (399 mg, 69%) as a pale yellow solid. ES / MS m / z 580 (M-BOC+H).

[0120] Preparation 51 Ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-3-piperidinyl]anilino]phenyl]piperidine-4-carboxylate (isomer 1) HCl (2 M in diethyl ether, 5.88 mmol, 2.9 mL) was added to a solution of trans-3-[3-[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3-piperidinyl]anilino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (isomer 1, 0.4 g, 0.59 mmol) in DCM (2 mL). The mixture was reacted at room temperature for 16 hours. After 16 hours, the solvent was removed under a stream of N2. The compound was dissolved in MeOH, loaded onto an SCX column (10 g), eluted with MeOH, and then eluted with MeOH / NH3 (2N). The MeOH / NH3 wash mixture was then concentrated under vacuum to give the title product (0.182 g, 65%) as a pale yellow oil. ES-MS m / z 480 (M+H).

[0121] Example 1 trans-3-[3-(prop-2-ynylamido)phenyl]piperidine-4-carboxylic acid; 2,2,2-trifluoroacetic acid (racemic mixture) Trans-1-tert-butoxycarbonyl-3-[3-(propane-2-ynylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture, 0.1026 g, 0.2755 mmol) was added to DCM (1.05 mL), and the mixture was stirred at 0 °C until the reactants were completely dissolved. Then, TFA (203 µL, 0.273 mmol) was added, and the mixture was stirred at 0 °C for 1 hour at room temperature. The solvent was evaporated by purging with N2 and dried in a vacuum oven to give the title compound as a yellow solid (0.1142 g, quantitative yield). ES / MS m / z : 273 (M+H).

[0122] Example 2 trans-3-[3-[4-[[4-(3-chloro-4-methylphenyl)piperazin-1-yl]methyl]triazol-1-yl]phenyl]piperidin-4-carboxylic acid; dihydrochloride (isomer 2) Trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methyl-phenyl)piperazin-1-yl]methyl]triazol-1-yl]phenyl]piperidin-4-carboxylic acid (isomer 2, 9.1 mg, 0.015 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 0.19 mL, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed under N2 and the mixture was dried under vacuum at 40 °C for 16–18 hours to give the title compound as a white solid (9 mg, quantitative yield). ES-MS m / z 495 (M+H).

[0123] Example 3a trans-3-[3-[3-(1H-indol-3-yl)propionylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture) A solution of trans-1-tert-butoxycarbonyl-3-[3-[3-(1H-indol-3-yl)propionylamino]phenyl]piperidin-4-carboxylic acid (racemic mixture, 150 mg, 0.305 mmol) was dissolved in HCl (5.50 M in IPA, 2.77 mL, 15.25 mmol). The mixture was stirred at room temperature for about 1 hour. The reaction mixture was concentrated to dryness under vacuum. The crude product was purified using a 5 g SCX column (adjusted with MeOH). The residue was dissolved in MeOH and packed into the column, eluted with MeOH, and then eluted with NH3 / MeOH (2 N). The NH3 / MeOH eluent was concentrated to dryness under vacuum to give the title product (0.0402 g, 32%) as a pale yellow solid. ES / MS m / z : 392 [M+H-Cl].

[0124] Example 3 trans-3-[3-[3-(1H-indol-3-yl)propionylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) A solution of trans-3-[3-[3-(1H-indol-3-yl)propionylamino]phenyl]piperidin-4-carboxylic acid (40.2 mg, 0.103 mmol) was dissolved in HCl (5.50 M in isopropanol, 0.93 mL, 5.13 mmol). The mixture was stirred at room temperature for about 2 hours. The reaction mixture was concentrated to dryness under vacuum. The resulting solid was washed with MTBE, filtered, and dried under vacuum. The residue was then dissolved in HCl (4.0 M in 1,4-dioxane) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness under vacuum. The resulting solid was washed with MTBE, filtered, and dried under vacuum to give the title compound (21 mg, 44%) as a pale yellow solid. ES / MS m / z : 392 [M+H].

[0125] Example 4 trans-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidine-1-yl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidine-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 1). ES-MS m / z 396 (M+H).

[0126] Example 5 trans-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid (isomer 2). ES-MS m / z 304 (M+H).

[0127] Example 6 trans-3-[3-(prop-2-ynylamino)phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-(prop-2-ynylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 259 (M+H).

[0128] Example 7 trans-3-[3-[2-(4-chlorophenyl)ethylcarbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2) The title compound was prepared essentially as described in Example 2 using trans-3-[3-(benzylcarbamoylamino)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (isomer 2). ES-MS m / z 402 (M+H).

[0129] Example 8 trans-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 2). ES-MS m / z 379 (M+H).

[0130] Example 9 trans-3-[3-[(4-phenylpiperidin-1-carbonyl)amino]phenyl]piperidin-4-carboxylic acid; hydrochloride (isomer 1) At room temperature, LiOH (1 M in H₂O, 6 mL, 6 mmol) and a few drops of MeOH were added to a solution of trans-3-[3-[(4-phenylpiperidin-1-carbonyl)amino]phenyl]piperidin-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester (isomer 1, 0.307 g, 0.5731 mmol) in THF (6 mL). The mixture was stirred at 50 °C for 16–18 h. HCl (1 N) was added, and the compound was extracted with EtOAc. The organic layer was separated, washed with H₂O (2x), dried over MgSO₄, and evaporated under vacuum. The residue was dissolved in DCM (4 mL), HCl (4 M in 1,4-dioxane, 2 mL, 8 mmol) was added, and the reaction was carried out for 2 h. The reaction solvent was evaporated under vacuum to give a beige solid. The solid was sonicated in MTBE / DCM, filtered, and dried under vacuum to give the title compound (0.14 g, 55%) as a white solid. ES / MS m / z : 408 (M+H).

[0131] The table below shows examples of preparation in two steps: Step 1 – Using essentially the procedure described in Preparation 14, trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2) was reacted with a suitable isocyanate. After completion, the reactants were concentrated and purified on an HLB column, eluting first with an aqueous solution of NH4HCO3 (20 mM, pH 9), followed by elution with ACN. The product was then purified via an SCX column, eluting first with MeOH, discarding the MeOH eluent, then eluting with 2 M NH3 / MeOH, collecting and concentrating. The product was further purified by reversed-phase chromatography to obtain a BOC-protected intermediate.

[0132] Step 2: Using a procedure substantially as described in Example 2, the BOC-protected intermediate prepared in Step 1 is converted into the listed example compounds.

[0133] Table 2 .

[0134] Example 12 trans-3-[3-[(3-methoxyazacyclobutane-1-carbonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared in two steps. Step 1 – essentially as described in Preparation 19, using 3-methoxyazinocyclic butane. Step 2 – essentially as described in Example 9, using the product from Step 1 to obtain the title compound. ES / MS m / z : 334 (M+H).

[0135] Example 13 trans-3-[3-[[(1-methyltriazol-4-yl)methyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[((1-methyltriazol-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 316 (M+H).

[0136] Example 14 trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 467 (M+H).

[0137] Example 15 trans-3-[3-[3-(4-methoxyphenoxy)propylsulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[3-(4-methoxyphenoxy)propylsulfonylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 449 (M+H).

[0138] Example 16 trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared essentially as described in Example 2 using 3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (isomer 1). ES-MS m / z 476 (M+H).

[0139] Example 17 trans-3-[3-[[(4-phenylphenyl)methyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[(4-phenylphenyl)methyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 388 (M+H).

[0140] Example 18 trans-3-(3-(2-(naphth-2-yl)acetamyl)phenyl)piperidine-4-carboxylate salt (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[[2-(2-naphthyl)acetyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 389 (M+H).

[0141] Example 19 trans-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid. ES-MS m / z 400 (M+H).

[0142] Example 20 trans-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 467 (M+H).

[0143] Example 21 trans-3-[3-[2-[2-[[4-(2-pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) To a solution of trans-3-[3-[2-[2-[[4-(2-pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester (isomer 1, 0.042 g, 0.0543 mmol, 80% by mass) in DCM (2 mL), HCl (4 M in 1,4-dioxane, 3.258 mmol, 0.608 g) was added, and the reaction was carried out at room temperature for 16 h. The solvent was removed, the mixture was dissolved in water, and loaded onto an SCX column. The column was eluted with MeOH, and the eluent was discarded. Elution was then carried out with 2 M NH3 / MeOH, collected, and concentrated. The residue was dissolved in MeOH (0.5 mL), and NaOH (2 M in water, 0.14 mL) was added, and the reaction was carried out at room temperature for 16 h. The solvent was removed. Water was added and the mixture was acidified to pH 5, followed by extraction with EtOAc (x4). The organic layers were combined and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography using a gradient of 10–100% ACN / NH4HCO3 aqueous solution (10 mM, pH 9). The product was dissolved in HCl (1 M, 2 mL) and stirred at room temperature for 16 hours. The mixture was concentrated to give the title compound (0.0301 g, 28%) as a pale yellow oil. ES / MS m / z : 491 (M+H).

[0144] Example 22 trans-3-[3-[(5-chloro-3-methyl-benzothiophene-2-yl)sulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[(5-chloro-3-methyl-benzothiophene-2-yl)sulfonamide]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 465 (M+H).

[0145] Example 23 trans-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid (isomer 2). ES-MS m / z 403 (M+H).

[0146] Example 24 trans-3-(3-aminophenyl)piperidine-4-carboxylic acid; hydrochloride (isomer 2) The title compound was prepared essentially as described in Example 2 using trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2). ES-MS m / z 221 (M+H).

[0147] Example 25 trans-3-(3-((2-hydroxyethyl)amino)phenyl)piperidine-4-carboxylate (isomer 1) To a solution of trans-3-(3-(2-oxooxazolidine-3-yl)phenyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)-4-ethyl ester (isomer 1, 188 mg, 0.45 mmol) in MeOH (4 mL) and THF (4 mL), NaOH (1 M aqueous solution, 4.5 mmol, 4.5 mL) was added. The resulting mixture was stirred at 50 °C for approximately 16–24 hours. The mixture was concentrated to dryness under vacuum. The crude product was dissolved in EtOAc, neutralized to pH 4 with HCl (0.5 M), extracted with EtOAc (3X), and washed with saturated NaCl aqueous solution (2X). The organic matter was dried over MgSO4, filtered, and concentrated to dryness under vacuum. The residue was dissolved in ACN / H2O and purified using an SCX column (25 gr loaded). First, the SCX column was eluted twice with ACN. Then, the mixture was loaded onto the column and eluted with ACN and NH3 / MeOH (2 N). The NH3 / MeOH eluent was concentrated to dryness, and the resulting solid was washed with MTBE, filtered, and dried under vacuum. The product was dissolved in HCl (4 M in 1,4-dioxane, 2.81 mL, 11.23 mmol), and the mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to dryness under vacuum. The resulting solid was washed with MTBE, filtered, and dried under vacuum to give the title product (119 mg, 88%) as a brown solid. ES / MS m / z : 265 [M+1].

[0148] Example 26 trans-3-[3-[[7-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carbonyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared in two steps. Step 1 – essentially the procedure described in Preparation 19, using 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline. Step 2 – essentially the procedure described in Example 9, using the product from Step 1 to obtain the title compound. ES / MS m / z : 448 (M+H).

[0149] Example 27 trans-3-[3-[[2-(chloromethyl)-3-methoxy-propyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared in two steps. Step 1 – essentially as described in Preparation 19, using 3-(methoxymethyl)azacyclobutane hydrochloride. Step 2 – essentially as described in Example 9, using the product from Step 1, to give the ring-opening title compound under the reaction conditions. ES / MS m / z : 482 [MH].

[0150] Example 28 trans-3-[3-[(6-pyrrolidine-1-ylpyridin-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture) The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidine-1-ylpyridin-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 395 (M+H).

[0151] Example 29 trans-3-[3-[[3-[(4-chlorophenyl)methyl]imidazol-4-carbonyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared essentially as described in Example 9 using trans-3-[3-[[3-[(4-chlorophenyl)methyl]imidazolium-4-carbonyl]amino]phenyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (isomer 1). ES-MS m / z 439(M+H).

[0152] Example 30 trans-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)phenyl)piperidine-4-carboxylate (isomer 1) The title compound was prepared in two steps: Step 1: Basically follow the procedure described in Preparation 13, using 1-methylimidazolidine-2-one, purified using an HLB column, eluted with a gradient of 0 to 100% ACN / NH4HCO3 aqueous solution (pH 9).

[0153] Step 2: Basically as described in Example 2, the BOC group from the product of Step 1 was removed to obtain the title compound. ES / MS m / z = 304 [M+H].

[0154] Example 31 trans-3-(3-(3-(3-methoxyphenyl)-1,3-dimethylurea)phenyl)piperidine-4-carboxylate (isomer 1) The title compound was prepared essentially as described in Example 9 using 1-(tert-butyl)-4-ethyl trans-3-(3-(3-methoxyphenyl)-1,3-dimethylureo)phenyl)piperidine-1,4-dicarboxylic acid (isomer 1). ES-MS m / z 398 (M+H).

[0155] Example 32 trans-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1) The title compound was prepared essentially as described in Example 9 using trans-1-tert-butoxycarbonyl-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid (isomer 1). ES-MS m / z 400 (M+H).

[0156] Example 33 trans-3-[3-[[3-(trans-4-carboxy-3-piperidinyl)phenyl]carbamoylamino]phenyl]piperidin-4-carboxylic acid; dihydrochloride (isomer 1) To a solution of trans-3-[3-[[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3-piperidinyl]phenyl]carbamoylamino]phenyl]piperidin-1,4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (isomer 1, 144 mg, 0.199 mmol) in THF (10 mL), LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH were added. The reaction was stirred at room temperature for 24 hours. Then, HCl (1N) was added, and the compound was extracted with EtOAc. The organic layer was separated, dried over MgSO4, and evaporated under vacuum. The residue was dissolved in THF (10 mL), LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH were added, and the mixture was stirred at room temperature for 36 hours. HCl (1N) was added, and the compound was extracted with EtOAc. The organic layer was separated, dried over MgSO4, and evaporated under vacuum. The resulting solid was dissolved in DCM (2 mL), and HCl (2 M in Et₂O, 4 mL, 8 mmol) was added. The reaction was stirred at room temperature for 16–18 hours. The solvent was evaporated under vacuum, and the residue was co-evaporated with water to remove residual solvent, yielding the title compound as a white powder (0.077 g, 72%). ES / MS m / z : 467 (M+H).

[0157] Example 34 trans-3-[3-[3-[trans-4-carboxy-1-methyl-3-piperidinyl]anilino]phenyl]-1-methyl-piperidin-4-carboxylic acid; dihydrochloride (isomer 1) Ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-1-methyl-3-piperidinyl]anilino]phenyl]-1-methyl-piperidin-4-carboxylate (isomer 1) (75 mg, 0.148 mmol) in THF (0.74 mL) and MeOH (0.30 mL) was mixed with NaOH (2 M in water, 0.67 mL, 1.33 mmol), and the mixture was stirred at 50 °C for 16 h, followed by solvent concentration. The residue was purified by reversed-phase rapid chromatography using a gradient of 0 to 100% ACN / NH4HCO3 aqueous solution (10 mM, pH 9). The product was treated with HCl (1 N) and stirred at room temperature for 30 min, and the solvent was removed under vacuum to give the title compound (49 mg, 62%) as a pale green solid. ES-MS m / z 452 (M+H).

[0158] Example 35 trans-3-[3-[3-[trans-4-carboxy-3-piperidinyl]anilino]phenyl]piperidin-4-carboxylic acid; dihydrochloride (isomer 1) NaOH (1.877 mmol, 2 M) was added to a solution of ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-3-piperidinyl]anilino]phenyl]piperidin-4-carboxylate (isomer 1, 0.1 g, 0.21 mmol) in THF (1 mL) and MeOH (0.4 mL). The mixture was heated at 50 °C for 16 h, and then the solvent was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography using a gradient of 0–100% ACN / NH4HCO3 aqueous solution (10 mM, pH 9). The product was then dissolved in HCl (1 N) and stirred at room temperature for 30 min. The solvent was removed under vacuum and the product was dried under vacuum to give the title compound (0.099 mg, 96%) as a pale green solid. ES / MS m / z 424 (M+H).

[0159] In vitro Lp(a) assembly detection The ability of the compounds to inhibit Lp(a) particle formation in vitro was assessed using a cell-free assembly assay. Conditioned medium (supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin in DMEM) was collected from confluent wild-type HepG2 cells (the source of endogenously expressed ApoB) and from a stable HEK293 cell line expressing human Apo(a) protein with 17 Kringle repeats (selected on 1 mg / ml genistein) after 24 hours of culture at 37°C and 5% CO2. In vitro assembly assays were performed by combining equal portions of HepG2 and HEK293 conditioned medium with serially added test compounds (final concentrations 0.01–100 nM). The reaction was incubated at 37°C for 2 hours and then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Lp(a) capture antibody and HRP-labeled anti-ApoB detection antibody. ELISA was performed using TMB colorimetry, terminated with 1 N sulfuric acid, and read out at 450 nm using a Molecular Devices reader. The percentage inhibition of Lp(a) formed under each experimental condition was determined by setting the assembly reaction without inhibitors (with a matched DMSO concentration of 1%) as 0% inhibition and the assembly reaction with minimal HepG2 conditioned medium (50-fold dilution) as 100% inhibition. Data were fitted to a 4-parameter curve to determine the IC50 values ​​summarized in Table 3.50 Values. Adding the test compounds from the examples to conditioned medium containing ApoB and Apo(a) resulted in concentration-dependent inhibition of in vitro Lp(a) formation as summarized in Table 3. The results indicate that these compounds inhibit the assembly of Lp(a) by Apo(a) and LDL particles.

[0160] Table 4 .

Claims

1. A compound of the formula: ###0001### or a pharmaceutically acceptable salt thereof, wherein n is independently at each occurrence 0, 1, 2, or 3; R 1 is H or CH3; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid glycol ester, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NR 15 CONR 15 (CH2) n R 10 , -(CH2) n NR 15 CO(CH2) n R 10 , -O(CH2) n R 10 , -(CH2) n NR 15 SO2(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 , NH2, -NHCONH2, or ; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; halo; R 10 selected from the group consisting of: NH2; C optionally substituted by one to four OH or OCH3 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; naphthyl; phenoxy optionally substituted with methoxy; 3,4-dihydro-2H-1 λ 2 - quinoline; m is 0 or 1; 4-, 5- or 6-membered heterocycle, which is optionally substituted by OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl, wherein phenyl is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, which is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; p is 1, 2, 3, 4, or 5; and 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: ###0002### wherein R 15 is H or C 1-3 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Q 2 is H. naphthyl; 。 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -(CH2) n NR 15 CONR 15 (CH2) n R 10 , -(CH2) n NR 15 CO(CH2) n R 10 , -O(CH2) n R 10 , -(CH2) n NR 15 SO2(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 , NH2, or .

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Q 1 is -NHCH2R 10 , -NHCONHR 10 , -NHCONHCH2R 10 , -NHCONH(CH2)2R 10 , -N(CH3)CON(CH3)R 10 , -NHCOR 10 , -NHCOCH2R 10 , -NHCO(CH2)2R 10 , CH2NHSO2R 10 , -NHSO2R 10 , -O(CH2)2R 10 , -NHSO2(CH2)3R 10 , -N(CH3)SO2(CH2)2R 10 , -CH2O(CH2)2O(CH2)2OCH2R 10 , NH2, or .

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Q 1 is -NHCH2R 10 , 10 , 10 , 10 , 10 , 10 , or .

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -(CH2) n NR 15 CONR 15 (CH2) n R 10 , -(CH2) n NR 15 CO(CH2) n R 10 , -O(CH2) n R 10 , -(CH2) n NR 15 SO2(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 , or and R 10 is selected from: C optionally substituted by one to four OH 1-4 alkyl; C 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; phenoxy; 3,4-dihydro-2H-1 λ 2 - quinoline; CH3; CH2OH; cyclopropyl; CH2CH(CH2C1)CH2OCH3; ethynyl; naphthyl; 3,4-dihydro-2H-l λ2-quinoline substituted with CF3; phenoxy; 4- or 6-membered heterocycle, which is optionally substituted by OCH3or (CH2) m phenyl, which is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl, optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine or benzyl, wherein benzyl is optionally substituted with halogen; and phenyl optionally substituted with one to three substituents independently selected from halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or -(CH2) n phenyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from: piperazine, piperidine, or azetidine, wherein the piperazine, piperidine, or azetidine is optionally substituted with OCH3 or phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from the group consisting of CI and CH3; indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein the indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is optionally substituted with one or two substituents selected from the group consisting of CH3, CI, pyrrolidine, and benzyl, wherein the benzyl is substituted with CI; and phenyl optionally substituted with one or two substituents independently selected from the group consisting of CI, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, and phenyl. cyclopropyl, ethynyl, phenoxy, 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from: phenyl-substituted piperazine, wherein the phenyl is substituted with CI and CH3, phenyl-substituted piperidine, OCH3-substituted azetidine, indole, thiophene, CH3-substituted pyrazole, OCH3, CI, or CH3-substituted phenyl.

11. A compound of the formula: ###0003### or a salt thereof, wherein n is independently at each occurrence 0, 1, 2, or 3; halo; R 1a is H, CH3, or a protecting group; X is OH or C 1-4 alkoxy; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid glycol ester, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NR 15 CONR 15 (CH2) n R 10 , -(CH2) n NR 15 CO(CH2) n R 10 , -O(CH2) n R 10 , -(CH2) n NR 15 SO2(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) n R 10 , -(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 , NH2, -NHCONH2, or ; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; NH2; R 10 selected from the group consisting of: naphthyl; C optionally substituted by one to four OH or OCH3 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; phenoxy optionally substituted with methoxy; m is 0 or 1; 3,4-dihydro-2H-1 λ 2 - quinoline; p is 1, 2, 3, 4, or 5; and 4-, 5- or 6-membered heterocycle, which is optionally substituted by OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl, wherein phenyl is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; 13. Use of a compound according to claim 11 or claim 12, or a salt thereof, in the preparation of an oligomer.

14. An oligomer prepared from a compound according to claim 11 or claim 12, or a salt thereof. R 15 is H or C 1-3 alkyl, wherein if X is OH, then R 1a must be a protecting group.

12. The compound according to claim 11, or a salt thereof, wherein R 1a is a protecting group and the protecting group is selected from the group consisting of: tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, tritylamine, and p-toluenesulfonamide.

15. The oligomer according to claim 14, comprising at least two piperidine moieties.

16. The oligomer according to claim 14, comprising at least three piperidine moieties.

17. A compound of the formula: ###0004### or a pharmaceutically acceptable salt thereof, wherein p is independently at each occurrence 0 or 1; 19. The compound according to claim 17 or claim 18, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula: ###0005### R 1 independently at each occurrence H or CH3; L is -(CH2) p NHC(O)NH(CH2) p -, -(CH2) p NH(CH2) p -, or ; 21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)-. Q 3 independently at each occurrence is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen, or CN; L 2 is C1-3alkylene or a bond.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Q 3 is H.

22. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein L is -NH-. 。 20. The compound or pharmaceutically acceptable salt thereof of any one of claims 17-19, wherein L is -(CH2) p NHC(O)NH(CH2) p - or -(CH2) p NH(CH2) p -.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. ​ ​ 24. A method of treating a cardiovascular disease in a patient comprising administering to the patient an effective amount of a compound of any one of claims 1-10 or 17-22, or a pharmaceutically acceptable salt thereof.

25. A method of treating elevated plasma levels of Lp(a) in a patient comprising administering to the patient an effective amount of a compound of any one of claims 1-10 or 17-22, or a pharmaceutically acceptable salt thereof.

26. A compound of any one of claims 1-10 or 17-22, or a pharmaceutically acceptable salt thereof, for use in therapy.

27. A compound of any one of claims 1-10 or 17-22, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disease.

28. A compound of any one of claims 1-10 or 17-22, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated plasma levels of Lp(a).

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