Piperidine compounds having Lp(a)-reducing activity

Abstract

This disclosure provides compounds of formula: and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising these compounds, and their use in the treatment of cardiovascular disease and elevated Lp(a) plasma levels. [Formula 1] TIFF2026524960000122.tif53128

Description

[Technical Field]

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

[0002] There have been remarkable advances in the treatment of cardiovascular disease (CVD). Despite these advances, patients continue to experience cardiovascular events such as angina, myocardial infarction, and stroke, which can be fatal if left untreated. Dyslipidemia remains a major risk factor for CVD. Dyslipidemia can be divided into four common risk factors: elevated low-density lipoprotein cholesterol (LDL-c), decreased high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated Lp(a). There are various treatment regimens targeting high LDL-c, low HDL-c, and high triglycerides. There are few approved treatment options for patients with high Lp(a) levels. In some cases, apheresis can be used to filter the blood and remove LDL and Lp(a), however, its effect is temporary and typically needs to be repeated every two weeks. Currently, there are no approved drug treatments specifically for lowering Lp(a) levels.

[0003] Lp(a) is a genetically determined, independent cardiovascular risk factor. Elevated serum Lp(a) levels exceeding 50 mg / dL or 125 nmol / L, found in approximately 20% of the population, result in at least a 1.6-fold increased risk of the first cardiovascular event (Kronenberg, F. Clin. Res. Cardiol. Suppl. 14, 5-12 (2019)) and a more than 1.42-fold increased risk of the second event (Madsen, C et al. Arterioscler. Thromb. Vasc. Biol. 40, 255-266 (2020)). Lp(a) can exhibit both prothrombinogenic and antithrombotic properties, as well as both atherogenic and atherothrombotic properties. Lp(a) inhibits fibrinolysis and can accumulate in the vascular wall, inducing thrombus formation and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially among individuals. Unlike other risk factors, Lp(a) plasma levels are not significantly altered by diet and exercise.

[0004] Lp(a) is similar to LDL-c in that it contains an LDL lipid core with an associated apolipoprotein B (apoB), but unlike LDL-c, Lp(a) contains its own apolipoprotein (a) (apo(a)) bound to apoB via a disulfide bond. apo(a) is synthesized in the liver. Aggregations of apo(a) and Lp(a) from LDL particles can occur in hepatocytes, on the cell wall, or in plasma. Inhibition of LDL particle aggregation with apo(a) lowers Lp(a) levels.

[0005] International Publication No. 2020 / 247429 discloses compounds that inhibit Lp(a) formation by blocking the interaction between Apo(a) and ApoB.

[0006] Additional treatment options are desired for patients suffering from cardiovascular diseases, particularly for patients suffering from dyslipidemia or lipid abnormalities. Additional treatment options are needed for patients in whom cardiovascular risk is not adequately managed using current standard treatments, such as diet therapy, exercise, and / or the use of one or more drugs such as statins, fibrates, niacin. More particularly, there is a need for further alternative pharmaceutically acceptable compounds that inhibit the formation of Lp(a) and thus lower plasma Lp(a) levels. SUMMARY OF THE INVENTION

[0007] Thus, in a first aspect, a compound of formula I, wherein

[0008]

Chemical formula

[0009] [ka] and; Q 2 However, H, C 1~4 Alkyl, cyclopropyl, CF3, OH, C 1~4 It is an alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is independently 0, 1, 2, or 3 at each occurrence; R 10 but, Hello; C is optionally substituted with 1 to 4 OH groups or with OCH3 groups. 1~4 alkyl; C is optionally replaced with one or two halos. 3~6 Cycloalkyl; C is optionally substituted with OCH3. 1~4 Haloalkyl; C 2~6 Alkinnil; NH2; Naphthyl; 3,4-dihydro-2H-1λ is optionally substituted with CF3. 2 -Quinoline; Phenoxy selected to be substituted with methoxy; O CH3, C 1~4 Alkyl, (CH2)pyridine, O(CH2)phenyl, or (CH2) m A 4, 5, or 6-membered heterocycle optionally substituted with phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from halo and CH3; C 1~4Five- or six-membered heteroaryls or nine- or ten-membered bicyclic heteroaryls optionally substituted with one or two substituents selected from alkyl, halo, pyrrolidine, benzyl, or phenyl, wherein the benzyl or phenyl is optionally substituted with a halo; and Hello, C 1~4 Alkoxy, C 1~4 Alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or -(CH2) n Phenyl is optionally substituted with 1 to 3 substituents independently selected from phenyl, wherein the phenyl is optionally substituted with 1 or 2 halos; m is 0 or 1; p is 1, 2, 3, 4, or 5; R 15 However, H or C 1~3 Alkyl compounds, Or a pharmaceutically acceptable salt thereof is provided.

[0010] In the second embodiment, the compound is of formula II,

[0011] [ka] During the ceremony, R 1a However, it is H, CH3, or a protecting group; X is OH or C 1~4 It is an alkoxy; Q 1 However, -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, ethylene glycol boronic acid, pinacol boronic acid, propylene-1,3-diol boronic acid, 2,2-dimethylpropylene-1,3-diol boronic acid, -(CH2) n NR 15 CONR15 (CH2) n R 10 ,-(CH2) n NR 15 CO(CH2) n R 、10 -O(CH2) n R 、10 -(CH2) n NR 15 SO2(CH2) n R 10 ,-(CH2) n O(CH2) p O(CH2) n R 10 ,-(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 NH2, -NHCONH2,

[0012] [ka] and; Q 2 However, H, C 1~4 Alkyl, cyclopropyl, CF3, OH, C 1~4 It is an alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is independently 0, 1, 2, or 3 at each occurrence; R 10 but, Hello; C is optionally substituted with 1 to 4 OH groups or with OCH3 groups. 1~4 alkyl; C is optionally replaced with one or two halos. 3~6 Cycloalkyl; C is optionally substituted with OCH3. 1~4 Haloalkyl; C 2~6 Alkinnil; NH2; Naphthyl; 3,4-dihydro-2H-1λ is optionally substituted with CF3. 2 -Quinoline; Phenoxy optionally substituted with methoxy; OCH3, C 1~4 Alkyl, (CH2)pyridine, O(CH2)phenyl, or (CH2) m A 4-, 5-, or 6-membered heterocycle optionally substituted with phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents selected from halo and CH3; C 1~4 A 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with 1 or 2 substituents selected from alkyl, halo, pyrrolidine, or benzyl, or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and Halo, C 1~4 Alkoxy, C 1~4 Alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or -(CH2) n Phenyl optionally substituted with 1 to 3 substituents independently selected from phenyl, wherein the phenyl is optionally substituted with 1 or 2 halos; m is 0 or 1; p is 1, 2, 3, 4, or 5; R 15 Is H or C 1~3 Alkyl, a compound, Or a salt thereof (when X is OH, R 1a Must be a protecting group) is provided.[[ID=3」]]

[0013] 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.

[0014] In a fourth aspect, there is provided an oligomer prepared from a compound of formula II or a salt thereof. In one embodiment, the oligomer comprises at least two piperidine moieties. In another embodiment, the oligomer comprises at least three piperidine moieties.

[0015] In the fifth aspect, the compound is of formula III,

[0016] [ka] R 1 However, at each occurrence, it is independently either H or CH3; L is -(CH2) p NHC(O)NH(CH2) p -,-(CH2) p NH(CH2) p -,

[0017] [ka] and; p is either 0 or 1 independently at each occurrence; Q 3 However, at each occurrence, H and C appear independently. 1~4 Alkyl, cyclopropyl, CF3, OH, C 1~4 It is an alkoxy, O-cyclopropyl, OCF3, halo, or CN; L 2 However, C 1~3 A compound that is alkylene or bonded, Or a pharmaceutically acceptable salt thereof is provided.

[0018] In the sixth embodiment, a pharmaceutical composition is provided comprising a compound of formula I or III, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0019] A seventh aspect provides a method for treating a 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.

[0020] In the eighth aspect, a method is provided for treating an elevation of 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.

[0021] In the ninth aspect, compounds of formula I or III, or pharmaceutically acceptable salts thereof, are provided for use in therapy.

[0022] In a tenth embodiment, compounds of formula I or III, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of cardiovascular disease.

[0023] In the eleventh aspect, compounds of formula I or III, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of elevated Lp(a) plasma levels. [Modes for carrying out the invention]

[0024] In one embodiment of the compound of formula I, R 1 However, it is H.

[0025] In one embodiment of the compound of formula I, Q 2 However, it is H.

[0026] In one embodiment, the compound of formula Ia:

[0027] [ka] Or a pharmaceutically acceptable salt thereof is provided. Formula Ia encompasses Formula I, and the following references to Formula I in, for example, therapeutic methods and therapeutic uses shall also be read as references to Formula Ia.

[0028] In one embodiment of the compound of formula I, Q 1 However, -(CH2) n NR 15 (CH2) n R 10 ,-(CH2) n NR 15 CONR15 (CH2) n R 10 ,-(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 ,-(CH2) n NR 15 SO2(CH2) n R 10 ,-(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 NH2,

[0029] [ka] In a particular embodiment, Q 1 However, NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10 -NHCONH(CH2)2R 10 ,-N(CH3)CON(CH3)R 10 , -NHCOR 10 -NHCOCH2R 10 -NHCO(CH2)2R 10 CH2NHSO2R 10 , -NHSO2R 10 -O(CH2)2R 10 -NHSO2(CH2)3R 10 ,-N(CH3)SO2(CH2)2R 10 -CH2O(CH2)2O(CH2)2OCH2R 10 NH2,

[0030] [ka] In a more specific embodiment, Q 1 However, NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10-NHCONH(CH2)2R 10 , -NHCOR 10 -NHCO(CH2)2R 10 ,

[0031] [ka] That is the case.

[0032] In one embodiment of the compound of formula I, Q 1 However, -(CH2) n NR 15 (CH2) n R 10 ,-(CH2) n NR 15 CONR 15 (CH2) n R 10 ,-(CH2) n NR 15 CO(CH2) n R 10 -O(CH2) n R 10 ,-(CH2) n NR 15 SO2(CH2) n R 10 ,-(CH2) n O(CH2) p O(CH2) p O(CH2) n R 10 ,

[0033] [ka] And R 10 but, C is optionally substituted with 1 to 4 OH groups. 1~4 alkyl; C 3~6 Cycloalkyl; C is optionally substituted with OCH3. 1~4 Haloalkyl; C 2~6 Alkinnil; Naphthyl; 3,4-dihydro-2H-1λ is optionally substituted with CF3. 2 -Quinoline; Phenoxy; A 4- or 6-membered heterocycle optionally substituted with OCH3 or CH2m phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from halo and CH3; C 1~4 A 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from alkyl, halo, pyrrolidine, or benzyl, wherein the benzyl is optionally substituted with halo; and Hello, C 1~4 Alkoxy, C 1~4 Alkyl, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or -(CH2) n Selected from phenyl molecules optionally substituted with 1 to 3 substituents independently selected from phenyl. Preferably, R 10 but, CH3;CH2OH;cyclopropyl;CH2CH(CH2Cl)CH2OCH3;ethinyl;naphthyl, 3,4-dihydro-2H-1λ2-quinoline substituted with CF3;phenoxy; Piperazine, piperidine, or azetidine, wherein the piperazine, piperidine, or azetidine is optionally substituted with OCH3 or phenyl, and the phenyl is optionally substituted with one or two substituents optionally selected from Cl and CH3; Indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is optionally substituted with one or two substituents selected from CH3, Cl, pyrrolidine, or benzyl, and benzyl is substituted with Cl; and Selected from Cl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2 phenyl, or phenyl optionally substituted with one or two substituents independently selected from phenyl. More preferably, R 10 but, Cyclopropyl, ethinyl, phenoxy; A piperazine substituted with phenyl, wherein the phenyl is substituted with Cl and CH3; Phenyl-substituted piperidine; Azetidine substituted with OCH3; Indole; Thiofen; CH3-substituted pyrazole; Selected from OCH3, Cl, or phenyl substituted with CH3.

[0034] In one embodiment, the compound is of formula Ia, wherein, Q 1 However, NHCH2R 10 -NHCONHR 10 NHCONHCH2R 10 -NHCONH(CH2)2R 10 ,-N(CH3)CON(CH3)R 10 , -NHCOR 10 -NHCOCH2R 10 -NHCO(CH2)2R 10 CH2NHSO2R 10 , -NHSO2R 10 -O(CH2)2R 10 -NHSO2(CH2)3R 10 ,-N(CH3)SO2(CH2)2R 10 -CH2O(CH2)2O(CH2)2OCH2R 10 NH2,

[0035] [ka] and; R 10 but, CH3;CH2OH;cyclopropyl;CH2CH(CH2Cl)CH2OCH3;ethinyl;naphthyl, 3,4-dihydro-2H-1λ2-quinoline substituted with CF3;phenoxy; Piperazine, piperidine, or azetidine, wherein the piperazine, piperidine, or azetidine is optionally substituted with OCH3 or phenyl, and the phenyl is optionally substituted with one or two substituents optionally selected from Cl and CH3; Indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is optionally substituted with one or two substituents selected from CH3, Cl, pyrrolidine, or benzyl, and benzyl is substituted with Cl; and A compound of formula Ia, or a pharmaceutically acceptable salt thereof, selected from phenylCl, OCH3, CH3, CF3, CN, -OCH2CH2OCH3, phenoxy, pyridine, -OCH2phenyl, or phenyl optionally substituted with one or two substituents independently selected from phenyl.

[0036] In one embodiment, the compound of formula I is

[0037] [ka]

[0038] [ka]

[0039] [ka] It is a salt selected from or pharmaceutically acceptable thereof.

[0040] In one embodiment of the compound of formula II, R1a However, the protecting group is selected from tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide. In certain embodiments, R 1a However, it is tert-butyloxycarbonyl.

[0041] In one embodiment of the compound of formula III, Q 3 However, it is H.

[0042] In one embodiment, a compound of formula IIIa:

[0043] [ka] Or a pharmaceutically acceptable salt thereof is provided. Formula III encompasses Formula IIIa, and the following references to Formula III in, for example, therapeutic methods and therapeutic uses shall also be read as references to Formula IIIa.

[0044] In one embodiment of the compound of formula III, L is -(CH2) p NHC(O)NH(CH2) p - or - (CH2) p NH(CH2) p -. In certain embodiments, L is -NHC(O)-. In alternative embodiments, L is -NH-.

[0045] In one embodiment, the compound of formula III is

[0046] [ka] It is a salt selected from or pharmaceutically acceptable thereof.

[0047] In one embodiment, a method is provided for treating a patient requiring treatment for cardiovascular disease, comprising administering an effective amount of a compound of formula I or III, or a pharmaceutically acceptable salt thereof. In another embodiment, a method is provided for treating a patient requiring 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.

[0048] In one embodiment, compounds of formula I or III, or pharmaceutically acceptable salts thereof, are provided for use in therapy.

[0049] In one embodiment, a compound of formula I or III, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cardiovascular disease. In another embodiment, a compound of formula I or III, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of elevated Lp(a) plasma levels.

[0050] In one embodiment, the use of a compound of formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of cardiovascular disease is provided. In another embodiment, the use of a compound of formula I or III, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of elevated Lp(a) plasma levels is provided.

[0051] The terms "halogen" or "halo" refer to fluorine, chlorine, bromine, or iodine.

[0052] "C 1~n The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to n carbon atoms. 1~4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. 1~3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, and propyl.

[0053] "C 1~3The term "alkylene" refers to a divalent linear or branched chain of C 1~3 This refers to an alkyl group.

[0054] "C 1~4 The term "haloalkyl" is defined herein as C, which is substituted with one or more halogens. 1~4 Refers to an alkyl group. 1~4 Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0055] "C 1~4 The term "alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 4 carbon atoms with terminal "O" atoms in the chain, i.e., -O (alkyl). 1~4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0056] "C 2~6 The term "alkynyl" refers to a linear or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one triple bond.

[0057] "C 3~6 The term "cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing 3 to 6 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0058] The term "heteroaryl" preferably refers to a monocyclic aromatic ring containing one or more heteroatoms selected from N, S, and O. Examples of five-membered heteroaryls include, but are not limited to, pyrazoles, triazoles, and thiazoles. Examples of six-membered heteroaryls include, but are not limited to, pyridines and pyridazines.

[0059] The term "bicyclic heteroaryl" preferably refers to a bicyclic aromatic ring containing one or more heteroatoms selected from N, S, and O. Examples of nine-membered bicyclic heteroaryls include, but are not limited to, indole, isoindole, indazole, and pyrazolopyridine. Examples of ten-membered bicyclic heteroaryls include, but are not limited to, quinoline and chromene.

[0060] The term "4, 5, or 6-membered heterocycle" refers to a 4, 5, or 6-membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine and piperidine.

[0061] As used herein, the term “elevated Lp(a) plasma levels” means Lp(a) plasma levels of approximately 50 mg / dL or higher. The compounds provided herein can be used for therapeutic purposes to lower Lp(a) plasma levels.

[0062] As used herein, the term “oligomer” means a compound having at least two piperidine moieties represented by formula I or II. As used herein, “piperidine moiety” means an optionally substituted piperidine. The piperidine moieties in the oligomer may be the same or different.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies 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 SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. In particular, compounds of formula I or III may be zwitterionic, monoacid, diacid, or triacid addition salts.

[0064] The pharmaceutical compositions of the present invention may be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable" means one or more carriers, diluents, and / or excipients that are compatible with the other components of the composition and are not pharmaceutically harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation are well known to those skilled in the art and can be found, for example, in "Remington: The Science and Practice of Pharmacy," Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012.

[0065] As used herein, the term “effective dose” refers to the dosage that is effective in treating a disorder. The effective dose for a particular patient can be determined by a skilled healthcare professional.

[0066] As used herein, the terms “to treat,” “to cure,” or “to treat” include slowing, reducing, preventing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, “to treat a cardiovascular disease” means slowing, reducing, preventing, or reversing the progression of a disease of the heart or blood vessels.

[0067] As used herein, the term “patient” refers to a mammal; preferably, the patient is a human.

[0068] The pharmaceutical composition can be formulated as tablets or capsules for oral administration, as a solution for oral administration, or as an injectable solution. In one embodiment, the composition is suitable for oral administration.

[0069] Certain abbreviations may refer to the following: "ACN" for acetonitrile, "Apo" for apolipoprotein, "BOC" for tert-butoxycarbonyl, "DCC" for N,N-dicyclohexylcarbodiimide, "DCM" for dichloromethane, "DMA" for dimethylacetamide, "DMAP" for 4-dimethylaminopyridine, "DMEA" for dimethylethanolamine, and "DMEM" for 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, "Â" refers to ethyl acetate, and "FBS" refers to fetal bovine serum. "HEC" refers to hydroxyethyl cellulose, "HEK" refers to human embryonic kidney, "HepG2" refers to human hepatocellular carcinoma cell line, "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, "HLB" refers to hydrophilic lipophilic balance, "h" refers to time, "HRP" refers to horseradish peroxidase, and "IC 50" refers to the concentration of the drug that produces 50% of the maximum possible inhibitory response for that drug, "IPA" refers to isopropyl alcohol or isopropanol, "MeCN" refers to acetonitrile, "min" refers to minutes, "MTBE" refers to methyl tert-butyl ether, "RT" refers to room temperature, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, and "TMB" refers to 3,3',5,5'-teramethylbenzidine.

[0070] Individual isomers, enantiomers, and diastereomers may be separated or divided by methods known to those skilled in the art, such as selective crystallization techniques or chiral chromatography, at any convenient point in the synthesis of the compounds listed below.

[0071] Compounds of formula I or III are readily convertible to pharmaceutically acceptable salts and can be isolated as pharmaceutically acceptable salts. Salt formation can be carried out by adding a pharmaceutically acceptable acid to form an acid addition salt, or by adding a pharmaceutically acceptable base to form a base addition salt. Salts can also be formed simultaneously with the deprotection of nitrogen or oxygen, i.e., the removal of the protecting group. Examples, reactions, and conditions for salt formation are known to those skilled in the art.

[0072] Compounds of formula I or III, or any of the illustrated formulas, or salts thereof, may be prepared by various procedures, some of which are illustrated in the following preparations and examples. The compounds or salts of the present invention may be prepared by combining specific synthesis steps of each described pathway in different ways, or by combining steps of different pathways. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0073] In the following schemes, all substituents are as previously defined unless otherwise indicated. Reagents and starting materials are readily available to those skilled in the art. Without limiting the scope of the present invention, the following schemes, preparations, and examples are provided to further illustrate the invention. Compounds of the formulas shown above, or salts thereof, can be prepared by using starting materials or intermediates having the corresponding desired stereochemical configuration.

[0074] Scheme 1

[0075] [ka]

[0076] Scheme 1 shows the preparation of key intermediates 6 and 7 used in the preparation of the compounds of the present invention. In step A, compound 1 is reacted with NaH in N,N-dimethylacetamide, followed by the addition of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-fluoride sulfonyl at 40°C, or alternatively, with TEA and trifluoromethylsulfonyl trifluoromethanesulfonic acid at -78°C, followed by heating to room temperature to obtain sulfonate compound 2. Compound 2 is then cross-coupled in step B at high temperature using a palladium catalyst and a carbonate base with either a boronic acid (3a) or a boronic acid ester (3b) to obtain coupling product 4. Next, in step C, the ring is reduced using hydrogen gas and a palladium catalyst to obtain compound 5 with cis-relative stereochemistry, and then in step D, it is epimerized in ethanol with an alkoxide base such as sodium methoxide while heating to obtain compound 6. When water is added to the reactants and heated for a long time, the ester is hydrolyzed to obtain compound 7. 2 Q is defined as in formula I or II, and 3 This is as defined in Equation III.

[0077] Scheme 2

[0078] [ka]

[0079] Scheme 2 shows the preparation of advanced intermediates used in the preparation of the compounds of the present invention. In step A, aniline compound 8 is converted to halogen 9 by using tert-butyl nitrite, sulfonic acid (methanesulfonic acid or p-toluenesulfonic acid), cupric bromide, and either tetrabutylammonium iodide or tetrabutylammonium bromide. In step B, compound 9 is carbonylated at high temperature using a 100 psi CO / H2 gas mixture, a palladium catalyst, and N,N,N',N'-tetramethylethylenediamine to obtain aldehyde 10. In step C, the aldehyde is reduced in EtOH at 0°C with sodium borohydride to obtain alcohol compound 42, which is then treated with NaH and reacted in step D with alkyl halide 11a or 11b to obtain compound 12a or 12b, respectively.

[0080] Aniline compound 8 can also be converted to azide in the presence of azidotrimethylsilane and tert-butyl nitrite, which then undergoes click chemistry with nitrile 15 to obtain 1,2,3-triazole compound 16 in step F, which can be carried out using a flow reactor.

[0081] In step E, compound 14 can also be obtained by coupling the halide 9 with the imidazolidined-2-one compound 13 using a palladium catalyst and an alkoxide base while heating in 1,4-dioxane. 2 Q is defined as in formula I or II, and 3 This is defined in Equation III. 10 n, p, and X are as defined in Equation II.

[0082] Scheme 3

[0083] [ka]

[0084] Scheme 3 shows the preparation of primary amine compound 18, and nitrile compound 17 is reduced using hydrogen gas, an amine base, a palladium catalyst, and a mixture of THF and EtOH. Q 2 Q is defined as in formula I or II, and 3 X is defined as in Equation III. X is defined as in Equation II.

[0085] Scheme 4

[0086] [ka]

[0087] Scheme 4 shows the reaction with amino intermediate 19. Amide 27 is obtained by reaction with acid chloride 20 and amine base, or by coupling with acid 21 using a coupling reagent such as DCC. Urea compound 28 is obtained by reaction of amino intermediate 19 with isocyanate 22, or alternatively, by reaction with triphosgene and amine base, followed by reaction with amine 23. Compound 29 is obtained by alkylating amino intermediate 19 with alkyl halide 24 and carbonate base, and compound 30 is obtained by reductive amination of intermediate 19 and aldehyde 25 with sodium triacetoxyborohydride. Finally, compound 31 is obtained by reacting amino intermediate 19 with sulfonyl chloride 26 using pyridine and a catalytic amount of DMAP. Optionally, R 15 Compounds 28 and 31, which are =H, can be first treated with NaH, and then methylated by adding iodomethane. 2 Q is defined as in formula I or II, and 3 This is defined in Equation III. 10 , R 15 n and X are as defined in Equation II.

[0088] Scheme 5

[0089] [ka]

[0090] Scheme 5 shows the preparation of polymerized urea compounds 32 and 33. Amino compound 19 is reacted with 1,1'-carbonyldiimidazole in THF at high temperature to obtain symmetric urea compound 32. Aniline compound 8 is coupled with aryl bromide 9 using a palladium catalyst and a carbonate base to obtain dimerized compound 33. Q 3 This is defined in Equation III. n and X are defined in Equation II.

[0091] Scheme 6

[0092] [ka]

[0093] Scheme 6 shows the final deprotection and optional methylation steps for obtaining the compounds of the present invention. In step A, compound 34 is first subjected to ester hydrolysis in the presence of a strong basic aqueous solution to obtain acid compound 35. Then, in step B, the BOC group is removed using HCl in an organic solvent, such as diethyl ether or 1,4-dioxane, to obtain 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 with HCl in an organic solvent, such as diethyl ether or 1,4-dioxane, in step C, and purified by ion exchange (SCX) to obtain a free amine. Then, in step D, the product is subjected to reductive amination with paraformaldehyde and sodium triacetoxyborohydride while heating to obtain compound 37. Subsequently, in step E, compound 38 is obtained by ester hydrolysis using a strong basic aqueous solution.

[0094] These same deprotection steps are used to obtain the polymer compound. Compound 39 undergoes de-BOC and ester hydrolysis steps (steps A and B, respectively) to obtain compound 40. Alternatively, compound 41 is obtained by BOC deprotection (step C), methylation (step D), and ester hydrolysis (step E). Q 1 and Q 2 This is as defined in formula I or II. Q 3 And L are as defined in Equation III.

[0095] Preparation 1 1-tert-butyl4-ethyl5-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0096] [ka]

[0097] To a suspension of N,N-dimethylacetamide (300 mL) of sodium hydride (60% by mass in mineral oil, 420 mmol), 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) was slowly added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. Finally, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (CAS No. 375-72-4, 116 g, 69.2 mL, 385 mmol) was added dropwise, and the mixture was stirred at room temperature and then at 40°C overnight. The reaction product was diluted with MTBE and quenched with saturated aqueous NH4Cl. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic phase was washed twice with water, followed by a saturated aqueous NaCl solution. The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using a 0-50% siRNA gradient in hexane to obtain 87 g (45%) of the title compound. ES / MSm / z498(M-tert-Bu+H)

[0098] Preparation 2 O1-tert-butylO4-ethyl5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0099] [ka]

[0100] To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (85 g, 313 mmol, 1.0 equivalent) and TEA (95 g, 94 mmol, 130 mL, 3.0 equivalents) in DCM (850 mL), trifluoromethylsulfonyl trifluoromethanesulfonic acid (132 g, 470 mmol, 77 mL, 1.5 equivalents) was added dropwise over 30 minutes at -78°C under N2 conditions, while the temperature was maintained at -78°C and the mixture was stirred for 1 hour. The mixture was then heated to 25°C and stirred for 2 hours. The reaction product was quenched with water (1 L) and extracted with DCM (1 L x 2). All organic phases were combined, washed with brine (2.5 L), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (586 g, yield 95%, purity 82%) as a dark brown liquid, which was carried over to the next step without further purification. TLC (petroleum ether: SiO₂ = 3:1 R) f = 0.24.

[0101] Preparation 3 1-tert-butyl 4-ethyl 5-(3-aminophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0102] [ka]

[0103] To a suspension of K2CO3 (86.9 g, 628.8 mmol) in 1,4-dioxane (609 mL), (3-aminophenyl)boronic acid (CAS No. 30418-59-8, 25.9 g, 189 mmol) was added, and the mixture was heated to 75°C for 15 minutes under nitrogen. To this mixture, 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) was added, followed by the addition of Pd(dppf)Cl2 (2.30 g, 3.144 mmol). The mixture was then heated to 95°C for 45 minutes. The mixture was cooled to room temperature and diluted with ELISA (500 mL). The mixture was filtered through a diatomaceous earth pad, and the pad was washed with siRNA. The filtrate was concentrated, dissolved in siRNA, and washed twice with water and saturated NaCl aqueous solution. 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 0-100% siRNA in hexane to obtain a pale yellow solid, which was pulverized with MTBE / hexane (1:1, 200 mL) and sonicated. The solid was filtered, washed with hexane, and dried under vacuum at 45°C to obtain the title compound (47 g, 86%) as a white solid. ES-MS m / z 347 (M+H).

[0104] Alternatively, the title compound was prepared in 37% yield using O1-tert-butyl O4-ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate, KF as the base, and Pd(PPh3)4 as the catalyst, and purified by silica gel chromatography using a gradient of 17-25% ethyl phosphate in petroleum ether.

[0105] Preparation 4 cis-1-tert-butyl)4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, isomer 1, and isomer 2)

[0106] [ka]

[0107] 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), palladium (10% on charcoal, 121.2 mmol, 12.90 g) was added, and the mixture was mixed at room temperature under a hydrogen pressure of 110 psi for 18 hours. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the plug was washed further with MeOH and EtOH. The filtrate was concentrated under vacuum, and the residue was purified by filtration through a silica plug (with ethyl acetate as eluent). The mixture was dried under vacuum at room temperature for several days to obtain a racemic mixture of the title compound as a pale pink solid (40.69 g, 96.32%). ES-MS m / z 293 (M-Boc).

[0108] A 3.0 g racemic mixture was purified by chiral chromatography (column: Chiralpak IC 5 × 25 cm, 5 μm; mobile phase: solvent A - CO2, solvent B - 0.2% dimethylethylamine in IPA, solvent B - 20% isocratic solvent A; flow rate: 250 g / min) to obtain isomer 1 (the first isomer to elute, 1.15 g) and isomer 2 (the second isomer to elute, 1.15 g).

[0109] Preparation 5 trans-3-(3-aminophenyl)-1-tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, isomer 1, and isomer 2)

[0110] [ka]

[0111] A solution of cis-1-(tert-butyl)4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, 10 g, 28.70 mmol) in EtOH (5.74 mL) was stirred at room temperature. Sodium ethoxide (2 equivalents, 57.41 mmol, 21% by mass, 18.60 g) was added to the EtOH, and the mixture was heated at 80°C for approximately 48 hours. The mixture was then cooled to room temperature, H2O (29 mL) was added, and the mixture was refluxed for a further 2 hours. The reaction mixture was concentrated to dryness, dissolved in ELISA, and quenched with 5% citric acid aqueous solution until pH=4. The layers were separated, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reverse-phase chromatography using a 0% to 60% ACN gradient in NH4CO3 aqueous solution (pH9) to obtain the title compound (3.1 g, 87%) as a pale yellow solid. ES / MS 265[M+H-tBu].

[0112] Optically pure enantiomas (isomers 1 and 2) were prepared using isomers 1 and 2 of the starting material cis-1-(tert-butyl)4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate, respectively, by essentially the method described above.

[0113] Preparation 6 trans-1-tert-butoxycarbonyl-3-[3-(propa-2-inoylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0114] [ka]

[0115] 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 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 dropwise, and the mixture was stirred at room temperature for 1.5 hours. After 10 minutes, further solutions of propiolic acid (75 μL, 85 mg, 1.12 mmol) and DCC (0.2376 g, 1.140 mmol) in DCM (4.75 mL) were slowly added, and the mixture was reacted for about 1 hour. The mixture was extracted with acidic water (H2O containing a few drops of 1 M HCl up to pH=4) to obtain a white solid. The solid was filtered. Next, the organic layer was separated, dried over Na2SO4, and the solvent was evaporated by N2 flash. The crude product was dissolved in DMSO, purified using an HLB cartridge, and then purified by reverse-phase chromatography to obtain the title product (0.152 g, 41%) as a pale yellow solid. ES / MS m / z: 317 (M-tert-butyl + H).

[0116] Preparation 7 trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methylphenyl)piperazine-1-yl]methyl]triazole-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 2)

[0117] [ka]

[0118] The title compound was prepared using a flow reactor. Three solutions were prepared. Solution A: 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) were prepared by adding azidotrimethylsilane (0.62 g, 0.72 mL, 5.2 mmol) at room temperature. Solution B: tert-butylnitrite (0.54 g, 0.63 mL, 5.2 mmol) was added to DMF (17 mL). Solution C: 1-(3-chloro-4-methylphenyl)-4-(propa-2-in-1-yl)piperazine (1.3 g, 5.2 mmol) was added to DMF (17 mL).

[0119] Approximately one-fifth of the total volume of solutions A and B were pumped together through a 2 mL PTFE reactor at 80°C (flow rate A: 0.074 ml / min, flow rate B: 0.088 mL / min, residence time 12 minutes). Then, approximately one-fifth of the total volume of solution C was added to the eluate at a flow rate of 0.088 mL / min in a 10 mL copper reactor at 120°C (residence time 40 minutes). The eluate pool was diluted with  and washed with saturated NH4Cl aqueous solution, water, and saturated NaCl. The organic matter was dried over Na2SO4, filtered, and concentrated. The residue was passed through silica gel eluted with 10% MeOH in DCM. The eluate was concentrated and purified by reverse-phase HPLC to obtain 9.1 mg (2%) of the title compound. ES-MS m / z 595 (M+H).

[0120] Preparation 8 trans-1-tert-butoxycarbonyl-3-[3-[3-(1H-indole-3-yl)propanoylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0121] [ka]

[0122] To a solution of 3-indolepropionic acid (213 mg, 1.12 mmol) in DCM (4.72 mL), DCC (193 mg, 0.9363 mmol) and DMAP (137 mg, 1.12 mmol) were added. The mixture was stirred at room temperature for 10 minutes, and then trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (racemic mixture, 0.3 g, 0.9363 mmol) was added. The resulting mixture was stirred at room temperature. The crude product was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness. The residue was purified by reverse-phase chromatography using a 0% to 60% ACN gradient in aqueous NH4CO3 (pH 9) to obtain the title compound (0.242 g, 46% as a colorless oil; ES / MS m / z: 436 [M+H-tBu]).

[0123] Preparation 9 1-(3-methoxyphenyl)imidazolidined-2-one

[0124] [ka]

[0125] A mixture of copper(I) iodide (81 mg, 0.427 mmol), tribasic potassium phosphate (1.81 g, 8.546 mmol), N,N'-dimethylethylenediamine (0.2 g, 2 mmol), imidazolidined-2-one (3.67 g, 42.73 mmol), and 1-iodo-3-methoxybenzene (1 g, 4.273 mmol) in DMF (0.5 mL) was stirred at 120°C. The reaction mixture was cooled to room temperature, diluted with SiO2, and filtered through 5 g of diatomaceous earth. The resulting solution was washed with H2O, NH4OH aqueous solution, and saturated NaCl aqueous solution. The organic phase was separated, dried on MgSO4, and evaporated under vacuum. The residue was purified by flash silica gel column chromatography (20-100% SiO2 / hexane) to obtain the title compound (0.319 g, 37%) as a white solid. ES-MS m / z193(M+H)

[0126] Preparation 10 Trans-1-tert-butyl4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, isomer 1, isomer 2)

[0127] [ka]

[0128] To a solution of cis-1-(tert-butyl)4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, 100 g, 287 mmol, 1.00 equivalent) in EtOH (1.5 L), sodium methanelate (190 g, 2.8 mol, 9.7 equivalents) was added all at once, and the mixture was stirred at 80°C for 15 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The crude product was washed with petroleum ether:ethyl acetate = 10:1 (0.8 L) to obtain a racemic mixture of the title compound (89 g, 255 mmol, yield 44%) as a yellow solid. ES-MS m / z 249 (M-BOC+H).

[0129] A 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 obtain isomer 1 (first eluting isomer, 34.9 g, >98% ee) and isomer 2 (second eluting isomer, 35.5 g, >98% ee).

[0130] Preparation 11 trans-1-tert-butyl4-ethyl3-(3-iodophenyl)piperidine-1,4-dicarboxylate (isomer 1)

[0131] [ka]

[0132] 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) was dissolved in dry ACN (45 mL) together with p-toluenesulfonic acid (1 g, 5.1 mmol). 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 was stirred at room temperature for 5 minutes. Next, it was heated at 70 °C for 16-18 hours. The reaction mixture was then poured into H₂O and extracted with diethyl ether. The organic matter was washed with H₂O, dried over Na₂SO₄, evaporated, and dried under vacuum. The crude residue was purified by silica gel column chromatography using DCM to obtain the title compound (1.48 g, 72%) as a dense, brownish oily substance. ES / MS m / z 404(M-tBu+H)

[0133] Preparation 12 trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4-carboxylic acid (isomer 1)

[0134] [ka]

[0135] 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 anhydrous EtOH (15 mL) and H2O were added. Then, lithium hydroxide (201 mg, 8.39 mmol) was added to the solution, and the final reaction mixture was heated at 70 °C for about 6 h. The reaction mixture was concentrated to remove EtOH, the resulting mixture was poured into H2O, 1 M HCl (8.5 mL) was added, and then it was extracted with DCM (2 times). 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)

[0136] Preparation 13 trans-1-tert-Butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 1)

[0137]

Chemical formula

[0138] A solution of trans-1-tert-butoxycarbonyl-3-(3-iodophenyl)piperidine-4-carboxylic acid (isomer 1, 150 mg, 0.3478 mmol), 1-(3-methoxyphenyl)imidazolidined-2-one (73.5 mg, 0.3826 mmol), tBuXPhos-Pd-G3 (28 mg, 0.03478 mmol), and sodium tert-butoxide (100 mg, 1.043 mmol) in 1,4-dioxane (3.5 mL) was stirred at 100°C for 16-18 hours under N2. The reaction mixture was diluted with water, filtered through a diatomaceous earth cartridge, and the solution was extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl, and the compound was isolated by extraction with ethyl acetate. The compound was then purified using silica gel that eluted with ethyl acetate to obtain the title compound (0.12 g, 70%) as a grayish-white solid. ES / MS m / z:396(M-BOC+H)

[0139] Preparation 14 trans-1-tert-butoxycarbonyl-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid (isomer 2)

[0140] [ka]

[0141] 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), isocyanatocyclopropane (131 mg, 1.573 mmol) was added at room temperature, and the mixture was stirred at room temperature for approximately 2 hours. NaOH (1 N) was added, and the crude product was extracted with ethyl acetate, discarding the organic fraction. The pH was adjusted with HCl (1 N), and the final compound was extracted with ethyl acetate. The organic layer was collected, dried over MgSO4, filtered, and concentrated to obtain the title compound (0.32 g, 99%) as a beige solid. ES / MS m / z: 304 (M-BOC+H)

[0142] Preparation 15 trans-1-tert-butyl4-ethyl3-[3-(propa-2-inylamino)phenyl]piperidine-1,4-dicarboxylate (racemic mixture)

[0143] [ka]

[0144] Trans-1-tert-butyl4-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-bromopropa-1-yin (in toluene (80% by mass, 108.0 mg, 0.7262 mmol)) were added. The mixture was stirred at room temperature for 16-18 hours. H2O was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using an ethyl acetate gradient in hexane (10-40%) to obtain the title compound (0.09 g, 34%) as a yellow oil. ES / MS m / z 331 (M-tBu+H).

[0145] Preparation 16 trans-1-tert-butoxycarbonyl-3-[3-(propa-2-inylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0146] [ka]

[0147] 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 with NaOH (0.7 mL, 1 mmol, 2M) in H2O. The mixture was stirred at room temperature for about 36 h. Citric acid (5% in water) was added to pH = 4. The aqueous layer was extracted with EtOAc (3 times). The organic layer was separated and dried over Na2SO4. The residue was purified by reverse-phase chromatography H2 in O-MeCN 10 - 40%). The desired fractions were combined, then the solvent was removed under vacuum and then dried at 40 °C under vacuum to give the title compound (70 mg, 84%) as a yellow solid. ES / MS m / z: 303 (M-tert-butyl + H)

[0148] Preparation 17 trans-3-[3-(benzylcarbamoylamino)phenyl]-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (isomer 2)

[0149]

Chemical formula

[0150] The title compound was prepared essentially as described in Preparation 14 using 4-chlorophenethyl isocyanate and 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).

[0151] Preparation 18 trans-1-tert-butoxycarbonyl-3-[3-[4-(phenoxymethyl)triazol-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 2)

[0152]

Chemical formula

[0153] The title compound was prepared using propa-2-yloxybenzene essentially as described in Preparation 7, and purified by silica gel chromatography using acetone in hexane as the eluent. ES-MS m / z 479 (M+H).

[0154] Preparation 19 trans-1-tert-butyl4-ethyl3-[3-[(4-phenylpiperidine-1-carbonyl)amino]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0155] [ka]

[0156] To a solution of trans-1-tert-butyl4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (isomer 1, 0.217 g, 0.6228 mmol) in CHCl3 (6 mL), triphosgene (1 equivalent, 0.6228 mmol) and TEA (3 equivalents, 1.869 mmol) were added at room temperature. The mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under vacuum, and the residue was suspended in THF. Subsequently, 4-phenylpiperidine (3 equivalents, 1.869 mmol) was added, and stirring was continued at room temperature for approximately 1 hour. The solvent was evaporated, and the residue was extracted with 1N HCl and DCM. The organic layer was separated, dried, and evaporated to obtain a colorless oil. The crude product was purified by silica gel chromatography eluting with siRNA (25-100% in 10 CV) in hexane. The desired fraction was collected and evaporated under vacuum to yield the title compound (0.307 g, 92%) as a colorless oil. ES / MS m / z 436(M-BOC+H)

[0157] Preparation 20 trans-1-tert-butoxycarbonyl-3-[3-[((1-methyltriazole-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0158] [ka]

[0159] To a solution of trans-1-tert-butyl4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (racemic mixture, 100 mg, 0.31 mmol) in DCM (2 mL), 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (34 mg, 0.31 mmol) and sodium sulfate (220 mg, 1.55 mmol) were added. The mixture was stirred at room temperature for 3 hours, and then triacetoxyboron hydride (197 mg, 0.93 mmol) was added. The resulting mixture was stirred at room temperature for 16-18 hours. The reaction mixture was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified using reverse-phase flash chromatography (mobile phase: 10-60% ACN in aqueous NH4CO3 solution (pH 9)). The mixture was further purified using reverse-phase chromatography to obtain the title compound (34.2 mg, 25%). ES / MS m / z: 416[M+H].

[0160] Preparation 21 trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (racemic mixture)

[0161] [ka]

[0162] 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), catalytic amounts of DMAP and 4-(benzyloxy)benzene-1-sulfonyl chloride (0.28 mmol) were added. The reaction mixture was stirred at room temperature for approximately 1 hour. The solvent was evaporated under vacuum, and the residue was extracted with RINKAN and HCl 1N (3 mL each). The organic layer was separated, dried over MgSO4, and evaporated under vacuum. The residue was purified by reverse-phase HPLC to obtain the title compound (60.5 mg, 56%). ES-MS m / z 511 (M-tBu+H).

[0163] The following preparations were prepared essentially as described in Preparation 21, using the corresponding sulfonyl chloride.

[0164] [Table 1] Starting amine used: trans-3-(3-aminophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2)

[0165] Preparation 25 trans-1-tert-butyl4-ethyl3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0166] [ka]

[0167] 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), and purified by silica gel chromatography using a gradient of 0-40% ethyl hexane. ES / MS m / z: 564[M-(CO2Et)+H3O + ]

[0168] Preparation 26 trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (isomer 1)

[0169] [ka]

[0170] 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°C for 2.5 hours. The reaction mixture was cooled to room temperature. The mixture was acidified with aqueous HCl (1 M) and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain the title compound (0.236 g, 44%) as a white solid. ES / MS m / z: 592 [M + H] + .

[0171] Preparation 27 trans-1-tert-butoxycarbonyl-3-[3-[((4-phenylphenyl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0172] [ka]

[0173] The title compound was prepared using 4-phenylbenzaldehyde, essentially as described in Preparation 20. ES / MS m / z: 431 [M+1-tBu].

[0174] Preparation 28 trans-1-tert-butoxycarbonyl-3-[3-[[2-(2-naphthyl)acetyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0175] [ka]

[0176] 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), N,N-diisopropylethylamine (78 mg, 0.60 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then 2-(2-naphthyl)acetyl chloride (34 mg, 0.165 mmol) was added. The resulting mixture was stirred at room temperature for 16-18 hours. Additional N,N-diisopropylethylamine and 2-(2-naphthyl)acetyl chloride were added, and the resulting mixture was stirred at room temperature for 16-18 hours. The mixture was diluted with MeOH, concentrated to dryness under vacuum, and the residue was purified by reverse-phase flash chromatography using a gradient of 10-60% 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].

[0177] Preparation 29 1-tert-butyl 4-ethyl 5-(3-cyanophenyl)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate

[0178] [ka]

[0179] To a suspension of potassium carbonate (136 g, 979 mmol) in 1,4-dioxane (813 mL) and H2O (41 mL), (3-cyanophenyl)boronic acid (43.17 g, 293.8 mmol) was added, and the mixture was heated under N2 at 50-60°C for 15 minutes. To this mixture, 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) was added, followed by the addition of Pd(dppf)Cl2 (3.66 g, 4.90 mmol). The mixture was then stirred under N2 at 95°C for 2 hours. The solvent was evaporated to dryness, and H2O (200 mL) and  (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 column chromatography using a gradient of 10–30%  in hexane to obtain the title compound (66 g, 75.63%) as a yellow oil. ES / MS m / z: 301 (M-tBu+H).

[0180] Preparation 30 cis-1-tert-butyl4-ethyl3-[3-(aminomethyl)phenyl]piperidine-1,4-dicarboxylate (racemic mixture, isomer 1, and isomer 2)

[0181] [ka]

[0182] To a 2 L Pearl reactor, 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), and palladium (10% on charcoal, 50 wt% H2O, 185.2 mmol, 19.7 g) were added, and the mixture was adapted to hydrogen overnight at 300 psi. The mixture was filtered to remove the catalyst, and the reaction solvent was evaporated to dryness. The crude product was purified by silica gel chromatography using an siRNA gradient of 0-40% EtOH in heptane to obtain the title compound (41 g, 61%) as a yellow oily racemic mixture. ES-MS m / z 363 (M+H).

[0183] 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 obtain isomer 1 (first eluting isomer, 15.64 g, >96% ee) and isomer 2 (second eluting isomer, 13.27 g, >96% ee).

[0184] Preparation 31 trans-3-[3-(aminomethyl)phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (racemic mixture)

[0185] [ka]

[0186] A mixture of cis-1-tert-butyl4-ethyl3-[3-(aminomethyl)phenyl]piperidine-1,4-dicarboxylate (racemic mixture, 5 g, 13.8 mmol), sodium methoxide (30% by mass in MeOH, 69.0 mmol), and MeOH (69 mL) was heated at 90°C for 2 days. The reaction solvent was evaporated, and HCl(1N) was added until the pH of the mixture reached 7-8. The solid was filtered off and discarded. The pH of the aqueous mixture was adjusted to 5-6 with HCl(1N) and extracted with HCl. The organic phase was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound (2.8 g, purity 82% by mass, 50% yield). ES / MS m / z: 335 [M+H].

[0187] Preparation 32 Trans-1-tert-butoxycarbonyl-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0188] [ka]

[0189] A mixture of 3-cyanobenzenesulfonyl chloride (43 mg, 0.22 mmol) and trans-3-[3-(aminomethyl)phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (racemic mixture, 60 mg, 0.1794 mmol) was mixed with NaOH (1 M aqueous solution, 0.36 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solvent was then evaporated under an N2 atmosphere. The residue was dissolved in the minimum amount of MeOH, then packed into an SCX cartridge (5 g), eluted with MeOH, and the eluate was discarded. The eluate was collected, and 2 M NH3 in MeOH was concentrated. The residue was then purified by reverse-phase HPLC to obtain the title compound (27 mg, 30%). ES-MS m / z 444 (M-tBu+H).

[0190] Preparation 33 Trans-1-tert-butoxycarbonyl-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0191] [ka]

[0192] The title compound was prepared using 3-phenoxybenzenesulfonyl chloride, essentially as described in Preparation 32. ES-MS m / z 467 (M-BOC+H).

[0193] Preparation 34 2-[4-[2-(2-bromoethoxy)ethoxymethyl]phenyl]pyridine

[0194] [ka]

[0195] To a stirred solution of [4-(2-pyridyl)phenyl]methanol (0.2 g, 1.080 mmol) in DMF (2.5 g), sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol) was added under N2 at 0°C. The mixture was warmed to room temperature and stirred for 30 minutes. The resulting suspension was added to a solution of 1-bromo-2-(2-bromoethoxy)ethane (0.751 g, 3.239 mmol) in DMF (2.0 g) via syringe over 10 minutes, and the mixture was reacted at room temperature for 16 hours. H2O was added, the mixture was extracted with ELISA, the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified using silica gel with 0-25% ELISA in hexane to obtain the title compound (0.14 g, 39%) as a colorless oil. ES-MS m / z 336 (M+H).

[0196] Preparation 35 trans-1-tert-butyl4-ethyl3-(3-bromophenyl)piperidine-1,4-dicarboxylate (isomer 1)

[0197] [ka]

[0198] A mixture of trans-1-tert-butyl4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (isomer 1, 1 g, 2.87 mmol) and tetrabutylammonium bromide (6.32 mmol, 2.06 g) was dissolved in dry ACN (30 mL) together with 4-methylbenzenesulfonic acid monohydrate (3.33 mmol, 0.64 g). 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 was stirred at room temperature. The reaction mixture was poured into water and extracted with phenylethylamine. The organic matter was further washed with water, dried on NaSO4, and evaporated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 10-50% phenylethylamine in hexane to obtain the title compound (0.775 g, 64%) as a yellow, dense oil. ES-MS m / z356,358(M-tBu+H)

[0199] Preparation 36 trans-1-tert-butyl4-ethyl3-(3-formylphenyl)piperidine-1,4-dicarboxylate (isomer 1)

[0200] [ka]

[0201] Trans-1-tert-butyl4-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) were placed in toluene (12 mL) in a reaction vessel equipped with a stirring rod. The vessel was purged with N2 and pressurized with CO / H2 1:1. The gas was evacuated and the vessel was repressurized three times to 70 psi. The mixture was stirred at 100°C for 16-18 hours. The vessel was pressurized again with CO / H2 1:1, the gas was evacuated, and the vessel was repressurized three times to 70 psi. The reaction mixture was stirred at 100°C for 24-36 hours. The reaction mixture was cooled to room temperature, the crude product was diluted with RINKAN, and filtered through diatomaceous earth. The filtrate was concentrated under vacuum, and the residue was partitioned between RINKAN and HCl (1N). The organic layer was separated, washed twice with saturated NaCl aqueous solution, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with RINKAN (5-30%) in hexane to obtain the title compound (0.601 g, 88.47%) as a yellow oily substance. ES / MS m / z: 262 (M-BOC+H)

[0202] Preparation 37 trans-1-tert-butyl4-ethyl3-[3-(hydroxymethyl)phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0203] [ka]

[0204] To a solution of trans-1-tert-butyl4-ethyl3-(3-formylphenyl)piperidine-1,4-dicarboxylate (isomer 1, 0.601 g, 1.66 mmol) in EtOH (10 mL) at 0°C, sodium borohydride (1.2 equivalents, 0.0755 g) was added, and the reaction mixture was stirred for 16 hours. The solvent was removed, and the residue was extracted from siRNA and H2O. The organic layer was separated, washed twice with saturated NaCl aqueous solution, and evaporated under vacuum to obtain the title compound (0.3 g, 50%) as a colorless oil. 1H NMR(400MHz,CDCl3)δ7.28-7.25(m,3H),7.18-7.16(m,1H),4.70(s,2H),4.39-4.23(m,2H),3.94(q,J=7.1Hz,2H),2.98(td,J=11.5,4. 2Hz,1H), 2.78(td,J=11.6,3.7Hz,3H),1.99(dd,J=2.9,13.2Hz,1H),1.79(qd,J=12.7,4.4Hz,1H),1.49(s,9H),1.01(t,J=7.2Hz,3H).

[0205] Preparation 38 trans-1-tert-butyl4-ethyl3-[3-[2-[2-[[4-(2-pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0206] [ka]

[0207] To a stirred solution of trans-1-tert-butyl4-ethyl 3-[3-(hydroxymethyl)phenyl]piperidine-1,4-dicarboxylate (isomer 1, 0.1 g, 0.275 mmol) in DMF (0.7 mL), sodium hydride (60% in mineral oil, 0.33 mmol, 0.013 g) was added at 0°C under N2. This mixture was warmed to room temperature and stirred for 30 minutes. The resulting suspension was added to a solution of 2-[4-[2-(2-bromoethoxy)ethoxymethyl]phenyl]pyridine (0.4128 mmol, 0.1388 g) in DMF (0.6 mL) via syringe over 10 minutes, and the mixture was reacted at room temperature for 16 hours. H2O was added, and the mixture was extracted with ELISA. The aqueous layer was acidified with HCl (1N) to approximately pH 6 and extracted with ELISA. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The compound was purified twice by 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 obtain the title compound. ES / MS m / z: 619 (M+H).

[0208] Preparation 39 trans-1-tert-butoxycarbonyl-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid (isomer 2)

[0209] [ka]

[0210] 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), sodium hydride (60% by mass in mineral oil, 0.79 mmol) was added. The reaction mixture was stirred at 0°C for 15 minutes, then iodomethane (0.79 mmol) was added, and the reaction mixture was warmed to room temperature overnight. Water was added, and the reaction mixture was extracted with RINKAN. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using a 30-60% ACN gradient in aqueous NH4HCO3 (pH 9), followed by reverse-phase HPLC, to obtain 52 mg (33%) of the title compound as a yellow oil. ES-MS m / z 447 (M-tBu+H).

[0211] Preparation 40 trans-1-tert-butyl)4-ethyl3-(3-(2-oxoxazolidine-3-yl)phenyl)piperidine-1,4-dicarboxylate (isomer 1)

[0212] [ka]

[0213] A solution of trans-1-tert-butyl4-ethyl3-(3-bromophenyl)piperidine-1,4-dicarboxylate (isomer 1, 210 mg, 0.5093 mmol), oxazolidine-2-one (0.1331 g, 1.528 mmol), tBuXPhos-Pd-G3 (0.04046 g, 0.05093 mmol), and sodium tert-butoxide (0.1514 g, 1.528 mmol) in 1,4-dioxane (5 mL) was stirred at 100°C for approximately 16 to 24 hours under N2. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness under vacuum. The crude product was purified using an HLB cartridge (6 g packed) with a gradient of 0 to 75% ACN in NH4HCO3 (pH 9) to obtain the title product (170 mg) as a pale yellow solid. ES / MS m / z:363[M+H-tBu].

[0214] Preparation 41 trans-1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidine-1-ylpyridine-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0215] [ka]

[0216] The title compound was prepared using 6-pyrrolidine-1-ylpyridine-2-carboxylic acid, essentially as described in Preparation 8. ES-MS m / z 495 (M+H).

[0217] Preparation 42 trans-1-tert-butyl4-ethyl3-[3-[[3-[(4-chlorophenyl)methyl]imidazole-4-carbonyl]amino]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0218] [ka]

[0219] 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 10-100% ACN gradient in water, and then purified by reverse-phase HPLC. ES-MS m / z 567 (M+H).

[0220] Preparation 43 trans-1-tert-butyl4-ethyl3-[3-[(3-methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0221] [ka]

[0222] The title compound was prepared using trans-1-tert-butyl4-ethyl3-(3-aminophenyl)piperidine-1,4-dicarboxylate (isomer 1) and 1-isocyanato-3-methoxybenzene, essentially as described in Preparation 15, and purified by silica gel chromatography using a gradient of 0-10% DCM in hexane. ES-MS m / z 398 (M-BOC+H).

[0223] Preparation 44 trans-1-tert-butyl)4-ethyl3-(3-(3-(3-methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine-1,4-dicarboxylate (isomer 1)

[0224] [ka]

[0225] To a solution of trans-1-tert-butyl4-ethyl 3-[3-[(3-methoxyphenyl)carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (isomer 1, 150 mg, 0.301 mmol) in THF (3 mL), sodium hydride (60% by mass in mineral oil, 0.663 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, iodomethane (1.507 mmol) was added, and stirring was continued for approximately 2 hours. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaCl solution (3 times), dried on MgSO4, and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% ethyl acetate in heptane to obtain the title product (0.147 g, 89%) as a colorless oil. ES / MS m / z 526 (M+H).

[0226] Preparation 45 Methyl 2-[3-(2-methoxyethoxy)phenyl]acetate

[0227] [ka]

[0228] 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-methoxyethane (2.11 g, 1.45 mL, 15.2 mmol), and the reaction mixture was heated at 60°C under a nitrogen atmosphere. After 5 hours, 1-bromo-2-methoxyethane (0.37 g, 0.25 mL, 2.62 mmol) was added, and the reaction mixture was continued to heat at 60°C overnight. After 16 hours, the solvent was evaporated, and the residue was dissolved in diethyl ether / water. After separation, the organic matter was further washed with water, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (2.15 g, 95%) as a bright pale yellow oil. ES-MS m / z242(M+H2O) + .

[0229] Preparation 46 2-[3-(2-methoxyethoxy)phenyl]ethanol

[0230] [ka]

[0231] A solution of methyl 2-[3-(2-methoxyethoxy)phenyl]acetate (2.15 g, 9.6 mmol) in dry THF (50 mL) was cooled in an ice / water bath under a nitrogen atmosphere. Then, diisobutylaluminum hydride (1 M, 26 mL, 26 mmol) was added, and the final reaction mixture was continuously stirred in the bath. After 3 hours, the solvent was evaporated, and the residue was slowly poured into 1 M HCl. After gas generation, siRNA was added, and the mixture was shaken. After separation, the organic matter was washed with water, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography using a gradient of 2% MeOH in DCM to obtain the title compound (1.29 g, 69%) as a light brown oily substance. ES-MS m / z 197 (M+H).

[0232] Preparation 47 trans-1-tert-butoxycarbonyl-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid (isomer 1)

[0233] [ka]

[0234] 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 (which also functioned as a solvent), and the reaction mixture was stirred at 105°C for 22.5 hours. The reaction mixture was dissolved in water and ELISA. Next, 1 M HCl (7 mL) was added, and the mixture was shaken. The layers were separated, the organic matter was further washed with water, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using 25% ethylethanol in DCM, followed by a second silica gel chromatography using a gradient of 0-25% ethylethanol in DCM. The product was then purified by reverse-phase chromatography to obtain 51 mg (10%) of the title compound as a pale yellow oily substance. ES-MS m / z 444 (M-tBu+H).

[0235] Preparation 48 trans-1-tert-butyl4-ethyl3-[3-[[3-[trans-1-tert-butoxycarbonyl-4-ethoxycarbonyl-3-piperidyl]phenyl]carbamoylamino]phenyl]piperidine-1,4-dicarboxylate (isomer 1)

[0236] [ka]

[0237] A solution of trans-1-tert-butyl4-ethyl3-(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 room temperature for 24 hours. The reaction mixture was then heated at 70°C for 24 hours with stirring. 1,1'-carbonyldiimidazole (0.251 mmol) was added, and stirring and heating continued at reflux temperature for approximately 4 hours. The reaction mixture was then heated again to 70°C and stirred for 36 hours. HCl (1N) was added, and the compound was extracted with ELISA. The organic phase was separated, dried on MgSO4, and evaporated under vacuum. The residue was purified by silica gel chromatography eluting with DCM in hexane (0% to 50% gradient) to obtain the title compound (0.144 g, 20%) as a white solid. ES / MS m / z: 623 (M-BOC+H).

[0238] Preparation 49 Ethyltrans-3-[3-[3-[trans-4-ethoxycarbonyl-1-methyl-3-piperidyl]anilino]phenyl]-1-methyl-piperidine-4-carboxylate (isomer 1)

[0239] [ka]

[0240] Ethyl trans-3-[3-[3-[trans[4-ethoxycarbonyl-3-piperidyl]anilino]phenyl]piperidine-4-carboxylate (isomer 1, 90 mg, 0.188 mmol) was added to MeOH (2 mL), and paraformaldehyde (87 mg, 0.94 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (199 mg, 0.938 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Further addition of paraformaldehyde (87 mg, 0.94 mmol) and sodium triacetoxyborohydride (199 mg, 0.938 mmol) was added, and the mixture was heated at 50°C for 16 hours. The reaction solvent was removed under a stream of N2, and the residue was purified by reverse-phase flash chromatography using a 0-100% ACN gradient in an aqueous solution of NH4HCO3 (10 mM, pH 9) to obtain the title compound (75 mg, 76%) as a pale yellow oily substance. ES-MS m / z 508(M+H).

[0241] 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)

[0242] [ka]

[0243] A solution of trans-1-tert-butyl4-ethyl3-(3-bromophenyl)piperidine-1,4-dicarboxylate (isomer 1, 350 mg, 0.85 mmol), trans-1-tert-butyl4-ethyl3-(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 at 110 °C under N2 atm for 16-18 hours. The reaction product was filtered through diatomaceous earth and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography using a 0-95% siRNA gradient in hexane to obtain the title compound as a pale yellow solid (399 mg, 69%). ES / MS m / z 580 (M-BOC+H).

[0244] Preparation 51 Ethyltrans-3-[3-[3-[trans-4-ethoxycarbonyl-3-piperidyl]anilino]phenyl]piperidine-4-carboxylate (isomer 1)

[0245] [ka]

[0246] HCl (2M 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 reacted at room temperature for 16 hours. After 16 hours, the solvent was removed under a stream of N2. The compound was dissolved in MeOH and packed into an SCX cartridge (10 g), and eluted with MeOH, and then with MeOH / NH3 (2N). The MeOH / NH3 washing solution of the mixture was then concentrated under vacuum to obtain the title product as a pale yellow oil (0.182 g, 65%). ES-MS m / z 480 (M+H).

[0247] Example 1 trans-3-[3-(propa-2-inoylamino)phenyl]piperidine-4-carboxylic acid; 2,2,2-trifluoroacetic acid (racemic mixture)

[0248] [ka]

[0249] A racemic mixture of trans-1-tert-butoxycarbonyl-3-[3-(propa-2-inoylamino)phenyl]piperidine-4-carboxylic acid (0.1026 g, 0.2755 mmol) was added to DCM (1.05 mL), and the mixture was stirred at 0°C until the reactants were completely dissolved. Then, TFA (203 μL, 0.273 mmol) was added, and the mixture was stirred at 0°C and room temperature for 1 hour. The solvent was evaporated by N2 flash, and the mixture was dried in a vacuum oven to obtain the title compound (0.1142 g, quantitative yield) as a yellow solid. ES / MS m / z: 273 (M+H).

[0250] Example 2 trans-3-[3-[4-[[4-(3-chloro-4-methylphenyl)piperazine-1-yl]methyl]triazole-1-yl]phenyl]piperidine-4-carboxylic acid; dihydrochloride (isomer 2)

[0251] [ka]

[0252] Trans-1-tert-butoxycarbonyl-3-[3-[4-[[4-(3-chloro-4-methylphenyl)piperazine-1-yl]methyl]triazole-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 room temperature for 1 hour. The solvent was removed under N2, and the mixture was dried under vacuum at 40°C for 16-18 hours to obtain the title compound (9 mg, quantitative yield) as a white solid. ES-MS m / z 495 (M+H).

[0253] Example 3a trans-3-[3-[3-(1H-indole-3-yl)propanoylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture)

[0254] [ka]

[0255] A solution of trans-1-tert-butoxycarbonyl-3-[3-[3-(1H-indole-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 room temperature for approximately 1 hour. The reaction mixture was concentrated to dryness under vacuum. The crude product was purified using a 5 g SCX cartridge prepared with MeOH. The residue was dissolved in MeOH, packed into the cartridge, and eluted with MeOH, and then with NH3 / MeOH (2N). The NH3 / MeOH washing solution was concentrated to dryness under vacuum to obtain the title product (0.0402 g, 32%) as a pale yellow solid. ES / MS m / z: 392 [M+H-Cl].

[0256] Example 3 trans-3-[3-[3-(1H-indole-3-yl)propanoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0257] [ka]

[0258] A solution of trans-3-[3-[3-(1H-indole-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 room temperature for approximately 2 hours. The reaction mixture was concentrated to dryness under vacuum. The resulting solid was washed with MTBE, filtered, and dried under vacuum. The residue was then dissolved in HCl (4.0 M in 1,4-dioxane) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness under vacuum. The resulting solid was washed with MTBE, filtered, and dried under vacuum to obtain the title compound (21 mg, 44%) as a pale yellow solid. ES / MS m / z: 392 [M+H].

[0259] Example 4 trans-3-[3-[3-(3-methoxyphenyl)-2-oxoimidazolidined-1-yl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0260] [ka]

[0261] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[3-(3-methoxyphenyl)-2-oxoimidazolidin-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 1) essentially as described in Example 2. ES-MS m / z 396(M+H).

[0262] Example 5 trans-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2)

[0263] [ka]

[0264] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-(cyclopropylcarbamoylamino)phenyl]piperidine-4-carboxylic acid (isomer 2) essentially as described in Example 2. ES / MS m / z: 304 (M+H).

[0265] Example 6 trans-3-[3-(propa-2-inylamino)phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0266] [ka]

[0267] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-(propa-2-inylamino)phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES / MS m / z: 259 (M+H).

[0268] Example 7 trans-3-[3-[2-(4-chlorophenyl)ethylcarbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2)

[0269] [ka]

[0270] The title compound was prepared using trans-3-[3-(benzylcarbamoylamino)phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (isomer 2) essentially as described in Example 2. ES / MS m / z: 402 (M+H).

[0271] Example 8 trans-3-[3-[4-(phenoxymethyl)triazole-1-yl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2)

[0272] [ka]

[0273] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[4-(phenoxymethyl)triazole-1-yl]phenyl]piperidine-4-carboxylic acid (isomer 2) essentially as described in Example 2. ES / MS m / z: 379 (M+H).

[0274] Example 9 trans-3-[3-[(4-phenylpiperidine-1-carbonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0275] [ka]

[0276] 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), LiOH (1 M in H2O, 6 mL, 6 mmol) and a few drops of MeOH were added at room temperature. The mixture was stirred at 50°C for 16-18 hours. HCl (1 N) was added, and the compound was extracted with ELISA. The organic layer was separated, washed with H2O (twice), dried on MgSO4, and evaporated under vacuum. The residue was dissolved in DCM (4 mL), HCl (4 M in 1,4-dioxane, 2 mL, 8 mmol) was added, and the mixture was reacted for 2 hours. The reaction solvent was evaporated under vacuum to obtain a beige solid. Next, the solid was sonicated in MTBE / DCM, filtered, and dried under vacuum to obtain the title compound (0.14 g, 55%) as a white solid. ES / MS m / z: 408 (M+H).

[0277] The following table shows an example prepared in two steps. Step 1 – Trans-3-(3-aminophenyl)-1-tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2) was reacted with a suitable isocyanate using essentially the procedure described in Preparation 14. Upon completion, the reaction product was concentrated and purified by an HLB cartridge eluted with an aqueous solution of NH4HCO3 (20 mM, pH 9), followed by ACN. The product was then purified by an SCX cartridge eluting first with MeOH, discarding the MeOH eluate, then eluting 2 M NH3 in MeOH, collecting and concentrating the product. The product was further purified by reverse-phase chromatography to obtain a BOC-protected intermediate.

[0278] Step 2 - Using essentially the procedure described in Example 2, the BOC-protected intermediate prepared in Step 1 was converted to the listed example compounds.

[0279] [Table 2]

[0280] Example 12 trans-3-[3-[(3-methoxyazetidine-1-carbonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0281] [ka]

[0282] The title compound was prepared in two steps. Step 1: Using 3-methoxyazetidine, the procedure essentially described in Preparation 19 was used. Step 2: Using the procedure essentially described in Example 9 together with the product from Step 1, the title compound was obtained. ES / MS m / z: 334 (M+H).

[0283] Example 13 trans-3-[3-[((1-methyltriazole-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0284] [ka]

[0285] The title compound was prepared essentially as described in Example 2 using trans-1-tert-butoxycarbonyl-3-[3-[((1-methyltriazole-4-yl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture). ES / MS m / z 316[M+H].

[0286] Example 14 trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0287] [ka]

[0288] The title compound was prepared essentially as described in Example 2 using trans-3-[3-[(4-benzyloxyphenyl)sulfonylamino]phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (racemic mixture). ES-MS m / z 467 (M+H).

[0289] Example 15 trans-3-[3-[3-(4-methoxyphenoxy)propylsulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0290] [ka]

[0291] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[3-(4-methoxyphenoxy)propylsulfonylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES-MS m / z 449 (M+H).

[0292] Example 16 Trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0293] [ka]

[0294] The title compound was prepared using trans-3-[3-[[3,5-bis(trifluoromethyl)phenyl]carbamoylamino]phenyl]-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (isomer 1) essentially as described in Example 2. ES / MS m / z: 476[M+H].

[0295] Example 17 trans-3-[3-[((4-phenylphenyl)methyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0296] [ka]

[0297] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[(4-phenylphenyl)methyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES / MS m / z: 388[M+H].

[0298] Example 18 trans-3-(3-(2-(naphthalene-2-yl)acetamide)phenyl)piperidine-4-carboxylate hydrochloride (racemic mixture)

[0299] [ka]

[0300] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[[2-(2-naphthyl)acetyl]amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES / MS m / z: 389 [M+H].

[0301] Example 19 trans-3-[3-[[(3-cyanophenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0302] [ka]

[0303] 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).

[0304] Example 20 trans-3-[3-[[(3-phenoxyphenyl)sulfonylamino]methyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0305] [ka]

[0306] 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).

[0307] Example 21 trans-3-[3-[2-[2-[[4-(2-pyridyl)phenyl]methoxy]ethoxy]ethoxymethyl]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0308] [ka]

[0309] To a solution of trans-1-tert-butyl4-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, and the mixture was reacted at room temperature for 16 hours. The solvent was removed, the mixture was dissolved in water, and packed into an SCX cartridge. The cartridge was eluted with MeOH, and the eluate was discarded. Elution was collected, and 2 M NH3 in MeOH was concentrated. The residue was dissolved in MeOH (0.5 mL), NaOH (2 M in water, 0.14 mL) was added, and the mixture was reacted at room temperature for 16 hours. The solvent was removed. Water was added to acidify to pH 5, and then the mixture was extracted with ELISA (×4). The organic layers were combined and concentrated under vacuum. The residue was purified by reverse-phase chromatography using a gradient of 10–100% ACN in NH4HCO3 aqueous solution (10 mM, pH 9). The product was dissolved in HCl (1 M, 2 mL) and stirred at room temperature for 16 hours. The mixture was concentrated to obtain the title compound (0.0301 g, 28%) as a pale yellow oil. ES / MS m / z: 491 (M+H).

[0310] Example 22 trans-3-[3-[(5-chloro-3-methylbenzothiophen-2-yl)sulfonylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0311] [ka]

[0312] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[(5-chloro-3-methylbenzothiophen-2-yl)sulfonylamino]phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES-MS m / z 465 (M+H).

[0313] Example 23 trans-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 2)

[0314] [ka]

[0315] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[methyl(2-phenylethylsulfonyl)amino]phenyl]piperidine-4-carboxylic acid (isomer 2) essentially as described in Example 2. ES / MS m / z 403(M+H)

[0316] Example 24 trans-3-(3-aminophenyl)piperidine-4-carboxylic acid; hydrochloride (isomer 2)

[0317] [ka]

[0318] The title compound was prepared using trans-3-(3-aminophenyl)-1-tert-butoxycarbonyl)piperidine-4-carboxylic acid (isomer 2) essentially as described in Example 2. ES-MS m / z 221 (M+H).

[0319] Example 25 trans-3-(3-((2-hydroxyethyl)amino)phenyl)piperidine-4-carboxylate hydrochloride (isomer 1)

[0320] [ka]

[0321] To a solution of trans-1-(tert-butyl)4-ethyl 3-(3-(2-oxoxazolidine-3-yl)phenyl)piperidine-1,4-dicarboxylate (isomer 1, 188 mg, 0.45 mmol) in MeOH (4 mL) and THF (4 mL), NaOH (1 M aqueous solution, 4.5 mmol, 4.5 mL) was added. The reaction mixture was stirred at 50°C for approximately 16-24 hours. The reaction mixture was concentrated to dryness under vacuum.

[0322] The crude product was dissolved in HCl, neutralized to pH 4 with HCl (0.5 M), extracted with HCl (3 times), and washed with saturated NaCl aqueous solution (2 times). The organic matter was dried over MgSO4, filtered, and concentrated to dryness under vacuum. The residue was dissolved in ACN / H2O and purified using an SCX cartridge (25g packed). The SCX cartridge was first prepared by eluting twice with ACN, then the mixture was packed into the cartridge and eluted with ACN and NH3 / MeOH (2N). The NH3 / MeOH washing solution was concentrated to dryness, the obtained solid was washed with MTBE, filtered, and dried under vacuum. The product was dissolved in HCl (4M in 1,4-dioxane, 2.81 mL, 11.23 mmol), the mixture was stirred at room temperature for 5 hours, and then the mixture was concentrated to dryness under vacuum. The obtained solid was washed with MTBE, filtered, and dried under vacuum to obtain the title product as a brown solid (119 mg, 88%). ES / MSm / z:265[M+1].

[0323] Example 26 trans-3-[3-[[7-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carbonyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0324] [ka]

[0325] The title compound was prepared in two steps. Step 1: Using 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline, the procedure essentially described in Preparation 19 was used. Step 2: The title compound was obtained by using the procedure essentially described in Example 9 together with the product from Step 1. ES / MS m / z: 448 [M+H] Example 27 trans-3-[3-[[2-(chloromethyl)-3-methoxypropyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0326] [ka]

[0327] The title compound was prepared in two steps. Step 1: Using 3-(methoxymethyl)azetidine hydrochloride, the procedure essentially described in Preparation 19 was used. Step 2: Using the procedure essentially described in Example 9 together with the product from Step 1, the ring-opened title compound was obtained under reaction conditions. ES / MS m / z: 482 [MH].

[0328] Example 28 trans-3-[3-[(6-pyrrolidine-1-ylpyridine-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (racemic mixture)

[0329] [ka]

[0330] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[(6-pyrrolidine-1-ylpyridine-2-carbonyl)amino]phenyl]piperidine-4-carboxylic acid (racemic mixture) essentially as described in Example 2. ES-MS m / z 395 (M+H).

[0331] Example 29 trans-3-[3-[[3-[(4-chlorophenyl)methyl]imidazole-4-carbonyl]amino]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0332] [ka]

[0333] The title compound was prepared essentially as described in Example 9 using trans-1-tert-butyl4-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).

[0334] Example 30 trans-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)phenyl)piperidine-4-carboxylate hydrochloride (isomer 1)

[0335] [ka]

[0336] The title compound was prepared in two steps.

[0337] Step 1: The procedure essentially described in Preparation 13 was carried out using 1-methylimidazolidinedione-2-one and purified using an HLB cartridge that eluted in an aqueous NH4HCO3 solution (pH 9) with a gradient of 0-100% ACN.

[0338] Step 2: The BOC group in the product from Step 1 was removed essentially as described in Example 2 to obtain the title compound. ES / MS m / z = 304 [M + H].

[0339] Example 31 trans-3-(3-(3-(3-methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine-4-carboxylate hydrochloride (isomer 1)

[0340] [ka]

[0341] The title compound was prepared using trans-1-(tert-butyl)4-ethyl 3-(3-(3-(3-methoxyphenyl)-1,3-dimethylureido)phenyl)piperidine-1,4-dicarboxylate (isomer 1) essentially as described in Example 9. ES / MS m / z 398 (M+H).

[0342] Example 32 trans-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid; hydrochloride (isomer 1)

[0343] [ka]

[0344] The title compound was prepared using trans-1-tert-butoxycarbonyl-3-[3-[2-[3-(2-methoxyethoxy)phenyl]ethoxy]phenyl]piperidine-4-carboxylic acid (isomer 1) essentially as described in Example 2. ES-MS m / z 400 (M+H).

[0345] Example 33 trans-3-[3-[[3-[trans-4-carboxy-3-piperidyl]phenyl]carbamoylamino]phenyl]piperidine-4-carboxylic acid; dihydrochloride (isomer 1)

[0346] [ka]

[0347] To a solution of trans-1-tert-butyl4-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), LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH were added. The reaction mixture was stirred at room temperature for 24 hours. Then, HCl (1 N) was added, and the compound was extracted with HCl. The organic layer was separated, dried on MgSO4, and evaporated under vacuum. The residue was dissolved in THF (10 mL), LiOH (1 M in water, 3 mL, 3 mmol) and a few drops of MeOH were added, and the mixture was stirred at room temperature for 36 hours. HCl (1 N) was added, and the compound was extracted with HCl. The organic phase was separated, dried on MgSO4, and evaporated under vacuum. The obtained solid was dissolved in DCM (2 mL), and HCl (2 M in Et2O, 4 mL, 8 mmol) was added. The reaction mixture was stirred at room temperature for 16-18 hours. The solvent was evaporated under vacuum, and the residue was co-evaporated with water to remove the residual solvent, obtaining the title compound as a white powder (0.077 g, 72%). ES / MS m / z: 467 (M+H).

[0348] Example 34 trans-3-[3-[3-[trans-4-carboxy-1-methyl-3-piperidyl]anilino]phenyl]-1-methyl-piperidine-4-carboxylic acid; dihydrochloride (isomer 1)

[0349] [ka]

[0350] 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 solution, 0.67 mL, 1.33 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The solvent was then concentrated. The residue was purified by reverse-phase chromatography using a gradient of 0 to 100% ACN in NH4HCO3 aqueous solution (10 mM, pH 9). The product was diluted with HCl (1N), stirred at room temperature for 30 minutes, and the solvent was removed under vacuum to obtain the title compound (49 mg, 62%) as a pale green solid. ES-MS m / z 452 (M+H).

[0351] Example 35 trans-3-[3-[3-[trans-4-carboxy-3-piperidyl]anilino]phenyl]piperidine-4-carboxylic acid; dihydrochloride (isomer 1)

[0352] [ka]

[0353] NaOH (1.877 mmol, 2M) 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 stirred at 50°C for 16 hours, and then the solvent was removed under vacuum. The residue was purified by reverse-phase chromatography eluting in aqueous NH4HCO3 with a gradient of 0 to 100% ACN (10 mM, pH 9). The product was then dissolved in HCl (1 N) and stirred at room temperature for 30 minutes. The solvent was removed under vacuum, and the mixture was dried under vacuum to obtain the title compound as a pale green solid (0.099 mg, 96%). ES / MS m / z 424 (M+H).

[0354] In vitro Lp(a) aggregation assay The ability of the compounds to inhibit Lp(a) particle formation in vitro was evaluated by a cell-free aggregation assay. Conditioning media (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin) were cultured at 37°C and 5% CO2 for 24 hours, and then collected from confluent wild-type HepG2 cells (source of endogenously expressed ApoB) and from HEK293 stable cell lines expressing human Apo(a) containing 17 kringle repeats (selected with 1 mg / ml Geneticin). In vitro aggregation assays were performed by combining test compounds with equal volumes of HepG2 and HEK293 conditioning media in a dilution series (final concentrations 0.01–100 nM). The reaction mixtures were incubated at 37°C for 2 hours, then stopped by adding 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 colorimetrically developed using TMB and stopped with 1N sulfuric acid, and the signal was read at 450 nm with a Molecular Devices plate reader. The inhibition percentage of Lp(a) formed under each test condition was set to 0% inhibition for the aggregate reaction in the absence of the inhibitor (corresponding to a 1% DMSO concentration) and to 100% inhibition for the minimum amount of HepG2 conditioned medium present (50-fold dilution). To determine the IC50 values ​​summarized in Table 3, the data were fitted to a four-parameter curve. As summarized in Table 3, the addition of exemplary test compounds to conditioned media containing ApoB and Apo(a) resulted in concentration-dependent inhibition of Lp(a) formation in vitro. The results indicate that these compounds inhibit the aggregation of Lp(a) from Apo(a) and LDL particles.

[0355] [Table 3]

Claims

1. formula: 【Chemistry 1】 During the ceremony, R １ However, H or -CH ３ And; Q １ is -(CH ２ ), ｎ NR １５ (CH ２ ), ｎ R １０ ,-B(OR １０ ), ２ ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethyl-propylene-1,3-diol boronic acid ester,-(CH ２ ), ｎ NR １５ CONR １５ (CH ２ ), ｎ R １０ ,-(CH ２ ), ｎ NR １５ CO(CH ２ ), ｎ R １０ , -O(CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ NR １５ SO ２ (CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ 、NH ２ 、-NHCONH ２ 、 【Chemistry 2】 And; Q ２ However, H, C １～４ Alkyl, cyclopropyl, CF ３ OH, C １～４ Alkoxy, O-cyclopropyl, OCF ３ , halo, or CN; n is independently 0, 1, 2, or 3 at each occurrence; R １０ but, Hello; With 1 to 4 OH groups or OCH ３ C is optionally replaced by １～４ Alkyl; C is optionally replaced with one or two halos. ３～６ Cycloalkyl; OCH ３ C is optionally replaced by １～４ Haloalkyl; C ２～６ Alkinyl; NH ２ ; Naphthyl; CF ３ 3,4-dihydro-2H-1λ is optionally substituted. ２ - Quinoline; Phenoxy selected to be substituted with methoxy; OCH ３ , C １～４ Alkyl, (CH ２ ) Pyridine, O(CH ２ ) Phenyl, or (CH ２ ) ｍ A 4, 5, or 6-membered heterocycle optionally substituted with phenyl, wherein the phenyl is a halo and CH ３ A 4, 5, or 6-membered heterocycle optionally substituted with one or two substituents selected from the following: C １～４ A 5 or 6-membered heteroaryl or 9 or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from alkyl, halo, pyrrolidine, benzyl, or phenyl, wherein the benzyl or phenyl substituent is optionally substituted with halo; and Hello, C １～４ Alkoxy, C １～４ Alkyl, CF ３ CN, OCF ３ , -OCH ２ CH ２ OCH ３ , phenoxy, pyridine, -OCH ２ Phenyl, or -(CH ２ ) ｎ A phenyl molecule optionally substituted with one to three substituents independently selected from phenyl, wherein the phenyl molecule is optionally substituted with one or two halos; m is 0 or 1; p is 1, 2, 3, 4, or 5; R １５ However, H or C １～３ Alkyl compounds, or a pharmaceutically acceptable salt thereof.

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

3. Q ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein H is present.

4. The compound according to any one of claims 1 to 3, wherein the compound is a compound of the following formula: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

5. Q １ が、-(CH ２ ) ｎ NR １５ (CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ NR １５ CONR １５ (CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ NR １５ CO(CH ２ ) ｎ R １０ 、-O(CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ NR １５ SO ２ (CH ２ ) ｎ R １０ 、-(CH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ 、NH ２ 、 【Chemistry 4】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. Q １ が、-NXCH ２ R １０ 、-NHGNHR １０ 、-NHGNHCH ２ R １０ 、-NHGNH(CH ２ ) ２ R １０ 、-N(CH ３ )CONN(CH ３ ) １０ 、-NHAR １０ 、-NHCOCH ２ R １０ 、-NHA(CH ２ ) ２ R １０ 、CH ２ NHSO ２ R １０ 、-NHSO ２ R １０ 、-O(CH ２ ) ２ R １０ 、-NHSO ２ (CH ２ ) ３ R １０ 、-N(CH 化３ )SO ２ (CH ２ ) ２ R １０ 、-CH ２ O(CH ２ ) ２ O(CH ２ ) ２ OCH ２ R １０ 、NH ２ 、 【Transformation 5】 The compound according to claim 5, or a pharmaceutically acceptable salt thereof.

7. Q １ が、-NHCH ２ R １０ 、-NHCONHR １０ 、-NHCONHCH ２ R １０ 、-NHCONH(CH ２ ) ２ R １０ 、-NHCOR １０ 、-NHCO(CH ２ ) ２ R １０ 、 【Transformation 6】 The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. Q １ が、-(CH ２ ) ｎ NR １５ (CH) ２ ) ｎ R １０ ,-(EH ２ ) ｎ NR １５ CONR １５ (CH) ２ ) ｎ R １０ ,-(EH ２ ) ｎ NR １５ CO ２ ) ｎ R １０ ,-O(CH ２ ) ｎ R １０ ,-(EH ２ ) ｎ NR １５ SO ２ (CH) ２ ) ｎ R １０ ,-(EH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ 、 【Transformation 7】 And; R １０ but, C is optionally substituted with 1 to 4 OH groups. １～４ Alkyl; C ３～６ Cycloalkyl; OCH ３ C is optionally replaced by １～４ Haloalkyl; C ２～６ Alkinyl; Naphthyl; CF ３ 3,4-dihydro-2H-1λ is optionally substituted. ２ - Quinoline; Phenoxy; OCH ３ or CH ２ A 4- or 6-membered heterocycle optionally substituted with mphenyl, wherein the phenyl is a halo and CH ３ A four- or six-membered heterocycle optionally substituted with one or two substituents selected from the following: C １～４ A 5- or 6-membered heteroaryl or 9-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from alkyl, halo, pyrrolidine, or benzyl, wherein the benzyl is optionally substituted with halo; and Hello, C １～４ Alkoxy, C １～４ Alkyl, CF ３ , CN, -OCH ２ CH ２ OCH ３ , phenoxy, pyridine, -OCH ２ Phenyl, or -(CH ２ ) ｎ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from phenyls optionally substituted with one to three substituents independently selected from phenyl.

9. R １０ but, CH ３ CH ２ OH; cyclopropyl; CH ２ CH (CH ２ Cl)CH ２ OCH ３ Ethinyl;naphthyl, CF ３ 3,4-dihydro-2H-1λ2-quinoline substituted with; phenoxy; Piperazine, piperidine, or azetidine, wherein the piperazine, piperidine, or azetidine is OCH ３ Alternatively, it may be optionally substituted with phenyl, wherein the phenyl may optionally be Cl and CH ３ Piperazine, piperidine, or azetidine, optionally substituted with one or two substituents selected from the following: Indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, wherein the indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene is CH ３ indole, thiophene, pyrazole, imidazole, pyridine, or benzothiophene, which are optionally substituted with one or two substituents selected from Cl, pyrrolidine, or benzyl, wherein the benzyl is substituted with Cl; and PhenylCl, OCH ３ ,CH ３ CF ３ , CN, -OCH ２ CH ２ OCH ３ , phenoxy, pyridine, -OCH ２ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, selected from phenyl, or phenyl optionally substituted with one or two substituents independently selected from phenyl.

10. R １０ but, Cyclopropyl, ethinyl, phenoxy; A piperazine substituted with phenyl, wherein the phenyl is Cl and CH ３ Piperazine, which is substituted with; Phenyl-substituted piperidine; OCH ３ Azetidine substituted with; Indole; Thiofen; CH ３ Pyrazole substituted with; OCH ３ or CH ３ A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from phenyl substituted with .

11. formula: 【Transformation 8】 During the ceremony, R １ａ However, H, CH ３ , or a protecting group; X is OH or C １～４ It is an alkoxy; Q １ However, - (CH ２ ) ｎ NR １５ (CH ２ ) ｎ R １０ , -B(OR １０ ) ２ , ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethylpropylene-1,3-diol boronic acid ester, -(CH ２ ) ｎ NR １５ CONR １５ (CH ２ ) ｎ R １０ ,-(CH ２ ) ｎ NR １５ CO(CH ２ ) ｎ R １０ , -O(CH ２ ) ｎ R １０ ,-(CH ２ ) ｎ NR １５ SO ２ (CH ２ ) ｎ R １０ ,-(CH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ ,-(CH ２ ) ｎ O(CH ２ ) ｐ O(CH ２ ) ｐ O(CH ２ ) ｎ R １０ NH ２ ,-NHCONH ２ , 【Chemistry 9】 And; Q ２ However, H, C １～４ Alkyl, cyclopropyl, CF ３ OH, C １～４ Alkoxy, O-cyclopropyl, OCF ３ , halo, or CN; n is independently 0, 1, 2, or 3 at each occurrence; R １０ but, Hello; With 1 to 4 OH groups or OCH ３ C is optionally replaced by １～４ Alkyl; C is optionally replaced with one or two halos. ３～６ Cycloalkyl; OCH ３ C is optionally replaced by １～４ Haloalkyl; C ２～６ Alkinyl; NH ２ ; Naphthyl; CF ３ 3,4-dihydro-2H-1λ is optionally substituted. ２ - Quinoline; Phenoxy selected to be substituted with methoxy; OCH ３ , C １～４ Alkyl, (CH ２ ) Pyridine, O(CH ２ ) Phenyl, or (CH ２ ) ｍ A 4, 5, or 6-membered heterocycle optionally substituted with phenyl, wherein the phenyl is a halo and CH ３ A 4, 5, or 6-membered heterocycle optionally substituted with one or two substituents selected from the following: C １～４ A 5 or 6-membered heteroaryl or 9 or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from alkyl, halo, pyrrolidine, benzyl, or phenyl, wherein the benzyl or phenyl substituent is optionally substituted with halo; and Hello, C １～４ Alkoxy, C １～４ Alkyl, CF ３ CN, OCF ３ , -OCH ２ CH ２ OCH ３ , phenoxy, pyridine, -OCH ２ Phenyl, or -(CH ２ ) ｎ A phenyl molecule optionally substituted with one to three substituents independently selected from phenyl, wherein the phenyl molecule is optionally substituted with one or two halos; m is 0 or 1; p is 1, 2, 3, 4, or 5; R １５ However, H or C １～３ Alkyl compounds, or its salt (if X is OH, R １ａ However, it must be a protecting group.

12. R １ａ The compound according to claim 11, or a salt thereof, wherein the protecting group is selected from tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide.

13. Use of the compound according to claim 11 or claim 12, or a salt thereof, in the preparation of oligomers.

14. An oligomer prepared from the compound according to 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. formula: 【Chemistry 10】 R １ However, at each occurrence, independently, H or CH ３ And; Lが、-(CH ２ ) ｐ NHC(O)NH(CH) ２ ) ｐ -、-(CH ２ ) ｐ NH(CH) ２ ) ｐ - 【Chemistry 11】 And; p is either 0 or 1 independently at each occurrence; Q ３ However, at each appearance, H and C appear independently. １～４ Alkyl, cyclopropyl, CF ３ OH, C １～４ Alkoxy, O-cyclopropyl, OCF ３ , halo, or CN; L ２ However, C １～３ A compound that is alkylene or bonded, or a pharmaceutically acceptable salt thereof.

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

19. The compound according to claim 17 or claim 18, wherein the compound is a compound of the following formula: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

20. L is - (CH ２ ) ｐ NHC(O)NH(CH ２ ) ｐ - or - (CH ２ ) ｐ NH(CH ２ ) ｐ - The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)-.

22. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or 17 to 22, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

24. A method for treating a 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 for treating an elevation of 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.

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