WO2025024211A1 - Piperidine Compounds with Lp(a) Lowering Activity - Google Patents

Abstract

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

Description

Piperidine Compounds with Lp(a) Lowering Activity FIELD OF THE INVENTION [0001] This invention relates to piperidine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and therapeutic uses of the compounds, in particular their use in lowering lipoprotein(a) (Lp(a)) plasma levels. BACKGROUND OF THE INVENTION [0002] There have been significant advances in treating cardiovascular disease (CVD). Despite treatment advances, patients continue to experience cardiovascular disease events such as angina, myocardial infarction, and stroke, which if untreated, lead to death. Lipid disorder or dyslipidemia remains a major risk factor for CVD. Lipid disorders can be divided 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). There are a variety of treatment regimens targeting elevated LDL-c, low HDL-c, and elevated triglycerides. There are few approved treatment options for patients with elevated Lp(a) concentrations. In some cases, apheresis may be used to filter the blood to remove LDL and Lp(a); however, the effects are temporary and typically need to be repeated every two weeks. There is currently no pharmaceutical treatment approved specifically to lower 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 confer at least a 1.6-fold risk of a first cardiovascular event (Kronenberg, F. Clin. Res. Cardiol. Suppl. 14, 5-12 (2019)) and a >1.42-fold increase risk of a second event (Madsen, C. M. et al. Arterioscler. Thromb. Vasc. Biol.40, 255-266 (2020)). Lp(a) may exhibit both prothrombotic and antithrombotic properties, and atherogenic and atherothrombotic properties. Lp(a) may inhibit fibrinolysis and accumulate in the vascular wall inducing thrombogenesis and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially among individuals. Unlike the other risk factors, Lp(a) plasma levels do not vary significantly with diet and exercise. [0004] Lp(a) resembles LDL-c in that it includes an LDL lipid core with the attendant apolipoprotein B (apoB), but unlike LDL-c, Lp(a) also contains a unique apolipoprotein(a) (apo(a)) bound to the apoB via disulfide bond. 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 the LDL particle with apo(a) reduces Lp(a) levels. [0005] WO2020/247429 discloses compounds which inhibit the formation of Lp(a) by blocking the interaction between Apo(a) and ApoB. [0006] Additional treatment options are desired for patients suffering from cardiovascular diseases and, in particular, patients suffering from lipid disorders or dyslipidemia. There is a need for additional treatment options for patients whose cardiovascular risks are not adequately managed using current standard of care therapies, such as, diet, exercise and/or the use of one or more drugs such as statins, fibrates, and niacin. More particularly, there is a need for further, alternative pharmaceutically acceptable compounds which inhibit the formation of Lp(a) and thus, reduce plasma Lp(a) levels. SUMMARY OF THE INVENTION [0007] Accordingly, in a first aspect, there is provided a compound of Formula I:

wherein R¹ is H or CH₃; Q¹ is -(CH2)nNR¹⁵(CH2)nR¹⁰, -B(OR¹⁰)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH₂)_nNR¹⁵CONR¹⁵(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵CO(CH₂)_nR¹⁰, -O(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵SO₂(CH₂)_nR¹⁰, -(CH₂)_nO(CH₂)_pO(CH₂)_nR¹⁰, -(CH2)nO(CH2)pO(CH2)pO(CH2)nR¹⁰, NH2, -NHCONH2,

Q² is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is at each occurrence independently 0, 1, 2, or 3; R¹⁰ is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6 cycloalkyl optionally substituted with one or two halo; C_1-4 haloalkyl optionally substituted with OCH₃; C_2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF₃; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH₃; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4 alkoxy, C1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH₂)_nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; p is 1, 2, 3, 4 or 5; and R¹⁵ is H or C1-3 alkyl, or a pharmaceutically acceptable salt thereof. [0008] In a second aspect, there is provided a compound of Formula II:

wherein R^1a is H, CH3 or a protecting group; X is OH or C_1-4 alkoxy; Q¹ is -(CH2)nNR¹⁵(CH2)nR¹⁰, -B(OR¹⁰)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH₂)_nNR¹⁵CONR¹⁵(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵CO(CH₂)_nR¹⁰, -O(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵SO₂(CH₂)_nR¹⁰, -(CH₂)_nO(CH₂)_pO(CH₂)_nR¹⁰, -(CH2)nO(CH2)pO(CH2)pO(CH2)nR¹⁰, NH2, -NHCONH2,

Q² is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is at each occurrence independently 0, 1, 2, or 3; R¹⁰ is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C_3-6 cycloalkyl optionally substituted with one or two halo; C_1-4 haloalkyl optionally substituted with OCH₃; C2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF₃; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH₂)phenyl or (CH₂)_mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH₃; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C_1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4 alkoxy, C1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH₂)_nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; p is 1, 2, 3, 4 or 5; and R¹⁵ is H or C1-3 alkyl, or a salt thereof, wherein if X is OH then R^1a must be a protecting group. [0009] In a third aspect, there is provided the use of a compound of Formula II, or a salt thereof, in the preparation of an oligomer. [0010] In a fourth aspect, there is provided an oligomer prepared from a compound of Formula II, or a salt thereof. In an embodiment, the oligomer comprises at least two piperidine moieties. In another embodiment, the oligomer comprises at least three piperidine moieties. [0011] In a fifth aspect, there is provided a compound of Formula III:

III R¹ is at each occurrence independently H or CH3;

p is at each occurrence independently 0 or 1; Q³ is at each occurrence independently H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O- cyclopropyl, OCF₃, halo, or CN; L² is C1-3 alkylene or a bond; or a pharmaceutically acceptable salt thereof. [0012] In a sixth aspect, there is provided a pharmaceutical composition 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, there is provided a method of treating cardiovascular disease in a patient 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, there is provided a method of treating elevated Lp(a) plasma levels in a patient comprising administering to the patient an effective amount of a compound of Formula I or III, or a pharmaceutically acceptable salt thereof. [0015] In a ninth aspect, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in therapy. [0016] In a tenth aspect, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. [0017] In an eleventh aspect, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated Lp(a) plasma levels. DETAILED DESCRIPTION OF THE INVENTION [0018] In an embodiment of a compound of Formula I, R¹ is H. [0019] In an embodiment of a compound of Formula I, Q² is H. [0020] In an embodiment, there is provided a compound of Formula Ia:

, Ia or a pharmaceutically acceptable salt thereof. Formula I encompasses Formula Ia and reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to Formula Ia. [0021] In an embodiment of a compound of Formula I, Q¹ is -(CH2)nNR¹⁵(CH2)nR¹⁰, -(CH₂)_nNR¹⁵CONR¹⁵(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵CO(CH₂)_nR¹⁰, -O(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵SO₂(CH₂)_nR¹⁰, -(CH₂)_nO(CH₂)_pO(CH₂)_pO(CH₂)_nR¹⁰, NH₂,

C_1-4 alkyl optionally substituted with one to four OH; C_3-6 cycloalkyl; C1-4 haloalkyl optionally substituted with OCH3; C2-6 alkynyl; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF₃; phenoxy; 4- or 6- membered heterocycle optionally substituted with OCH₃ or (CH₂)_mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C_1-4 alkyl, halo, pyrrolidine, or benzyl, wherein the benzyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C_1-4 alkoxy, C_1-4 alkyl, CF₃, CN, -OCH₂CH₂OCH₃, phenoxy, pyridine, -OCH₂phenyl or -(CH₂)_nphenyl. Preferably, R¹⁰ is selected from: CH3; CH2OH; cyclopropyl; CH2CH(CH2Cl)CH2OCH3; ethynyl; naphthyl; 3,4-dihydro-2H-1λ2- quinoline substituted with CF3; phenoxy; piperazine, piperidine or azetidine, wherein the piperazine, piperidine or azetidine is optionally substituted OCH3 or phenyl, wherein the phenyl 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 is substituted with Cl; and phenyl optionally substituted with one or two substituents independently selected from: Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl or phenyl. More preferably, R¹⁰ is selected from: cyclopropyl, ethynyl, phenoxy, piperazine substituted with phenyl wherein the phenyl is substituted with Cl and CH3, piperidine substituted with phenyl, azetidine substituted with OCH₃, indole, thiophene, pyrazole substituted with CH3, phenyl substituted with OCH₃, Cl or CH_3. [0023] In an embodiment, there is provided a compound of Formula Ia wherein Q¹ is NHCH2R¹⁰, -NHCONHR¹⁰, NHCONHCH2R¹⁰, -NHCONH(CH2)2R¹⁰, - N(CH₃)CON(CH₃)R¹⁰, -NHCOR¹⁰, -NHCOCH₂R¹⁰, -NHCO(CH₂)₂R¹⁰, CH₂NHSO₂R¹⁰, - NHSO2R¹⁰, -O(CH2)2R¹⁰, -NHSO2(CH2)3R¹⁰, -N(CH3)SO2(CH2)2R¹⁰, -

R¹⁰ is selected from: CH3; CH2OH; cyclopropyl; CH2CH(CH2Cl)CH2OCH3; ethynyl; naphthyl; 3,4-dihydro-2H-1λ2- quinoline substituted with CF3; phenoxy; piperazine, piperidine or azetidine, wherein the piperazine, piperidine or azetidine is optionally substituted OCH3 or phenyl, wherein the phenyl 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 is substituted with Cl; and phenyl optionally substituted with one or two substituents independently selected from: Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl or phenyl, or a pharmaceutically acceptable salt thereof. [0024] In an embodiment, the compound of Formula I is selected from:

or a pharmaceutically acceptable salt thereof. [0025] In an embodiment of a compound of Formula II, R^1a is a protecting group and the protecting group is selected from: tert-butyloxycarbonyl, carboxybenzyl, 9- fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide. In a particular embodiment, R^1a is tert-butyloxycarbonyl. [0026] In an embodiment of a compound of Formula III, Q³ is H. [0027] In an embodiment, there is provided a compound of Formula IIIa:

, IIIa or a pharmaceutically acceptable salt thereof. Formula III encompasses Formula IIIa and reference to Formula III below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to Formula IIIa. [0028] In an embodiment of a compound of Formula III, L is -(CH2)pNHC(O)NH(CH2)p- or -(CH₂)_pNH(CH₂)_p-. In a particular embodiment, L is -NHC(O)-. In an alternate embodiment, L is -NH-. [0029] In an embodiment, the compound of Formula III is selected from:

or a pharmaceutically acceptable salt thereof. [0030] In an embodiment, there is provided a method of treating a patient in need of treatment for cardiovascular disease, comprising administering an effective amount of a compound of Formula I or III, or a pharmaceutically acceptable salt thereof. In an embodiment, there is provided a method of treating a patient in need of treatment for elevated Lp(a) plasma levels, comprising administering an effective amount of a compound of Formula I or III, or a pharmaceutically acceptable salt thereof. [0031] In an embodiment, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in therapy. [0032] In an embodiment, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. In an embodiment, there is provided a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, for use in treating elevated Lp(a) plasma levels. [0033] In an embodiment, there is provided the use of a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiovascular disease. In an embodiment, there is provided the use of a compound of Formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of elevated Lp(a) plasma levels. [0034] The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine. [0035] The term “C_1-n alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of a C1-4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of a C1-3 alkyl group include, but are not limited to, methyl, ethyl and propyl. [0036] The term “C1-3 alkylene” refers to a bivalent straight or branched C1-3 alkyl group. [0037] The term “C_1-4 haloalkyl” refers to a C_1-4 alkyl group, as defined herein, which is substituted with one or more halogen. Examples of C1-4 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl. [0038] The term “C_1-4 alkoxy” refers to a straight, or branched chain saturated hydrocarbon containing 1 to 4 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of C1-4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy. [0039] The term “C_2-6 alkynyl” refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms and at least one triple bond. [0040] The term “C3-6 cycloalkyl” refers to a monocyclic saturated carbon ring containing between 3 and 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 heteroaryls include, but are not limited to, pyrazole, triazole and thiazole. Examples of 6-membered heteroaryls include, but are not limited to, pyridine and pyridazine. [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 heteroaryls include, but are not limited to, indole, isoindole, indazole and pyrazolopyridine. Examples of 10-membered bicyclic heteroaryls 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, for example, pyrrolidine and piperidine. [0044] As used herein, the term “elevated Lp(a) plasma levels” means a plasma level of Lp(a) that is equal to or above about 50 mg/dL. A compound provided herein may be used in treatment to reduce Lp(a) plasma levels. [0045] As used herein, the term “oligomer” means compounds that have at least two of the piperidine moieties set out in formula I or II. As used herein, “piperidine moiety” refers to an optionally substituted piperidine. The piperidine moieties in an oligomer may be the same or different. [0046] The term “pharmaceutically acceptable salt” as used herein refers a salt of a compound that is acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley- VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. In particular, the compounds of Formula I or III may be a zwitterion, a mono-, di, or tri-acid addition salt. [0047] The pharmaceutical compositions for the present invention may be prepared using pharmaceutically acceptable additives. The term “pharmaceutically acceptable” refers to one or more carriers, diluents, and/or excipients that are compatible with the other components of the composition and not pharmaceutically deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation are well known to the skilled artisan, and can be found, for example, in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. [0048] As used herein, the term “effective amount” refers to a dosage amount that is effective in treating a disorder. The effective amount for a particular patient can be determined by a skilled health professional. [0049] As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, reducing, preventing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, “treating cardiovascular disease” means slowing, reducing, preventing, or reversing the progression of heart or blood vessel disease. [0050] As used herein, the term "patient" refers to a mammal. Preferably, the patient is a human. [0051] Pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. In an embodiment the composition is suitable for oral administration. [0052] Certain abbreviations may 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 dimethylacetamide; “DMAP” refers to 4-dimethylaminopyridine; “DMEA” refer to dimethylethanolamine; “DMEM” refers to Dulbecco’s Modified Eagle’s Medium; “DMF” refers to dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EACA” refers to epsilon-aminocaproic acid or 6-aminocaproic acid; “ELISA” refers to enzyme-linked immunosorbent assay; “EtOAc” refers to ethyl acetate; “FBS” refers to Fetal Bovine Serum; “HEC” refers to hydroxy ethyl cellulose; “HEK” refers to human embryonic kidney; “HepG2” refers to a human hepatoma cell line; “HEPES” refers to 4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid; “HLB” refers to hydrophilic-lipophilic balance; “h” refers to hour/hours; “HRP” refers to Horseradish Peroxidase; “IC₅₀” refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent; “IPA” refers to isopropyl alcohol or isopropanol; “MeCN” refers to acetonitrile; “min” refers to minute/s; “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’-teramethylbenzidine. [0053] Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds listed below, by methods known to the artisan, such as selective crystallization techniques or chiral chromatography. [0054] A compound of Formula I or III is readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt or by the addition of a pharmaceutically acceptable base to form a base addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, i.e., removing the protecting group. Examples, reactions and conditions for salt formation are known to the skilled artisan. [0055] The compounds of Formula I or III or any depicted formulae, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. [0056] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. Compounds of afore-depicted formulae, or salts thereof may be prepared by using starting materials or intermediates with the corresponding desired stereochemical configuration.

[0057] Scheme 1 shows the preparation of key intermediates 6 and 7, which are used in the preparation of compounds in the present invention. Reaction of compound 1 in Step A with NaH in N,N-dimethylacetamide followed by 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 warming up to RT gives sulfonate compound 2. Compound 2 then undergoes a cross-coupling reaction with either a boronic acid (3a) or boronic ester (3b) in Step B using a palladium catalyst and carbonate base at elevated temperature to give coupled product 4. The ring is subsequently reduced using hydrogen gas and a palladium catalyst in Step C to give compound 5 in cis- relative stereochemistry, which is then epimerized to trans- in Step D with an alkoxide base such as sodium methoxide in ethanol with heating to give compound 6. Prolonged heating with the addition of water to the reaction hydrolyzes the ester to give compound 7. Q² is as defined in Formula I or II and Q³ is as defined in Formula III. Scheme 2

[0058] Scheme 2 shows the preparation of advanced intermediates which are used in the preparation of compounds of the present invention. In Step A, aniline compound 8 is converted to halide 9 by using tert-butyl nitrite, a sulfonic acid (methanesulfonic acid or p-toluenesulfonic acid), cupric bromide, and either tetrabutylammonium iodide or tetrabutylammonium bromide. In Step B, compound 9 is carbonylated using CO/H₂ gas mixture at 100 psi, a palladium catalyst, and N,N,N’,N’-tetramethylethylenediamine at elevated temperature to give aldehyde 10. In Step C, the aldehyde is reduced using sodium borohydride in EtOH at 0 °C to give alcohol compound 42, which is then treated with NaH and reacted with alkyl halide 11a or 11b in Step D to give compound 12a or 12b, respectively. [0059] Aniline compound 8 can also be converted to an azide in the presence of azidotrimethylsilane and tert-butyl nitrite, which then undergoes click chemistry with nitrile 15 to give 1,2,3-triazole compound 16 in Step F, which can be performed utilizing a flow reactor. [0060] Halide 9 can also be coupled with imidazolidine-2-one compound 13 using a palladium catalyst and an alkoxide base with heating in 1,4-dioxane in Step E to afford compound 14. Q² is as defined in Formula I or II and Q³ is as defined in Formula III. R¹⁰, n, p and X are as defined in Formula II. Scheme 3

[0061] Scheme 3 shows the preparation of primary amine compound 18, wherein nitrile compound 17 is reduced using hydrogen gas, an amine base, a palladium catalyst, and a mixture of THF and EtOH. Q² is as defined in Formula I or II and Q³ is as defined in Formula III. X is as defined in Formula II. [0062] Scheme 4 shows reactions on amino intermediate 19. Reaction with either acid chloride 20 and an amine base or coupling with acid 21 using a coupling reagent such as DCC gives amide 27. Reaction of amino intermediate 19 with isocyanate 22 or, alternatively, with triphosgene and an amine base followed by reaction with amine 23 gives urea compound 28. Alkylation of amino intermediate 19 with alkyl halide 24 and a carbonate base gives compound 29, and reductive amination between intermediate 19 and aldehyde 25 with sodium triacetoxyborohydride gives compound 30. Finally, reaction of amino intermediate 19 with sulfonyl chloride 26 using pyridine and a catalytic amount of DMAP gives compound 31. Optionally, compounds 28 and 31 where R¹⁵ = H can be methylated, first treating with NaH and then adding iodomethane. Q² is as defined in Formula I or II and Q³ is as defined in Formula III. R¹⁰, R¹⁵, n and X are as defined in Formula II. Scheme 5

[0063] Scheme 5 shows the preparation of multimeric compounds 32 and 33. Amino compound 19 is reacted with 1,1'-carbonyldiimidazole in THF at an elevated temperature to give symmetrical urea compound 32. Aniline compound 8 is coupled with aryl bromide 9 using a palladium catalyst and a carbonate base to give the dimeric compound 33. Q³ is as defined in Formula III. n and X are as defined in Formula II.

[0064] Scheme 6 shows the final deprotection and optional methylation steps to give compounds of the present invention. Compound 34 first undergoes ester hydrolysis in the presence of a strong aqueous base to give acid compound 35 in Step A, 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 isolated as an HCl salt by concentrating the reaction solution to dryness. Alternatively, the piperidine nitrogen of compound 34 is first deprotected in Step C with HCl in an organic solvent such as diethyl ether or 1,4-dioxane, purified by ion exchange (SCX) to provide the free amine, and then in Step D the product undergoes reductive amination with paraformaldehyde and sodium triacetoxyborohydride with heating to give compound 37. Subsequent ester hydrolysis in Step E using strong aqueous base gives compound 38. [0065] These same deprotection steps are used to give multimeric 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) gives compound 41. Q¹ and Q² are as defined in Formula I or II. Q³ and L are as defined in Formula III. Preparation 1 1-tert-Butyl 4-ethyl 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine- 1,4-dicarboxylate

[0066] To a suspension of sodium hydride (60 mass% in mineral oil, 420 mmol) in N,N- dimethylacetamide (300 mL) at 0 ºC was slowly added a solution of 1-tert-butyl 4-ethyl 3- oxopiperidine-1,4-dicarboxylate (CAS No.71233-25-5, 100 g, 350 mmol) in N,N- dimethylacetamide (100 mL) and the resulting mixture was stirred at RT for 1h. 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 drop wise and the mixture was stirred at RT, then overnight at 40 ºC. The reaction was diluted with MTBE and quenched with a saturated aqueous solution of NH₄Cl. The phases were separated, and the aqueous layer extracted with MTBE. The combined organic phases were washed with water twice, then saturated aqueous NaCl. The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in hexanes to give the 87 g (45%) of title compound. ES/MS m/z 498 (M-tert-Bu+H) Preparation 2 O1-tert-Butyl O4-ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4- dicarboxylate

[0067] To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (85 g, 313 mmol, 1.0 eq) and TEA (95 g, 94 mmol, 130 mL, 3.0 eq) in DCM (850 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (132 g, 470 mmol, 77 mL, 1.5 eq) drop-wise at -78°C over a period of 30 mins under N2, during which the temperature was maintained -78^oC and stirred for 1h. 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 (1L x 2). All of the organic phase was combined and washed with brine (2.5 L), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the title compound (586 g, 95% yield, 82% purity) as a black brown liquid, which was carried forward without further purification. TLC (petroleum ether : EtOAc = 3:1 R_f = 0.24) Preparation 3 1-tert-Butyl 4-ethyl 5-(3-aminophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0068] To a solution suspension of K2CO3 (86.9 g, 628.8 mmol) in 1,4-dioxane (609 mL) was added (3-aminophenyl)boronic acid (CAS No.30418-59-8, 25.9 g, 189 mmol) and the mixture was heated to 75 ºC under nitrogen for 15 min. To this mixture was added a solution of 1-tert-butyl 4-ethyl 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine- 1,4-dicarboxylate (87 g, 157.2 mmol) in 1,4-dioxane (174 mL) followed by the addition Pd(dppf)Cl2 (2.30 g, 3.144 mmol). The mixture was then heated to 95 ºC for 45 min. The mixture was allowed to cool down to RT and was diluted with EtOAc (500 mL). The mixture was the filtered over a pad of diatomaceous earth, and the pad was washed with EtOAc. The filtrate was concentrated, dissolved in EtOAc and washed twice with water and saturated aqueous NaCl. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in hexanes to give a pale-yellow solid, which was triturated with MTBE/Hexane (1:1, 200 mL) and sonicated. The solid was filtered, washed with hexane, and dried in 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 O1-tert-Butyl O4- ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate, KF as base, and Pd(PPh₃)₄ as catalyst, purified by silica gel chromatography using a gradient of 17-25% EtOAc in petroleum ether. Preparation 4 Cis-1-(tert-butyl) 4-ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, Isomer 1, and Isomer 2)

[0070] To a solution of 1-tert-butyl 4-ethyl 5-(3-aminophenyl)-3,6-dihydro-2H-pyridine-1,4- dicarboxylate (42 g, 121.2 mmol) in MeOH (606 mL) was added palladium (10% on charcoal, 121.2 mmol, 12.90 g) and the mixture was mixed under 110 psi of hydrogen pressure and RT for 18 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the plug washed with further MeOH and EtOH. The filtrate was concentrated under vacuum, and the residue was purified by filtration through a silica plug (EtOAc as eluant) and dried for several days at RT under vacuum to give the racemic mixture of the title compound as a pale-pink solid (40.69 g, 96.32%). 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 20% solvent B in solvent A; flow rate: 250 g/min) to give Isomer 1 (first-eluting isomer, 1.15 g) and Isomer 2 (second-eluting isomer, 1.15 g). Preparation 5 Trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, Isomer 1, and Isomer 2)

[0072] A solution of cis-1-(tert-Butyl) 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (racemic mixture, 10 g, 28.70 mmol) in EtOH (5.74 mL) was stirred at RT. Sodium ethoxide in EtOH (2 equiv., 57.41 mmol, 21 mass%, 18.60 g) was added and the mixture heated at 80 °C for about 48 h. The mixture was then cooled to RT, and H2O (29 mL) was added and the mixture refluxed for additional 2 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc and quenched with 5% aqueous citric acid until pH = 4. The layers were separated, and the organics dried over Na2SO4, filtered, and concentrated under vacuum. The crude was purified by reversed-phase chromatography using a gradient of 0 to 60% ACN in aqueous NH₄CO₃ (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 (Isomer 1 and 2) were prepared in a manner essentially as described above, using Isomer 1 and Isomer 2 of starting cis-1-(tert-Butyl) 4-ethyl 3-(3- aminophenyl)piperidine-1,4-dicarboxylate, respectively. Preparation 6 Trans-1-tert-butoxycarbonyl-3-[3-(prop-2-ynoylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0074] A solution of propiolic acid (75 µL, 85 mg, 1.12 mmol) in DCM (4.75 mL) was added to DCC (0.2376 g, 1.140 mmol) and the mixture was stirred for 10 minutes. 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 drop wise and the mixture stirred at RT for 1.5 h. Then after 10 min, slowly, additional solution of propiolic acid (75 µL, 85 mg, 1.12 mmol) and DCC (0.2376 g, 1.140 mmol) in DCM (4.75 mL) was added and the mixture allowed to react for about 1 h. The mixture was extracted with acid water (H2O with few drops of HCl 1M until pH =4) and a white solid was obtained. The solid was filtered. Then organic layer was separated, dried with Na₂SO₄ and the solvent evaporated by N₂ flush. The crude was dissolved in DMSO and purified using a HLB cartridge, then by reversed-phase chromatography to give the title product as a pale-yellow solid (0.152 g, 41%). ES/MS m/z: 317 (M-tert- butyl+H). Preparation 7 Trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methyl-phenyl)piperazin-1- yl]methyl]triazol-1-yl]phenyl]piperidine-4-carboxylic acid (Isomer 2)

[0075] A flow reactor setup was used to prepare the title compound. Three solutions were prepared: • Solution A: 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 RT was added azidotrimethylsilane, (0.62 g, 0.72 mL, 5.2 mmol). • Solution B: tert-Butyl nitrite (0.54 g, 0.63 mL, 5.2 mmol) was added to DMF (17 mL). • Solution C: 1-(3-chloro-4-methylphenyl)-4-(prop-2-yn-1-yl)piperazine (1.3 g, 5.2 mmol) was added to DMF (17 mL). [0076] Approximately one-fifth of the total volume of Solutions A and B were pumped together through a 2 mL PTFE reactor (Flow rate A: 0.074 ml/min, Flow rate B: 0.088 mL/min, 12 min residence time) at 80 °C. Approximately one-fifth of the total volume of Solution C was then added to the eluent at a flow rate of 0.088 mL/min in a 10 mL copper reactor (40 min residence time) at 120 °C. The eluent pool was diluted with EtOAc, washed with saturated aqueous NH₄Cl, water, and saturated NaCl. The organics were dried over Na₂SO₄, filtered, and concentrated. The residue was passed through a silica gel cartridge eluting with 10% MeOH in 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). Preparation 8 Trans-1-tert-Butoxycarbonyl-3-[3-[3-(1H-indol-3-yl)propanoylamino]phenyl]piperidine-4- carboxylic acid (racemic mixture)

[0077] To a solution of 3-indolepropionic acid (213 mg, 1.12 mmol) in DCM (4.72 mL) was added DCC (193 mg, 0.9363 mmol) and DMAP (137 mg, 1.12 mmol). The mixture was stirred at RT 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 RT. The crude was diluted with MeOH, filtered through diatomaceous earth and concentrated to dryness. The residue was purified by reversed phase chromatography using a gradient of 0 to 60% ACN in aqueous NH4CO3 (pH 9) to give the title compound as a colorless oil (0.242 g, 46%). ES/MS m/z: 436 [M+H-tBu]. Preparation 9 1-(3-methoxyphenyl)imidazolidin-2-one [0078] A mixture of copper (I) iodide (81 mg, 0.427 mmol), potassium phosphate tribasic (1.81g, 8.546 mmol), N,N'-dimethylethylenediamine (0.2 g, 2 mmol), imidazolidin-2-one (3.67 g, 42.73 mmol), and 1-iodo-3-methoxy-benzene (1 g, 4.273 mmol) in DMF (0.5 mL) was stirred at 120 ºC. The reaction was cooled down to RT, diluted with EtOAc and filtered through a 5 g diatomaceous earth cartridge. The solution obtained was washed with H2O, aqueous NH4OH, and saturated aqueous NaCl. The organic layer was separated, dried on MgSO₄, and evaporated in vacuum. The crude was purified by silica gel chromatogrpahy (20 to 100% EtOAc in hexanes) to give the title compound (0.319 g, 37%) as a white solid. ES-MS m/z 193 (M+H) Preparation 10 Trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, Isomer 1, Isomer 2)

[0079] To a solution of cis-1-(tert-butyl) 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (racemic mixture, 100 g, 287 mmol, 1.00 eq) in EtOH (1.5 L) was added sodium methanolate (190 g, 2.8 mol, 9.7 eq) in one portion and stirred at 80 °C for 15 h. The mixture was cooled to 25 °C and concentrated in 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 (89 g, 255 mmol, 44% yield) as a yellow solid. ES-MS m/z 249 (M-BOC+H). [0080] 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 in CO2) to give Isomer 1 (first-eluting isomer, 34.9 g, >98% ee) and Isomer 2 (second-eluting isomer, 35.5 g, >98% ee). Preparation 11 Trans-1-tert-butyl 4-ethyl 3-(3-iodophenyl)piperidine-1,4-dicarboxylate (Isomer 1)

[0081] A mixture of tetrabutylammonium iodide (4.8 g, 13.0 mmol) and trans-1-tert-butyl 4- ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (Isomer 1, 1.5 g, 4.31 mmol) along with p- toulenesulfonic acid (1 g, 5.1 mmol) was dissolved in dry ACN (45 mL). Then, cupric bromide (45 mg, 0.20 mmol) and tert-butyl nitrite (600 µL, 520 mg, 5.04 mmol) were added, and the final reaction mixture stirred at RT for 5 min. Next, it was heated at 70 ºC for 16-18 h. The reaction was then poured into H₂O and extracted with diethyl ether. The organics were 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 dense brown oil. ES/MS m/z 404 (M-tBu+H) Preparation 12 Trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4-carboxylic acid (Isomer 1)

[0082] Trans-1-tert-butyl 4-ethyl 3-(3-iodophenyl)piperidine-1,4-dicarboxylate (Isomer 1, 1.28 g, 2.79 mmol) was purged under N2, and absolute EtOH (15 mL) and H2O were added. Lithium hydroxide (201 mg, 8.39 mmol) was then added to the solution and the final reaction mixture heated at 70º C for about 6 h. The reaction mixture was concentrated to remove EtOH and the resulting mixture was poured into H2O and added 1M HCl (8.5 mL), and then extracted (2x) with DCM. The combined organics were washed with H2O, dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (1.14 g, 99%) as a pale-yellow foam, which was triturated to give the title compound as a powder. ES/MS m/z 376 (M-tBu+H) Preparation 13 Trans-1-tert-Butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidin-1- yl]phenyl]piperidine-4-carboxylic acid (Isomer 1)

[0083] A solution of trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4- carboxylic acid (Isomer 1, 150 mg, 0.3478 mmol), 1-(3-methoxyphenyl)imidazolidin-2-one (73.5 mg, 0.3826 mmol), tBuXPhos-Pd-G3 (28 mg., 0.03478 mmol), sodium tert-butoxide (100 mg, 1.043 mmol) in 1,4-dioxane (3.5 mL) under N2 was stirred at 100 ºC for 16-18 h. The reaction mixture was diluted with water and filtered through a diatomaceous earth cartridge then the solution extracted with EtOAc. Compound was isolated by extraction with EtOAc after acidification with HCl 1N of the aqueous layer then purified using silica gel eluting with EtOAc to give the title compound (0.12 g, 70%) as an off-white solid. ES/MS m/z: 396 (M-BOC+H) Preparation 14 Trans-1-tert-Butoxycarbonyl-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid (Isomer 2)

[0084] 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) at RT was added isocyanatocyclopropane (131 mg, 1.573 mmol) and the mixture was stirred at RT for about 2 h. NaOH (1 N) was added, and the crude extracted with EtOAc and the organic fraction discarded. pH was adjusted with HCl (1 N), and the final compound 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) Preparation 15 Trans-1-tert-butyl 4-ethyl 3-[3-(prop-2-ynylamino)phenyl]piperidine-1,4-dicarboxylate (racemic mixture)

[0085] Trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (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 mass% in toluene, 108.0 mg, 0.7262 mmol) were added. The mixture was stirred at RT for 16-18 h. H2O was added to the mixture and the aqueous layer extracted with EtOAc. Organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica-gel chromatography using a gradient of EtOAc in hexanes (10-40%) to give the title compound (0.09 g, 34%) as a yellow oil. ES/MS m/z 331 (M-tBu+H). Preparation 16 Trans-1-tert-butoxycarbonyl-3-[3-(prop-2-ynylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0086] To a solution of trans-1-tert-butyl 4-ethyl 3-[3-(prop-2-ynylamino)phenyl]piperidine- 1,4-dicarboxylate (racemic mixture, 90 mg, 0.2329 mmol) in MeOH (1.4 mL) and THF (3 mL) was added NaOH in H₂O (0.7 mL, 1 mmol, 2 M). The mixture was stirred at RT for about 36 h. Citric acid (5% in water) was added until pH=4. The aqueous layer was extracted with EtOAc (3x). Organic layer was separated and dried over Na2SO4. The residue was purified by reverse phase chromatography (H₂O-MeCN 10-40%). Desired fractions were combined and then solvent removed under vacuum, then dried under vacuum at 40 ºC to give the title compound (70 mg, 84%) as a yellow solid. ES/MS m/z: 303 (M-tert-butyl+H) Preparation 17 Trans-3-[3-(benzylcarbamoylamino)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid

[0087] The title compound was prepared essentially as described in Preparation 14 using 4- chlorophenethyl isocyanate, purified by reverse phase flash chromatography using a gradient of 0-40% ACN in aqueous NH₄CO₃ (pH 9). ES/MS m/z: 402 (M-BOC+H). Preparation 18 Trans-1-tert-butoxycarbonyl-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4- carboxylic acid (Isomer 2)

[0088] The title compound was prepared essentially as described in Preparation 7 using prop-2-ynoxybenzene, purified by silica gel chromatography using acetone in hexanes as the eluent. ES-MS m/z 479 (M+H). Preparation 19 Trans-1-tert-Butyl 4-ethyl 3-[3-[(4-phenylpiperidine-1-carbonyl)amino]phenyl]piperidine-1,4- dicarboxylate (Isomer 1)

[0089] To a RT solution of trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (Isomer 1, 0.217 g, 0.6228 mmol) in CHCl₃ (6 mL) at RT was added triphosgene (1 equiv., 0.6228 mmol) and TEA (3 equiv., 1.869 mmol). The mixture was stirred at RT for 15 min. Solvent was evaporated under vacuum and the residue was suspended in THF followed by addition of 4-phenylpiperidine (3 equiv., 1.869 mmol) and stirring continued at RT for about 1 h. 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 was purified by silica gel chromatography eluting with EtOAc in hexanes (25 to 100% in 10 CV). The desired fractions were collected and evaporated under vacuum to give the title compound (0.307 g, 92%) as a colorless oil. ES/MS m/z 436 (M-BOC+H) Preparation 20 Trans-1-tert-butoxycarbonyl-3-[3-[((1-methyltriazol-4-yl)methyl)amino]phenyl]piperidine-4- carboxylic acid (racemic mixture)

[0090] A solution of trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (racemic mixture, 100 mg, 0.31 mmol) in DCM (2 mL) was added 1-methyl-1H- 1,2,3-triazole-4-carbaldehyde (34 mg, 0.31 mmol) and sodium sulfate (220 mg, 1.55 mmol). The mixture was stirred at RT for 3 h, and then sodium triacetoxyborohydride (197 mg, 0.93 mmol) was added. The resulting mixture was stirred at RT for 16-18 h. The reaction mixture was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified using reversed-phase flash chromatography (mobile phase: 10-60% ACN in aqueous NH₄CO₃ (pH 9). The mixture was further purified using reverse phase chromatography to give the title compound (34.2 mg, 25%). ES/MS m/z: 416 [M+H]. Preparation 21 Trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]-1-tert-butoxycarbonyl-piperidine-4- carboxylic acid (racemic mixture)

[0091] To a solution of trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (racemic mixture, 0.06 g, 0.19 mmol) in pyridine (1 mL, 12.4 mmol) was added a catalytic amount of DMAP and 4-(benzyloxy)benzene-1-sulfonyl chloride (0.28 mmol). The reactions were stirred at RT for about 1 h. The solvent was evaporated in vacuum and the residue was extracted EtOAc, HCl 1N (3 mL each). Organic layer was separated, dried on 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-tBu+H). [0092] The following preparations were prepared essentially as described in Preparation 21 using the corresponding sulfonyl chloride.

Table 1 Prep. # Name Structure ES-MS m/z 22 Trans-1-tert-butoxycarbonyl- 493 (M- 3-[3-[3-(4- tBu+H). methoxyphenoxy)propylsulfo nylamino]phenyl]piperidine- 4-carboxylic acid (racemic mixture) 23 Trans-1-tert-Butoxycarbonyl- 509 (M- 3-[3-[(5-chloro-3-methyl- tBu+H) benzothiophen-2- yl)sulfonylamino]phenyl]pipe ridine-4-carboxylic acid (racemic mixture)

24 Trans-1-tert-butoxycarbonyl- 487 (M-H) 3-[3-(2- phenylethylsulfonylamino)ph enyl]piperidine-4-carboxylic acid (Isomer 2)^a Starting amine used: trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (Isomer 2) Preparation 25 Trans-1-tert-Butyl 4-ethyl 3-[3-[[3,5- bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1)

[0093] The title compound was prepared essentially as described in Preparation 14 using 3,5-bis(trifluoromethyl)phenyl isocyanate and trans-1-tert-butyl 4-ethyl 3-(3- aminophenyl)piperidine-1,4-dicarboxylate (Isomer 1), purified by silica gel chromatography using a gradient of 0 to 40% EtOAc in hexanes. ES/MS m/z: 564 [M-(CO₂Et)+H₃O⁺] Preparation 26 Trans-3-[3-[[3,5-Bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]-1-tert-butoxycarbonyl- piperidine-4-carboxylic acid (Isomer 1) [0094] NaOH (0.205 g, 5.12 mmol) and H₂O (1 mL) were added to a solution of trans-1- tert-butyl 4-ethyl 3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-1,4- dicarboxylate (Isomer 1, 0.56 g, 0.92 mmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 80 ºC for 2.5 h. The reaction mixture was allowed to cool to RT. The mixture was acidified with aq. sol. HCl (1M) 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]⁺. Preparation 27 Trans-1-tert-butoxycarbonyl-3-[3-[((4-phenylphenyl)methyl)amino]phenyl]piperidine-4- carboxylic acid (racemic mixture)

[0095] The title compound was prepared essentially as described in Preparation 20 using 4- phenylbenzaldehyde. ES/MS m/z: 431 [M+1-tBu]. Preparation 28 Trans-1-tert-butoxycarbonyl-3-[3-[[2-(2-naphthyl)acetyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0096] 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) was added N,N-diisopropylethylamine (78mg, 0.60 mmol). The mixture was stirred at RT for 10 min and then, 2-(2-naphthyl)acetyl chloride (34 mg, 0.165 mmol) was added. The resulting mixture was stirred at RT for 16-18 h. Additional N,N-diisopropylethylamine and 2-(2-naphthyl)acetyl chloride was added and the resulting mixture stirred at RT for 16-18 h. The mixture was diluted with MeOH, concentrated under vacuum to dryness and the residue was purified by reversed-phase flash chromatography using a gradient of 10 to 60% ACN in aqueous NH₄CO₃ (pH 9) to give the title compound (14 mg, 17%) as a pale-yellow oil. ES/MS m/z: 433 [M+1-tBu]. Preparation 29 1-tert-Butyl 4-ethyl 5-(3-cyanophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0097] To a suspension of potassium carbonate (136 g, 979 mmol) in 1,4-dioxane (813 mL) and H2O (41 mL) was added (3-cyanophenyl)boronic acid (43.17 g, 293.8 mmol) and the mixture heated to 50-60 ºC under N₂ for 15 min. To this mixture was added a solution of 1-tert-butyl 4- ethyl 5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4- dicarboxylate (35.5 g, 244.5 mmol) in 1,4-dioxane (271 mL) followed by the addition of Pd(dppf)Cl₂ (3.66 g, 4.90 mmol). The mixture was then heated at 95 ºC for 2 h, under N₂. The solvent was evaporated to dryness and H₂O (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 gradient of 10 to 30% EtOAc in hexanes to give the title compound (66 g, 75,63%) as a yellow oil. ES/MS m/z: 301 (M-tBu+H). Preparation 30 Cis-1-tert-butyl 4-ethyl 3-[3-(aminomethyl)phenyl]piperidine-1,4-dicarboxylate (racemic mixture, Isomer 1, and Isomer 2)

[0098] To a 2L parr reactor was added: 1-tert-butyl 4-ethyl 5-(3-cyanophenyl)-3,6-dihydro- 2H-pyridine-1,4-dicarboxylate (66 g, 185.2 mmol), THF (330 mL), EtOH (330 mL), TEA (741 mmol, 103 mL, 75.0 g), palladium (10% on charcoal, 50 wt% H2O, 185.2 mmol, 19.7 g) and the mixture fitted with hydrogen at 300 psi overnight. The mixture was filtered to remove the catalyst and the reaction solvent was evaporated to dryness. The crude material was purified by silica gel chromatography using a gradient of 0 to 40% EtOH in EtOAc to give the racemic mixture of the title compound (41 g, 61%) 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 in CO₂; flow rate 5 mL/min) to give Isomer 1 (first- eluting isomer, 15.64 g, >96% ee) and Isomer 2 (second-eluting isomer, 13.27 g, >96% ee). Preparation 31 Trans-3-[3-(aminomethyl)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (racemic mixture)

[0100] A mixture of cis-1-tert-butyl 4-ethyl 3-[3-(aminomethyl)phenyl]piperidine-1,4- dicarboxylate (racemic mixture, 5 g, 13.8 mmol), sodium methoxide (30 mass% in MeOH, 69.0 mmol), and MeOH (69 mL) was heated at 90 °C over 2 days. The reaction solvent was evaporated and HCl (1 N) was added until pH of the mixture reached 7-8. A 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 saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (2.8 g, 82 mass% purity, 50% yield). ES/MS m/z: 335 [M+H]. Preparation 32 Trans-1-tert-butoxycarbonyl-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4- carboxylic acid (racemic mixture)

[0101] 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) was added NaOH (1M aqueous, 0.36 mL) and the mixture was agitated for 24 h at RT, then reaction solvent was evaporated under N2 atmosphere. The residue was taken up in a minimal amount of MeOH, then loaded onto an SCX cartridge (5g), which was eluted with MeOH and the eluent discarded. Eluted, collected, and concentrated 2 M NH₃ in MeOH, then the residue was purified by reversed-phase HPLC to give the title compound (27 mg, 30%). ES- MS m/z 444 (M-tBu+H). Preparation 33 Trans-1-tert-butoxycarbonyl-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine- 4-carboxylic acid (racemic mixture)

[0102] The title compound was prepared essentially as described in Preparation 32 using 3 phenoxybenzenesulfonyl chloride. ES-MS m/z 467 (M-BOC+H). Preparation 34 2-[4-[2-(2-Bromoethoxy)ethoxymethyl]phenyl]pyridine

[0103] To a stirred solution of [4-(2-pyridyl)phenyl]methanol (0.2 g, 1.080 mmol) in DMF (2.5 g) was added sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol) at 0 ºC under N₂. The mixture was allowed to warm to RT 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 allowed to react at RT for 16 h. H₂O was added and the mixture was extracted with EtOAc, the organic layer dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel using 0 to 25% EtOAc in hexanes to give the title compound (0.14 g, 39%) as a colorless oil. ES-MS m/z 336 (M+H). Preparation 35 Trans-1-tert-butyl 4-ethyl 3-(3-bromophenyl)piperidine-1,4-dicarboxylate (Isomer 1)

[0104] A mixture of trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (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 dry ACN (30 mL). Then, cupric bromide (0.287 mmol, 0.0648 g) and tert-butyl nitrite (3.73 mmol, 0.385 g) were added and the final reaction mixture stirred at RT. The reaction was poured into water and extracted with EtOAc. The organics were further washed with water, dried over NaSO₄, evaporated under vacuum. The crude residue was purified by silica gel chromatography using a gradient of 10% to 50% EtOAc in hexanes to give the title compound (0.775 g, 64%) as a yellow dense oil. ES-MS m/z 356, 358 (M-tBu+H) Preparation 36 Trans-1-tert-Butyl 4-ethyl 3-(3-formylphenyl)piperidine-1,4-dicarboxylate (Isomer 1)

[0105] Trans-1-tert-butyl 4-ethyl 3-(3-bromophenyl)piperidine-1,4-dicarboxylate (Isomer 1, 775 mg, 1.88 mmol), butyldi-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) were charged to a reaction vessel with stir bar, purged with N2 and the vessel was pressurized with CO/H21:1. The gas was vented and repressurized to 70 psi three times. The mixture was stirred at a temperature of 100 °C for 16-18 h. The vessel was pressurized again with CO/H₂1:1, the gas was vented and repressurized to 70 psi three times. The reaction was stirred at 100 °C for 24-36 h. Reaction was cooled to RT and the crude was diluted with EtOAc and filtered over diatomaceous earth. The filtrate was concentrated under vacuum and the residue partitioned between EtOAc and HCl (1 N). The organic layer was separated, washed twice with saturated aqueous NaCl and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc in 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) Preparation 37 Trans-1-tert-Butyl 4-ethyl 3-[3-(hydroxymethyl)phenyl]piperidine-1,4-dicarboxylate (Isomer 1)

[0106] To a 0 ºC solution of trans-1-tert-Butyl 4-ethyl 3-(3-formylphenyl)piperidine-1,4- dicarboxylate (Isomer 1, 0.601 g, 1.66 mmol) in EtOH (10 mL) was added sodium borohydride (1.2 equiv, 0.0755 g) and the reaction was stirred for 16 h. The solvent was removed, and the residue extracted from EtOAc and H₂O. The organic layer was separated, washed with saturated aqueous NaCl (2x) and evaporated under vacuum to give the title compound (0.3 g, 50%) as a colorless oil.1H NMR (400 MHz, 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, 4.4 Hz, 1H), 1.49 (s, 9H), 1.01 (t, J= 7.2 Hz, 3H). Preparation 38 Trans-1-tert-Butyl 4-ethyl 3-[3-[2-[2-[[4-(2- pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-1,4-dicarboxylate (Isomer1)

[0107] To a stirred solution of trans-1-tert-butyl 4-ethyl 3-[3- (hydroxymethyl)phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 0.1 g, 0.275 mmol) in DMF (0.7 mL) was added sodium hydride (60% in mineral oil, 0.33 mmol, 0.013 g) at 0 ºC under N₂. This mixture was allowed to warm to RT and stirred for 30 min. The resulting suspension was added via syringe over 10 minutes to a solution of 2-[4-[2-(2- bromoethoxy)ethoxymethyl]phenyl]pyridine (0.4128 mmol, 0.1388 g) in DMF (0.6 mL) allowing to react at RT for 16 h. H2O was added and the mixture was extracted with EtOAc. The aqueous phase was acidified with HCl (1 N) until pH = 6, and then extracted with EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated in vacuum. The compound was purified twice via silica gel chromatography, first using a gradient of 0-8% MeOH in DCM and then using a gradient of 0-6% MeOH in DCM to give the title compound. ES/MS m/z: 619 (M+H). Preparation 39 Trans-1-tert-butoxycarbonyl-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4- carboxylic acid (Isomer 2) [0108] To a solution of trans-1-tert-butoxycarbonyl-3-[3-(2- phenylethylsulfonylamino)phenyl]piperidine-4-carboxylic acid (Isomer 2, 154 mg, 0.32 mmol) in THF (3 mL) was added sodium hydride (60 mass% in mineral oil, 0.79 mmol). The reaction was stirred at 0 °C for 15 min, then iodomethane (0.79 mmol) was added and the reaction was allowed to warm up to RT overnight. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO₄, filterd, and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography using a gradient of 30-60% ACN in aqueous NH4HCO3 (pH9), and then again by reversed-phase HPLC to give 52 mg (33%) of the title compound as a yellow oil. ES-MS m/z 447 (M-tBu+H). Preparation 40 Trans-1-(tert-butyl) 4-ethyl 3-(3-(2-oxooxazolidin-3-yl)phenyl)piperidine-1,4-dicarboxylate (Isomer 1)

[0109] A solution of trans-1-tert-butyl 4-ethyl 3-(3-bromophenyl)piperidine-1,4- dicarboxylate (Isomer 1, 210 mg, 0.5093 mmol), oxazolidin-2-one (0.1331 g, 1.528 mmol), tBuXPhos-Pd-G3 (00.04046 g, 0.05093 mmol) and sodium tert-butoxide (0.1514 g, 1.528 mmol) in 1,4-dioxane (5 mL) was stirred under N₂ at 100 ºC for about 16-24 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and concentrated in vacuum to dryness. The crude was purified using an HLB cartridge (6 gr load) using a gradient of 0-75% ACN in NH₄HCO₃ (pH 9) to give the title product as a pale-yellow solid (170 mg). ES/MS m/z: 363 [M+H-tBu]. Preparation 41 Trans-1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidin-1-ylpyridine-2- carbonyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0110] The title compound was prepared essentially as described in Preparation 8 using 6- pyrrolidin-1-ylpyridine-2-carboxylic acid. ES-MS m/z 495 (M+H). Preparation 42 Trans-1-tert-Butyl 4-ethyl 3-[3-[[3-[(4-chlorophenyl)methyl]imidazole-4- carbonyl]amino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1)

[0111] The title compound was prepared essentially as described in Preparation 8 using trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (Isomer 1) and (3-[(4- chlorophenyl)methyl]imidazole-4-carboxylic acid), purified using an HLB cartridge eluting with a gradient of 10-100% ACN in water, then purified by reversed-phase HPLC. ES-MS m/z 567 (M+H). Preparation 43 Trans-1-tert-butyl 4-ethyl 3-[3-[(3-methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4- dicarboxylate (Isomer 1) [0112] The title compound was prepared essentially as described in Preparation 15 using trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4-dicarboxylate (Isomer 1) and 1- isocyanato-3-methoxy-benzene, purified by silica gel chromatography using a gradient of 0 to 10% DCM in hexanes. ES-MS m/z 398 (M-BOC+H). Preparation 44 Trans-1-(tert-butyl) 4-ethyl 3-(3-(3-(3-methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine- 1,4-dicarboxylate (Isomer 1)

[0113] To a solution of trans-1-tert-butyl 4-ethyl 3-[3-[(3- methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 150 mg, 0.301 mmol) in THF (3 mL) was added sodium hydride (60 mass% in mineral oil, 0.663 mmol) and the mixture stirred at RT for 30 min. Then iodomethane (1.507 mmol) was added and stirring continued for about 2 h. The mixture was extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl (3x), dried on MgSO4 and the solvent evaporated under vacuum. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexane to give the title product as (0.147 g, 89%) as a colorless oil. ES/MS m/z 526 (M+H). Preparation 45 Methyl 2-[3-(2-methoxyethoxy)phenyl]acetate [0114] 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. Then, acetone (70 mL) was added followed by 1-bromo-2-methoxy-ethane (2.11 g, 1.45 mL, 15.2 mmol) and the reaction mixture was heated at 60º C under nitrogen atmosphere. After 5 h more 1-bromo-2-methoxy-ethane (0.37 g, 0.25 mL, 2.62 mmol) was added and the reaction was kept overnight heating at 60 ºC. After 16 h, the solvent was evaporated and the residue was dissolved in diethyl ether/water. After separation, the organics were further washed with water, dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (2.15 g, 95%) as a light pale yellow oil. ES-MS m/z 242 (M+H2O)⁺. Preparation 46 2-[3-(2-Methoxyethoxy)phenyl]ethanol

[0115] A solution of methyl 2-[3-(2-methoxyethoxy)phenyl]acetate (2.15 g, 9.6 mmol) in dry THF (50 mL) was cooled down with ice/water bath, under nitrogen atmosphere. Then, diisobutylaluminum hydride (1 M, 26 mL, 26 mmol) was added and the final reaction mixture was kept stirring in the bath. After 3 h, the solvents were evaporated and the residue was slowly poured into 1M HCl. Once the gas evolved, EtOAc was added and the mixture was shaken. After separation, the organics were washed with water, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by silica gel chromatography using 2% MeOH in DCM to give the title compound (1.29 g, 69%) as a light brown oil. ES-MS m/z 197 (M+H). Preparation 47 Trans-1-tert-Butoxycarbonyl-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4- carboxylic acid (Isomer 1) [0116] A mixture of trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4-carboxylic acid (Isomer 1, 438 mg, 1.02 mmol), N,N-dimethylglycine hydrochloride (29 mg, 0.20 mmol), copper (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 was added (it also worked as solvent), and the reaction mixture was stirred at 105 ºC for 22.5 h. The reaction mixture was dissolved in water and EtOAc. Next, 1M HCl (7 ml) was added and the mixture was shaken. The layers were separated and the organics were further washed with water, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using 25% EtOAc in DCM, then a second silica gel chromatography was performed using a gradient of 0- 25% EtOAc in DCM. The product was then purified by reversed-phase chromatography to give 51 mg (10% of the title compound as a pale yellow oil. ES-MS m/z 444 (M-tBu+H). Preparation 48 Trans-1-tert-Butyl 4-ethyl 3-[3-[[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3- piperidyl]phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1)

[0117] A solution of trans-1-tert-butyl 4-ethyl 3-(3-aminophenyl)piperidine-1,4- dicarboxylate (Isomer 1, 350 mg, 1.01 mmol) and 1,1'-carbonyldiimidazole (0.502 mmol) in THF (10 mL) was stirred at RT for 24 h. The reaction was then heated at 70 ºC with stirring for 24 h. 1,1'-Carbonyldiimidazole (0.251 mmol) was added and stirring and heating continued at reflux temperature for approximately 4 h. Then reaction was again heated to 70 ºC and stirred for 36 h. HCl (1N) was added and the compound was extracted with EtOAc. Organic layer was separated, dried on MgSO₄ and evaporated in vacuum. The residue was purified by silica gel chromatography eluting with DCM in hexene (gradient from 0 to 50%) to give the title compound as a white solid (0.144 g, 20%). ES/MS m/z: 623 (M-BOC+H). Preparation 49 Ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-1-methyl-3-piperidyl]anilino]phenyl]-1-methyl- piperidine-4-carboxylate (Isomer 1)

[0118] To a suspension of ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-3- piperidyl]anilino]phenyl]piperidine-4-carboxylate (Isomer 1, 90 mg, 0.188 mmol) in MeOH (2 mL) was added paraformaldehyde (87 mg, 0.94 mmol), and the resulting mixture was stirred at RT for 15 min. Sodium triacetoxyborohydride (199 mg, 0.938 mmol) was then added and the mixture was stirred at RT for 16 h. More paraformaldehyde (87 mg, 0.94 mmol) and sodium triacetoxyborohydride (199 mg, 0.938 mmol) were added and the mixture was heated to 50 °C for 16 h. The reaction solvent was removed under a stream of N₂ and the residue was purified by reversed-phase flash chromatography using a gradient of 0-100% ACN in aqueous NH₄HCO₃ (10 mM, pH9) to give the title compound (75 mg, 76%) as a pale yellow oil. ES-MS m/z 508 (M+H). Preparation 50 1-tert-Butyl 4-ethyl trans-3-[3-[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3- piperidyl]anilino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1)

[0119] A solution of trans-1-tert-butyl 4-ethyl 3-(3-bromophenyl)piperidine-1,4- dicarboxylate (Isomer 1, 350 mg, 0.85 mmol), trans-1-tert-butyl 4-ethyl 3-(3- aminophenyl)piperidine-1,4-dicarboxylate (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 for 16-18 h. under N₂ atm at 110 ºC. The mixture was filtered through diatomaceous earth and concentrated under vacuum to dryness. The residue was purified by silica gel chromatography using a gradient of 0-95% EtOAc in hexanes to give the title compound as a pale-yellow solid (399 mg, 69%). ES/MS m/z 580 (M-BOC+H). Preparation 51 Ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-3-piperidyl]anilino]phenyl]piperidine-4-carboxylate (Isomer 1)

[0120] HCl (2 M in ether, 5.88 mmol, 2.9 mL) was added to a solution of 1-tert-Butyl 4- ethyl trans-3-[3-[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3- piperidyl]anilino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 0.4 g, 0.59 mmol) in DCM (2 mL). The mixture was allowed to react at RT for 16 h. After 16 h, the solvent was removed under N₂ stream. The compound was dissolved in MeOH, loaded onto an SCX cartridge (10g), and eluted with MeOH and then with MeOH/NH3 (2N). The mixture MeOH/NH3 wash was then concentrated under vacuum to give the title product as a pale-yellow oil (0.182 g, 65%). ES-MS m/z 480 (M+H). Example 1 Trans-3-[3-(prop-2-ynoylamino)phenyl]piperidine-4-carboxylic acid;2,2,2-trifluoroacetic acid (racemic mixture) [0121] Trans-1-tert-butoxycarbonyl-3-[3-(prop-2-ynoylamino)phenyl]piperidine-4- carboxylic acid (racemic mixture, 0.1026 g, 0.2755 mmol) was added in DCM (1.05 mL), and the mixture stirred until the reactant was completely dissolved at 0 ºC. Then, TFA (203 µL, 0.273 mmol) was added and the mixture stirred at 0 ºC, at RT for 1 h. The solvent was evaporated by N₂ flush and dried in a vacuum oven to give the title compound (0.1142 g, quantitative yield) as a yellow solid. ES/MS m/z: 273 (M+H). Example 2 Trans-3-[3-[4-[[4-(3-chloro-4-methyl-phenyl)piperazin-1-yl]methyl]triazol-1- yl]phenyl]piperidine-4-carboxylic acid;dihydrochloride (Isomer 2)

[0122] Trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methyl-phenyl)piperazin-1- yl]methyl]triazol-1-yl]phenyl]piperidine-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 RT for 1 h. The solvent was removed under N₂ and dried under vacuum at 40 ºC for 16-18 h to give the title compound (9 mg, quantitative yield) as a white solid. ES-MS m/z 495 (M+H). Example 3a Trans-3-[3-[3-(1H-indol-3-yl)propanoylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture) [0123] A solution of trans-1-tert-butoxycarbonyl-3-[3-[3-(1H-indol-3- yl)propanoylamino]phenyl]piperidine-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 RT for about 1 h. The reaction mixture was concentrated to dryness in vacuum. The crude was purified using a 5 g SCX cartridge which was conditioned with MeOH. The residue was dissolved in MeOH and loaded into the cartridge, eluted with MeOH and then NH3/MeOH (2 N). The NH3/MeOH washings were concentrated to dryness in vacuum to give the title product (0.0402 g, 32%) as a pale-yellow solid. ES/MS m/z: 392 [M+H-Cl]. Example 3 Trans-3-[3-[3-(1H-Indol-3-yl)propanoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0124] A solution of trans-3-[3-[3-(1H-indol-3-yl)propanoylamino]phenyl]piperidine-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 RT for about 2 h. The reaction mixture was concentrated to dryness under vacuum. The solid obtained 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 RT for 1 h. Then the reaction mixture was concentrated to dryness under vacuum. The solid obtained 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]. Example 4 Trans-3-[3-[3-(3-Methoxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 1)

[0125] The title compound was prepared essentially as described in Example 2 using trans- 1-tert-butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]piperidine-4- carboxylic acid (Isomer 1). ES-MS m/z 396 (M+H). Example 5 Trans-3-[3-(Cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 2)

[0126] 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). Example 6 Trans-3-[3-(prop-2-ynylamino)phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0127] 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). Example 7 Trans-3-[3-[2-(4-chlorophenyl)ethylcarbamoylamino]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 2)

[0128] 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). Example 8 Trans-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 2)

[0129] 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). Example 9 Trans-3-[3-[(4-phenylpiperidine-1-carbonyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 1) [0130] To a solution of trans-1-tert-Butyl 4-ethyl 3-[3-[(4-phenylpiperidine-1- carbonyl)amino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 0.307 g, 0.5731 mmol) in THF (6 mL) at RT was added LiOH (1M in H2O, 6 mL, 6 mmol) and a few drops of MeOH. The mixture was stirred at 50 ºC for 16-18 h. HCl (1 N) was added, and the compound 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) and HCl (4 M in 1,4- dioxane, 2 mL, 8 mmol) was added and allowed to react for 2 h. The reaction solvent was evaporated in vacuum to afford a beige solid. The solid was sonicated in MTBE/DCM, filtered, and dried in vacuum to give the title compound (0.14 g, 55%) as a white solid. ES/MS m/z: 408 (M+H). [0131] The following table shows examples which were prepared in 2 steps: Step 1 – using the procedure essentially as described in Preparation 14, trans-3-(3-aminophenyl)- 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (Isomer 2) was reacted with the appropriate isocyanate. Upon completion, the reactions were concentrated and purified on a HLB cartridge eluted with aqueous NH4HCO3 (20 mM, pH 9), then ACN. The products were then purified via SCX cartridge eluted first with MeOH, discarding the MeOH eluent, then eluting, collecting, and concentrating 2 M NH3 in MeOH. The products were further purified by reversed-phase chromatography to give the BOC-protected intermediate. Step 2 – using the procedure essentially as described in Example 2, the BOC-protected intermediate prepared in Step 1 was converted to the listed example compounds. Table 2 Example Name Structure ES-MS number m/z 10 Trans-3-[3-[2-(2- 374 thienyl)ethylcarbamoyla (M+H) mino]phenyl]piperidine- 4-carboxylic acid;hydrochloride (Isomer 2) 11 Trans-3-[3-((m- 368 tolylmethyl)carbamoyla (M+H) mino)phenyl]piperidine- 4-carboxylic acid;hydrochloride (Isomer 2) Example 12 Trans-3-[3-[(3-methoxyazetidine-1-carbonyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 1)

[0132] The title compound was prepared in two steps. Step 1 – the procedure essentially as described in Preparation 19 was used with 3-methoxyazetidine. Step 2 – the procedure essentially as described in Example 9 was used with the product from Step 1 to give the title compound. ES/MS m/z: 334 (M+H). Example 13 Trans-3-[3-[((1-methyltriazol-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0133] 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]. Example 14 Trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0134] 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). Example 15 Trans-3-[3-[3-(4-methoxyphenoxy)propylsulfonylamino]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture) [0135] 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). Example 16 Trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 1)

[0136] The title compound was prepared essentially as described in Example 2 using trans- 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]. Example 17 Trans-3-[3-[((4-phenylphenyl)methyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0137] 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]. Example 18 Trans-3-(3-(2-(naphthalen-2-yl)acetamido)phenyl)piperidine-4-carboxylic acid hydrochloride (racemic mixture)

[0138] 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]. Example 19 Trans-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0139] 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 (racemic mixture). ES-MS m/z 400 (M+H). Example 20 Trans-3-[3-[[(3-Phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture) [0140] 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). Example 21 Trans-3-[3-[2-[2-[[4-(2-Pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-4- carboxylic acid;hydrochloride (Isomer 1)

[0141] To a solution of trans-1-tert-Butyl 4-ethyl 3-[3-[2-[2-[[4-(2- pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 0.042 g, 0.0543 mmol, 80 mass%) in DCM (2 mL), HCl (4 M in 1,4-dioxane, 3.258 mmol, 0.608 g) was added, allowing to react at RT for 16 h. The solvent was removed and the mixture was taken up in water and loaded onto an SCX cartridge. The cartridge was eluted with MeOH and the eluent was discarded. Eluted, collected, and concentrated 2M NH3 in MeOH. The residue was dissolved in MeOH (0.5 mL) and NaOH (2 M in water, 0.14 mL) was added and allowed to to react at RT for 16 h. The solvent was removed. Water was added and acidified until pH 5, then was extracted with EtOAc (x4). The organic layers were combined and concentrated under vacuum. The residue was purified by reverse phase flash chromatograpy using a gradient of 10- 100% ACN in aqueous NH₄HCO₃ (10 mM, pH9). The product was dissolved in HCl (1 M, 2 mL) and stirred at RT for 16 h. 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). Example 22 Trans-3-[3-[(5-chloro-3-methyl-benzothiophen-2-yl)sulfonylamino]phenyl]piperidine-4- carboxylic acid;hydrochloride (racemic mixture)

[0142] The title compound was prepared essentially as described in Example 2 using trans- 1-tert-butoxycarbonyl-3-[3-[(5-chloro-3-methyl-benzothiophen-2- yl)sulfonylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES-MS m/z 465 (M+H). Example 23 Trans-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 2)

[0143] 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) Example 24 Trans-3-(3-aminophenyl)piperidine-4-carboxylic acid;hydrochloride (Isomer 2)

[0144] 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). Example 25 Trans-3-(3-((2-Hydroxyethyl)amino)phenyl)piperidine-4-carboxylic acid hydrochloride (Isomer

[0145] To a solution of trans-1-(tert-butyl) 4-ethyl 3-(3-(2-oxooxazolidin-3- yl)phenyl)piperidine-1,4-dicarboxylate (Isomer 1, 188 mg, 0.45 mmol) in MeOH (4 mL) and THF (4 mL) was added NaOH (1 M aqueous, 4.5 mmol, 4.5 mL). The resulting mixture was stirred at 50 °C for about 16-24 h. The mixture was concentrated in vacuum to dryness. The crude was dissolved in EtOAc and neutralized with HCl (0.5 M) to pH 4, extracted with EtOAc (3X), and washed with saturated aqueous NaCl (2X). The organics were dried over MgSO4, filtered, and concentrated in vacuum to dryness. The residue was dissolved in ACN/H₂O and purified using an SCX cartridge (25 gr load). The SCX cartridge was first conditioned eluting with ACN twice and then mixture was loaded onto the cartridge, eluted with ACN and NH3/MeOH (2 N). The NH3/MeOH washings were concentrated to dryness and the solid obtained 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 RT for 5 h, then the mixture was concentrated to dryness in vacuum. The solid obtained was washed with MTBE, filtered and dried under vacuum to give the title product as a brown solid (119 mg, 88%) ES/MS m/z: 265 [M+1]. Example 26 Trans-3-[3-[[7-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carbonyl]amino]phenyl]piperidine- 4-carboxylic acid;hydrochloride (Isomer 1) [0146] The title compound was prepared in two steps. Step 1 – the procedure essentially as described in Preparation 19 was used with 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline. Step 2 – the procedure essentially as described in Example 9 was used with the product from Step 1 to give the title compound. ES/MS m/z: 448 [M+H] Example 27 Trans-3-[3-[[2-(Chloromethyl)-3-methoxy-propyl]carbamoylamino]phenyl]piperidine-4- carboxylic acid;hydrochloride (Isomer 1)

[0147] The title compound was prepared in two steps. Step 1 – the procedure essentially as described in Preparation 19 was used with 3-(methoxymethyl)azetidine hydrochloride. Step 2 – the procedure essentially as described in Example 9 was used with the product from Step 1, which under the reaction conditions gave the ring-opened title compound. ES/MS m/z: 482 [M- H]. Example 28 Trans-3-[3-[(6-pyrrolidin-1-ylpyridine-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid;hydrochloride (racemic mixture)

[0148] The title compound was prepared essentially as described in Example 2 using trans- 1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidin-1-ylpyridine-2-carbonyl)amino]phenyl]piperidine-4- carboxylic acid (racemic mixture). ES-MS m/z 395 (M+H). Example 29 Trans-3-[3-[[3-[(4-chlorophenyl)methyl]imidazole-4-carbonyl]amino]phenyl]piperidine-4- carboxylic acid;hydrochloride (Isomer 1)

[0149] The title compound was prepared essentially as described in Example 9 using trans- 1-tert-butyl 4-ethyl 3-[3-[[3-[(4-chlorophenyl)methyl]imidazole-4- carbonyl]amino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1). ES-MS m/z 439 (M+H). Example 30 Trans-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)phenyl)piperidine-4-carboxylic acid hydrochloride (Isomer 1)

[0150] The title compound was prepared in two steps: Step 1: the procedure essentially as described in Preparation 13 was carried out using 1- methylimidazolidin-2-one, purified using an HLB cartridge eluting with a gradient of 0 to 100% ACN in aqueous NH4HCO3 (pH9). Step 2: The BOC group in the product from Step 1 was removed essentially as described in Example 2 to give the title compound. ES/MS m/z = 304 [M+H]. Example 31 Trans-3-(3-(3-(3-Methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine-4-carboxylic acid hydrochloride (Isomer 1)

[0151] The title compound was prepared essentially as described in Example 9 using trans- 1-(tert-butyl) 4-ethyl 3-(3-(3-(3-methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine-1,4- dicarboxylate (Isomer 1). ES/MS m/z 398 (M+H). Example 32 Trans-3-[3-[2-[3-(2-Methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid;hydrochloride (Isomer 1)

[0152] The title compound was prepared essentially as described in Example 2 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). Example 33 Trans-3-[3-[[3-[trans-4-carboxy-3-piperidyl]phenyl]carbamoylamino]phenyl]piperidine-4- carboxylic acid;dihydrochloride (Isomer 1)

[0153] A solution of trans-1-tert-Butyl 4-ethyl 3-[3-[[3-[trans-1-tert-butoxycarbonyl-4- ethoxycarbonyl-3-piperidyl]phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (Isomer 1, 144 mg, 0.199 mmol) in THF (10 mL) was added LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH. The reaction was stirred at RT for 24 h. HCl (1N) was then added and the compound extracted with EtOAc. Organic layer was separated, dried on MgSO4 and evaporated under vacuum. The residue was taken up in THF (10 mL) and LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH were added, and the mixture stirred for 36 h at RT. HCl (1N) was added and the compound extracted with EtOAc. Organic layer was separated, dried on MgSO4 and evaporated in vacuum. The solid obtained was dissolved in DCM (2 mL) and HCl (2 M in Et2O, 4 mL, 8 mmol) was added. The reaction was stirred at RT for 16-18 h. The solvent was evaporated in vacuum and the residue co-evaporated with water to remove residual solvents to give the title compound as a white powder (0.077 g, 72%). ES/MS m/z: 467 (M+H). Example 34 Trans-3-[3-[3-[trans-4-carboxy-1-methyl-3-piperidyl]anilino]phenyl]-1-methyl-piperidine-4- carboxylic acid;dihydrochloride (Isomer 1)

[0154] To a solution of ethyl trans-3-[3-[3-[trans-4-ethoxycarbonyl-1-methyl-3- piperidyl]anilino]phenyl]-1-methyl-piperidine-4-carboxylate (Isomer 1) (75 mg, 0.148 mmol) in THF (0.74 mL) and MeOH (0.30 mL), NaOH (2 M aqueous, 0.67 mL, 1.33 mmol) and the mixture was stirred at 50 ºC for 16 h, then the solvent was concentrated. The residue was purified by reverse phase flash chromatography using a gradient of 0 to 100% ACN in aqueous NH4HCO3 (10 mM, pH9). The product was HCl (1 N) and stirred at RT 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). Example 35 Trans-3-[3-[3-[trans-4-carboxy-3-piperidyl]anilino]phenyl]piperidine-4-carboxylic acid;dihydrochloride (Isomer 1) [0155] NaOH (1.877 mmol, 2 M) was added to a solution of ethyl trans-3-[3-[3-[trans-4- ethoxycarbonyl-3-piperidyl]anilino]phenyl]piperidine-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 ºC for 16 h, then the solvent was concentrated under vacuum. The residue was purified by reverse phase flash chromatography using a gradient of 0-100% ACN in aqueous NH₄HCO₃ (10 mM, pH9). The product was then dissolved in HCl (1 N) and stirred at RT for 30 min. The solvent was removed under vacuum and dried under vacuum to give the title compound as a pale green solid (0.099 mg, 96%). ES/MS m/z 424 (M+H). In vitro Lp(a) Assembly Assay [0156] The ability of compounds to inhibit the formation of Lp(a) particles in vitro was assessed by a cell-free assembly assay. Conditioned media (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin/streptomycin) was collected from confluent wild-type HepG2 cells (a source of endogenously expressed ApoB) and from a HEK293 stable cell line expressing human Apo(a) protein containing 17 Kringle repeats (selected on 1 mg/ml geneticin) after 24 h of culture at 37 °C and 5% CO2. An in vitro assembly assay was conducted by combining equal parts of HepG2 and HEK293 conditioned media with the test compounds added in dilution series (final concentration 0.01~100 nM). The reaction was incubated at 37 °C for 2 h and then stopped with the addition of 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with an anti-Lp(a) capture antibody and an HRP -conjugated anti-ApoB detection antibody. The ELISA was developed using TMB, stopped using 1 N sulfuric acid, and the signal was read at 450 nm on a Molecular Devices plate reader. The % inhibition of Lp(a) formed for each test condition was determined with an assembly reaction having no inhibitor present (with matched DMSO concentration at 1%) set to 0% inhibition, and an assembly reaction with a minimal amount of the HepG2 conditioned media present (50-fold dilution) set to 100% inhibition. Data were fitted to a 4-parameter curve to determine the IC50 values summarized in Table 3. Addition of the Example test compound to conditioned media containing ApoB and Apo(a) lead to concentration-dependent inhibition of Lp(a) formation in vitro, as summarized in Table 3. The results indicate that these compounds inhibit the assembly of Lp(a) from Apo(a) and the LDL particle. Table 4 Example IC50 nM (SEM, n) 1 4.05 (0.426, n = 3) 2 10.8 (n = 1) 3 13 (2.2, n = 5) 4 6.9 (n = 1) 5 18.6 (3.31, n = 2) 6 20.6 (0.773, n = 3) 7 25 (4.21, n = 3) 8 42.8 (8.81, n = 2) 9 48 (n = 1) 10 51.2 (8.75, n = 2) 11 64.2 (21.2, n = 2) 12 70.5 (n = 1) 13 76.2 (16.5, n = 4) 14 116 (24.4, n = 2) 15 123 (17.4, n = 2) 16 127 (28.3, n = 2) 17 130 (19.4, n = 3) 18 161 (29.5, n = 2) 19 179 (11.5, n = 2) 20 190 (32.7, n = 2) 21 72.9 (10.5, n = 4) 22 181 (9.33, n = 2) 23 188 (21, n = 2) 24 206 (29.4, n = 2) 25 224 (24.8, n = 2) 26 228 (57.1, n = 3) 27 575 (n = 1) 28 236 (57.1, n = 2) 29 417 (143, n = 2) 30 254 (n = 1) 31 309 (50.1, n = 3) 32 709 (n = 1)

Claims

CLAIMS We claim: 1. A compound of the formula:

wherein R¹ is H or CH3; Q¹ is -(CH2)nNR¹⁵(CH2)nR¹⁰, -B(OR¹⁰)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNR¹⁵CONR¹⁵(CH2)nR¹⁰, -(CH2)nNR¹⁵CO(CH2)nR¹⁰, -O(CH2)nR¹⁰, -(CH2)nNR¹⁵SO2(CH2)nR¹⁰, -(CH2)nO(CH2)pO(CH2)nR¹⁰, - (CH₂)_nO(CH₂)_pO(CH₂)_pO(CH₂)_nR¹⁰, NH₂, -NHCONH₂,

Q² is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is at each occurrence independently 0, 1, 2, or 3; R¹⁰ is selected from: halo; C_1-4 alkyl optionally substituted with one to four OH or with OCH₃; C_3-6 cycloalkyl optionally substituted with one or two halo; C1-4 haloalkyl optionally substituted with OCH3; C2-6 alkynyl; NH₂; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH₂)phenyl or (CH₂)_mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C_1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C_1-4 alkoxy, C_1-4 alkyl, CF₃, CN, OCF₃, -OCH₂CH₂OCH₃, phenoxy, pyridine, or -OCH₂phenyl or -(CH₂)_nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; p is 1, 2, 3, 4 or 5; and R¹⁵ is H or C_1-3 alkyl, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R¹ is H, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or claim 2, wherein Q² is H, or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of claims 1 to 4, wherein Q¹ is -(CH₂)_nNR¹⁵(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵CONR¹⁵(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵CO(CH₂)_nR¹⁰, -O(CH2)nR¹⁰, -(CH2)nNR¹⁵SO2(CH2)nR¹⁰, -(CH2)nO(CH2)pO(CH2)pO(CH2)nR¹⁰, NH2, C1-4 alkyl optionally substituted with one to four OH; C3-6 cycloalkyl; C_1-4 haloalkyl optionally substituted with OCH₃; C2-6 alkynyl; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF3; phenoxy; 4- or 6- membered heterocycle optionally substituted with OCH3 or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH₃; 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4 alkyl, halo, pyrrolidine, or benzyl, wherein the benzyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4 alkoxy, C1-4 alkyl, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl or -(CH₂)_nphenyl; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, wherein R¹⁰ is selected from: CH3; CH2OH; cyclopropyl; CH2CH(CH2Cl)CH2OCH3; ethynyl; naphthyl; 3,4-dihydro-2H-1λ2- quinoline substituted with CF₃; phenoxy; piperazine, piperidine or azetidine, wherein the piperazine, piperidine or azetidine is optionally substituted OCH3 or phenyl, wherein the phenyl 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 is substituted with Cl; and phenyl optionally substituted with one or two substituents independently selected from: Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl or phenyl, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, wherein R¹⁰ is selected from: cyclopropyl, ethynyl, phenoxy, piperazine substituted with phenyl wherein the phenyl is substituted with Cl and CH₃, piperidine substituted with phenyl, azetidine substituted with OCH3, indole, thiophene, pyrazole substituted with CH3, phenyl substituted with OCH3, Cl or CH3, or a pharmaceutically acceptable salt thereof. 11. A compound of the formula:

wherein R^1a is H, CH3 or a protecting group; X is OH or C_1-4 alkoxy; Q¹ is -(CH₂)_nNR¹⁵(CH₂)_nR¹⁰, -B(OR¹⁰)_2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNR¹⁵CONR¹⁵(CH2)nR¹⁰, -(CH2)nNR¹⁵CO(CH2)nR¹⁰, -O(CH₂)_nR¹⁰, -(CH₂)_nNR¹⁵SO₂(CH₂)_nR¹⁰, -(CH₂)_nO(CH₂)_pO(CH₂)_nR¹⁰, - (CH2)nO(CH2)pO(CH2)pO(CH2)nR¹⁰, NH2, -NHCONH2,

Q² is H, C_1-4 alkyl, cyclopropyl, CF₃, OH, C_1-4 alkoxy, O-cyclopropyl, OCF₃, halo, or CN; n is at each occurrence independently 0, 1, 2, or 3; R¹⁰ is selected from: halo; C_1-4 alkyl optionally substituted with one to four OH or with OCH₃; C3-6 cycloalkyl optionally substituted with one or two halo; C_1-4 haloalkyl optionally substituted with OCH₃; C_2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ²-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH₂)phenyl or (CH₂)_mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C_1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C_1-4 alkoxy, C_1-4 alkyl, CF₃, CN, OCF₃, -OCH₂CH₂OCH₃, phenoxy, pyridine, or -OCH₂phenyl or -(CH₂)_nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; p is 1, 2, 3, 4 or 5; and R¹⁵ is H or C_1-3 alkyl, or a salt thereof, wherein if X is OH then R^1a must be a protecting group. 12. The compound according to claim 11 wherein R^1a is a protecting group and the protecting group is selected from: tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide, or a salt thereof. 13. Use of a compound, or a salt thereof, according to claim 11 or claim 12 in the preparation of an oligomer. 14. An oligomer prepared from a compound, or a salt thereof, of claim 11 or claim 12. 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: R¹ is at each occurrence independently H or CH₃;

p is at each occurrence independently 0 or 1; Q³ is at each occurrence independently H, C_1-4 alkyl, cyclopropyl, CF₃, OH, C_1-4 alkoxy, O- cyclopropyl, OCF3, halo, or CN; L² is C1-3 alkylene or a bond; or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 17, wherein Q³ is H, or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 17 or claim 18, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 20. The compound according to any one of claims 17 to 19, wherein L is -(CH2)pNHC(O)NH(CH2)p- or -(CH2)pNH(CH2)p-, or a pharmaceutically acceptable salt thereof. 21. The compound according to claim 20, wherein L is -NHC(O)-, or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 20, wherein L is -NH-, or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10 or 17 to 22 and at least one pharmaceutically acceptable carrier, diluent, or excipient. 24. A method of treating cardiovascular disease in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof. 25. A method of treating elevated Lp(a) plasma levels in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof. 26. A compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof, for use in therapy. 27. A compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. 28. A compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated Lp(a) plasma levels.