Piperidine, morpholine and tetrahydropyridazine compounds with lp (a) reducing activity

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to piperidine, morpholine and tetrahydropyridazine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions and therapeutic uses of the compounds, in particular their use in lowering plasma levels of lipoprotein(a) (Lp(a)). BACKGROUND

[0002] Significant progress has been made in the treatment of cardiovascular disease (CVD). Despite therapeutic advances, patients continue to experience cardiovascular disease events, such as angina, myocardial infarction and stroke, which, if untreated, can lead to death. Dyslipidemia or lipid disorders remain a major risk factor for CVD. Dyslipidemia can be divided into four general risk factors: elevated low-density lipoprotein cholesterol (LDL-c), low high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated Lp(a). Various treatment options exist for elevated LDL-c, low HDL-c, and elevated triglycerides. For patients with elevated Lp(a) concentrations, few approved treatment options exist. In some cases, apheresis can be used to filter blood to remove LDL and Lp(a); however, the effect is temporary and typically requires repetition every two weeks. No drug therapy is currently approved specifically for lowering Lp(a) levels.

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

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

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

[0006] Patients with cardiovascular disease, in particular patients with dyslipidemia or lipid disorders, need additional treatment options. Patients whose cardiovascular risk cannot be adequately managed using current standard of care therapies, such as diet, exercise, and / or the use of one or more medications, such as statins, fibrates, and niacin, need additional treatment options. More particularly, additional alternative pharmaceutically acceptable compounds that inhibit the formation of Lp(a) and thus reduce plasma Lp(a) levels are needed. SUMMARY

[0007] Thus, in a first aspect, there is provided a compound of Formula I: wherein A 1 is NH, A 2 is CH and A 3 is O; A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH; Z is H, C 1-4 alkyl, OH, or cyclopropyl; Y is CH2, O, or S; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR10 )2, boronic acid ethylene glycol ester, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2or 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; n is 0, 1, 2 or 3; R 10 is selected from: halogen; C 1-4 alkyl optionally substituted with one to four OH or OCH3; C 3-6 cycloalkyl optionally substituted with one or two halogens; C 1-4 haloalkyl optionally substituted with OCH3; C 2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1 λ 2 -quinolinone optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6-membered heterocycle optionally substituted with OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl optionally substituted with one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) nphenyl, wherein the phenyl is optionally substituted with one or two halo; m is 0 or 1 ; and R 15 is H or C 1-3 alkyl.

[0008] In a second aspect, there is provided a compound of Formula II: wherein R 1a is H, CH3, or a protecting group; X is OH or C 1-4 alkoxy; Y is CH2, O, or S; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid glycol ester, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halo, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2, or 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R 10 is selected from: halo; C 1-4 alkyl optionally substituted with one to four OH or OCH3; C 3-6 cycloalkyl optionally substituted with one or two halo; C 1-4 haloalkyl optionally substituted with OCH3; C 2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1 λ 2 -quinolinone optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6-membered heterocycle optionally substituted with OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl substituted with one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; m is 0 or 1 ; and R 15 is H or C 1-3 alkyl, wherein if X is OH, R 1a must be a protecting group.

[0009] In a third aspect, there is provided a compound of formula III or a salt thereof: wherein R 1a is H, CH3or a protecting group; X is OH or C 1-4 alkoxy; Y is CH2, O or S; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid glycol ester, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2or 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; n is 0, 1, 2 or 3; R 10 selected from: halogen; C 1-4 alkyl optionally substituted with one to four OH or OCH3; C 3-6 cycloalkyl optionally substituted with one or two halogen; C 1-4 haloalkyl; C 2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-l 2 -quinolinone; phenoxy optionally substituted with methoxy; 4-, 5- or 6-membered heterocycle optionally substituted with OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl optionally substituted with one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl optionally substituted with one or two halogen; m is 0 or 1; and R 15 is H or C 1-3 alkyl, wherein if X is OH, R 1a must be a protecting group.

[0010] In a fourth aspect, there is provided the use of a compound of Formula II or Formula III, or a salt thereof, in the preparation of an oligomer.

[0011] In a fifth aspect, there is provided an oligomer prepared from a compound of Formula II or Formula III, or a salt thereof. In one embodiment, the oligomer comprises at least two piperidine moieties, at least two morpholine moieties, or a combination thereof. In one embodiment, the oligomer comprises at least three piperidine moieties, at least three morpholine moieties, or a combination thereof.

[0012] In a sixth aspect, there is provided a compound of Formula IV, or a pharmaceutically acceptable salt thereof: wherein A 1 is NH, A 2 is CH and A 3 is O; A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH; A 1a is NH, A 2a is CH and A 3a is O; A 1a is O, A 2a is CH and A 3a is NH; A 1a is CH, A 2a is NH and A 3a is NH; A 1a is CH, A 2a is NH and A 3a is CH; or A 1a is CH, A 2a is N(CH3) and A 3a is CH; Z is, at each occurrence, independently H, C 1-4 alkyl, OH, or cyclopropyl; Y is, at each occurrence, independently CH2, O, or S; L is -(CH2) p NHC(O)NH(CH2) p -, -(CH2) p NH(CH2) p -, a bond, or ; Q 3 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen, or CN; p is independently at each occurrence 0 or 1 ; A 1b is NH, A 2b is CH and A 3b is O; A 1b is O, A 2b is CH and A 3b is NH; A 1b is CH, A 2b is NH and A 3b is NH; A 1b is CH, A 2b is NH and A 3b is CH; or A 1b is CH, A 2b is N(CH3) and A 3b is CH; and L 2 is C1-3alkylene or a bond.

[0013] In a seventh aspect, a pharmaceutical composition comprising a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient is provided.

[0014] In an eighth aspect, a method of treating a cardiovascular disease in a patient comprising administering to the patient an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, is provided.

[0015] In a ninth aspect, a method of treating elevated Lp(a) plasma levels in a patient comprising administering to the patient an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, is provided.

[0016] In a tenth aspect, a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in therapy is provided.

[0017] In an eleventh aspect, a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cardiovascular disease is provided.

[0018] In a twelfth aspect, a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated Lp(a) plasma levels is provided. DETAILED DESCRIPTION

[0019] In one embodiment of the compounds of Formula I, Z is H.

[0020] In one embodiment of the compound of formula I, Y is CH2.

[0021] In one embodiment of the compound of formula I, A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH.

[0022] In one embodiment of the compound of formula I, Q 1 is H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, or 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl.

[0023] In one embodiment of the compound of formula I, Q 2 is H or halogen.

[0024] In one embodiment, there is provided a compound of formula Ia: or a pharmaceutically acceptable salt thereof. Formula I encompasses formula Ia, and references to formula I below, e.g. in the methods of treatment and therapeutic uses, are also to be interpreted as references to formula Ia.

[0025] In one embodiment, there is provided a compound of formula Ia, wherein A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH, and wherein Q 1 is H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2, or 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl, and Q 2 is H or halogen.

[0026] In one embodiment, the compound of formula I is selected from: or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment of the compound of Formula II or III, R 1a is a protecting group and the protecting group is selected from the group consisting of: tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, tritylamine, and p-toluenesulfonamide. In a particular embodiment, R 1a is tert-butyloxycarbonyl.

[0028] In one embodiment of the compound of Formula IV, Z is H at each occurrence.

[0029] In one embodiment of the compound of Formula IV, Y is CH2at each occurrence.

[0030] In one embodiment of the compound of Formula IV, Q 3 is H at each occurrence.

[0031] In one embodiment of the compound of Formula IV, L is -NHC(O)NH- or a bond.

[0032] In one embodiment of the compound of Formula IV, L is A 1 is O, A 2 is CH and A 3 is NH, and A 1a is O, A 2a is CH and A 3a is NH.

[0033] In one embodiment, a compound of Formula IVa is provided: or a pharmaceutically acceptable salt thereof. Formula IV encompasses Formula IVa, and references to Formula IV hereinafter, e.g., in the methods of treatment and therapeutic uses, are also to be interpreted as references to Formula IVa.

[0034] In one embodiment, a compound of Formula IVa is provided, wherein L is -NHC(O)NH- or a bond, and wherein A 1 is O, A 2 is CH and A 3 is NH, and A 1a is O, A 2a is CH and A 3a is NH.

[0035] In one embodiment, the compound of Formula IV is selected from: or pharmaceutically acceptable salts thereof.

[0036] In one embodiment, there is provided a method of treating a patient in need of treatment for cardiovascular disease comprising administering an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating a patient in need of treatment for elevated plasma levels of Lp(a) comprising administering an effective amount of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, there is provided a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0038] In one embodiment, there is provided a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. In one embodiment, there is provided a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated plasma levels of Lp(a).

[0039] In one embodiment, there is provided the use of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiovascular disease. In one embodiment, there is provided the use of a compound of Formula I or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of elevated plasma levels of Lp(a).

[0040] The term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0041] The term "C 1-n alkyl" means a straight or branched chain saturated hydrocarbon containing one to n carbon atoms. C 1-4 Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, and t-butyl.

[0042] The term "C 1-3 alkylene" means a divalent straight or branched chain C 1-3 alkyl.

[0043] The term "C 1-4 haloalkyl" means C 1-4 alkyl as defined herein, substituted with one or more halogens. C 1-4 Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0044] The term "C 1-4 alkoxy" means a straight or branched chain saturated hydrocarbon containing one to four carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). C 1-4 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0045] The term "C 2-6 Alkynyl" refers to a straight chain or branched hydrocarbon containing 2 to 6 carbon atoms and at least one triple bond. The term "C 2-3 Alkynyl" refers to a straight chain or branched hydrocarbon containing 2 to 3 carbon atoms and at least one triple bond.

[0046] The term "C 3-6 Cycloalkyl" refers to a monocyclic saturated carbon ring containing 3 to 6 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term "C 3-5 Cycloalkyl" refers to a monocyclic saturated carbon ring containing 3 to 5 carbon atoms.

[0047] The term "heteroaryl" refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from N, S, and O. Examples of 5-membered heteroaryl groups include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryl groups include, but are not limited to, pyridine and pyridazine.

[0048] The term "bicyclic heteroaryl" refers to a bicyclic aromatic ring containing one or more heteroatoms, preferably selected from N, S, and O. Examples of 9-membered bicyclic heteroaryl groups include, but are not limited to, indole, isoindole, indazole, and pyrazolopyridine. Examples of 10-membered bicyclic heteroaryl groups include, but are not limited to, quinoline and chromene.

[0049] The term "4-, 5-, or 6-membered heterocycle" refers to a 4, 5, or 6-membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine and piperidine.

[0050] As used herein, the term "elevated Lp(a) plasma levels" refers to Lp(a) plasma levels equal to or greater than about 50 mg / dL. The compounds provided herein can be used in the treatment to reduce Lp(a) plasma levels.

[0051] As used herein, the term "oligomer" refers to a compound having at least two piperidine or morpholine moieties as shown in Formula I, II, or III. As used herein, a "piperidine moiety" refers to an optionally substituted piperidine. As used herein, a "morpholine moiety" refers to an optionally substituted morpholine. The piperidine and morpholine moieties in the oligomer can be the same or different.

[0052] The term "pharmaceutically acceptable salt" as used herein refers to salts of compounds that are acceptable for clinical use and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for preparing them are found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., Second Edition, Wiley-VCH, 2011 and S.M. Berge et al., "Pharmaceutical Salts, Journal of Pharmaceutical Sciences In particular, the compound of Formula I or II can be a zwitterion, monoacid, diacid, or triacid addition salt.

[0053] The pharmaceutical compositions of the present application can be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable" refers to one or more carriers, diluents and / or excipients that are compatible with the other ingredients of the composition and not injurious to the patient in a pharmaceutical sense. Examples of pharmaceutical compositions and methods for their preparation are well known to those skilled in the art and can be found in, for example, "Remington: The Science and Practice of Pharmacy", Loyd, V. et al., eds., 22ndedition, Mack Publishing Co., 2012.

[0054] The term "effective amount" as used herein refers to a dosage that is effective for treating a disorder. An effective amount for a particular patient can be determined by an experienced healthcare professional.

[0055] The terms "treating," "to treat," or "treatment" as used herein include slowing, alleviating, preventing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, "treating cardiovascular disease" refers to slowing, alleviating, preventing, or reversing the progression of a heart or blood vessel disease.

[0056] The term "patient" as used herein refers to a mammal. Preferably, the patient is a human.

[0057] The pharmaceutical composition can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. In one embodiment, the composition is suitable for oral administration.

[0058] Certain abbreviations can refer to the following: "ACN" refers to acetonitrile; "Apo" refers to apolipoprotein; "BOC" refers to tert-butyloxycarbonyl; "DCC" refers to N,N'-dicyclohexylcarbodiimide; "DCM" refers to dichloromethane; "DMA" refers to dimethylacetamide; "DMAP" refers to 4-dimethylaminopyridine; "DMEA" refers to dimethyl ethanolamine; "DMEM" refers to Dulbecco's Modified Eagle's Medium; "DMF" refers to dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "EACA" refers to epsilon-amino caproic acid or 6-amino hexanoic acid; "ELISA" refers to enzyme-linked immunosorbent assay; "EtOAc" refers to ethyl acetate; "FBS" refers to fetal bovine serum; "HEC" refers to hydroxyethylcellulose; "HEK" refers to human embryonic kidney; "HepG2" refers to human hepatocarcinoma cell line; "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; "HLB" refers to hydrophilic-lipophilic balance; "h" refers to hour(s); "HRP" refers to horseradish peroxidase; "IC 50 " refers to the concentration of an agent that produces 50% of the maximum inhibitory response possible for that agent; "IPA" refers to isopropyl alcohol / isopropanol; "MeCN" refers to acetonitrile; "min" refers to minute(s); "MTBE" refers to methyl tert-butyl ether; "RT" refers to room temperature; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TMB" refers to 3,3',5,5'-tetramethylbenzidine.

[0059] The skilled artisan can isolate or resolve the individual isomers, enantiomers, and diastereomers at any convenient point in the synthesis of the following compounds by methods known to the skilled artisan, such as selective crystallization techniques or chiral chromatography.

[0060] Compounds of Formula I or IV are readily converted to and can be isolated as pharmaceutically acceptable salts. Salts can be formed when pharmaceutically acceptable acids are added to form acid addition salts or pharmaceutically acceptable bases are added to form base addition salts. Salts can also be formed simultaneously with deprotection of a nitrogen or oxygen, i.e., removal of a protecting group. Examples of reactions and conditions for forming salts are known to the skilled artisan.

[0061] Compounds of Formula I or IV or any depicted formula, or salts thereof, can be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps of the described routes can be combined in different ways, or combined with steps from different routes, to prepare compounds or salts of the application. The products of each step in the following Preparations can be recovered by conventional means, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0062] In the following schemes, all substituents are as defined above unless otherwise indicated. The reagents and starting materials are readily available to one of ordinary skill in the art. The following schemes, preparations and examples are provided to further illustrate the application and not to limit the scope of the application. The compounds of the above formula, or salts thereof, can be prepared using starting materials or intermediates having the corresponding desired stereochemical configuration.

[0063] In Scheme 1, Step A, a cyclization reaction is depicted involving 2-(benzylamino)ethanol (1) with 2-(2-iodoethylidene)malonic acid diethyl ester in the presence of a base such as TEA to give compound (2).

[0064] Step B shows the reaction of compound (2) with a 3-nitrobenzyl halide [compound (35), optionally substituted as defined for Q 2 or as defined for Q 3 in Formula IV, and wherein "X a " is CI, Br or I] in the presence of a base such as cesium carbonate to give compound (3).

[0065] Step C shows decarboxylation and acid hydrolysis of compound (3) using aqueous HCI at elevated temperature to give compound (4).

[0066] Step D depicts the conversion of compound (4) to compound (5) by reacting compound (4) with 2-tert-butyl-l,3-diisopropylisourea under suitable conditions such as in the presence of a solvent such as 2-methyltetrahydrofuran.

[0067] Step E shows the debenzylating of compound (5) using 1-chloroethyl chloroformate followed by methanolysis to give compound (6).

[0068] Step F shows the protection of the amine in compound (6) using di-tert-butyl dicarbonate to give compound (7).

[0069] Step G shows the hydrogenation of compound (7) in the presence of a palladium catalyst in an alcoholic solvent such as ethanol to give compound (8).

[0070] Step H shows the coupling and cyclization of compound (8) in the presence of 1,1'- carbonyldiimidazole and 2-methyltetrahydrofuran as solvent under suitable conditions to give compound (9).

[0071] Step I depicts the deprotection of compound (9) using HCI as the acid and using a solvent such as DCM under acidic conditions to give compound (10) [compound of Formula IV].

[0072] In Scheme 2, Step A, a halogenation reaction is depicted in which an aniline compound (8) (optionally substituted as defined in Q 2 or as defined in Q 3 IV) is converted to an aryl bromide compound (11) by reaction of copper bromide in the presence of tert-butyl nitrite, tetrabutylammonium bromide as catalyst, an acid such as methylbenzenesulfonic acid monohydrate, and MeCN as solvent.

[0073] Step B shows the conversion of compound (11) to compound (12) as a byproduct of a palladium catalyzed cross-coupling reaction with a boronate ester (e.g. using Pd(dppf)Cl2and a carbonate base in a solvent such as 1,4-dioxane).

[0074] Step C shows the deprotection of compound (12) under acidic conditions (simultaneous removal of the BOC group and the tert-butyl ester) to give compound (13) [a compound of Formula IV]. An excess of HC1 is used to give the HC1 salt compound.

[0075] Step D depicts the formation of boronate ester compound (14) by reaction of compound (11) with bis(pinacolato)diboron in the presence of a palladium catalyst (e.g. Pd(dppf)Cl2), a base such as potassium acetate, and a solvent such as 1,4-dioxane.

[0076] Step E shows the Suzuki cross-coupling reaction of compound (14) with a 5-membered heteroaryl boronic acid or boronate ester in the presence of a palladium catalyst such as Pd(dppf)Cl2under appropriate conditions to give compound (15). "W" represents a 5-membered heteroaryl group optionally substituted with C 3-5 cycloalkyl.

[0077] Step F shows the deprotection of compound (15) in excess HC1 to give HC1 salt compound (16).

[0078] Step G depicts the deprotection of compound (9) in excess HC1 to give HC1 salt compound (17).

[0079] In Scheme 3, Step A, a cyclization reaction is depicted by reaction of compound (18) with ethyl 4-bromocrotonate in the presence of TEA to form compound (19).

[0080] Step B shows the formation of compound (20) by reaction of compound (19) with a benzaldehyde compound (36) (Q 1 and Q 2 as defined in Formula I) in the presence of potassium bis(trimethylsilyl)amide and a solvent such as THF.

[0081] Step C shows de-benzylation of compound (20) using a palladium catalyst and hydrogen gas to give compound (21).

[0082] Step D shows BOC protection of the amine in compound (21) by reaction of compound (21) with di-tert-butyldecarbonate and an amine base.

[0083] Step E shows hydrolysis of the ester compound (22) using MeOH and aqueous sodium hydroxide and a solvent such as THF to give compound (23).

[0084] Step F shows acid deprotection of compound (23) with excess HCl in diethyl ether and a solvent such as DCM to give HCl salt compound (24).

[0085] In Scheme 4, Step A, the formation of compound (26) is depicted by reaction of compound (25) with benzyl halide (36) (where "X a " is CI, Br or I, Q 1 and Q 2 as defined in Formula I) in the presence of potassium bis(trimethylsilyl)amide and a solvent such as THF.

[0086] Step B shows ester hydrolysis of compound (26) to form acid compound (27). The reaction is carried out in the presence of an aqueous base such as NaOH, MeOH and a solvent such as THF.

[0087] Step C shows removal of the BOC protecting group from compound (27) with excess HCl in diethyl ether and a solvent such as DCM to give HCl salt compound (28).

[0088] Step D shows removal of the BOC protecting group from compound (26) using HCl and a solvent such as 1,4-dioxane, DCM to give compound (29).

[0089] Step E: a reductive methylation is carried out by reaction of compound (29) with formaldehyde and sodium triacetoxyborohydride in the presence of a solvent such as MeOH to give compound (30).

[0090] Step F shows ester hydrolysis of compound (30) using MeOH and aqueous sodium hydroxide to give compound (31). Optionally, the product is treated with HCl and concentrated to provide the HCl salt of compound (31).

[0091] Step G shows a Sonogashira coupling reaction between ethynyl(trimethyl)silane and copper iodide and compound (26) (when Q 1 is CI, Br or I can occur) and a palladium catalyst [e.g. prepared in situ from 1,3-bis(diphenylphosphino)propane and tris(dibenzylideneacetone)dipalladium(0)] to give compound (32).

[0092] Step H shows ester hydrolysis and simultaneous alkynyl desilylation of compound (32) using aqueous base (e.g. sodium hydroxide) and MeOH and THF as solvents to give compound (33).

[0093] Step I shows removal of the BOC protecting group from compound (33) in the presence of excess HCI / ether to give compound (34) as the HCI salt.

[0094] Preparation 1 2-[4-benzylmorpholin-2-yl]propanedioic acid diethyl ester (racemic mixture) To a solution of 2-(2-iodoethyl)propanedioic acid diethyl ester (19 g, 61 mmol), 2-(benzylamino)ethanol (8.7 mL, 61 mmol) in H2O (1.5 mL / mmol, 91 mL) was added TEA (8.5 mL, 61 mmol) and the mixture was stirred at 100 °C for 1 hour. The reaction was cooled to room temperature, quenched with H2O and extracted with EtOAc. The solution was concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a light yellow oil (13 g, 64%). ES / MS (m / z). 336 [M+H].

[0095] Preparation 2 2-[(3-nitrophenyl)methyl]-2-[4-benzylmorpholin-2-yl]propanedioic acid diethyl ester (racemic mixture) To a solution of 2-[4-benzylmorpholin-2-yl]propanedioic acid diethyl ester (11.5 g, 34.3 mmol) in MeCN (171 mL) was added cesium carbonate (16.8 g, 51.4 mmol). The mixture was stirred at room temperature for 10 minutes, then 3-nitrobenzyl chloride (8.8 g, 51.4 mmol) was added. The resulting mixture was stirred at 80 °C for 16-18 hours. The reaction was cooled to room temperature, filtered, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a light yellow oil (14 g, 80%). ES / MS (m / z). 471 [M+H].

[0096] Preparation 3 3-(3-nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoic acid (mixture of isomers) To a solution of 2-[(3-nitrophenyl)methyl]-2-[4-benzylmorpholin-2-yl]propanedioic acid diethyl ester (racemic mixture, 14 g, 29.8 mmol) in 1,4-dioxane (149 mL) was added hydrochloric acid (6 M aqueous solution, 298 mL). The resulting mixture was stirred at 140 °C for 16-18 hours. The reaction was then cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH / DCM to give the title compound as a light yellow oil (10 g, 85%). ES / MS (m / z). 371 [M+H].

[0097] Preparation 4 3-(3-nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoic acid tert-butyl ester (mixture of isomers) To a solution of 3-(3-nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoic acid (mixture of isomers, 10 g, 27 mmol) in 2-methyltetrahydrofuran (162 mL) was added 2-tert-butyl-l,3-diisopropylisourea (25 mL, 108 mmol). The resulting mixture was stirred at 60 °C for 16-18 hours. The reaction was cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a light yellow oil (7 g, 61%). ES / MS (m / z). 427 [M+H].

[0098] Preparation 5 3-(3-nitrophenyl)-2-[morpholin-2-yl]propanoic acid tert-butyl ester (mixture of isomers) A mixture of 1-chloroethyl chloroformate (4.7 mL, 42.7 mmol) and N,N- diisopropylethylamine (5.7 mL, 32.8 mmol) was added to a solution of 3-(3- nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoic acid tert-butyl ester (mixture of isomers, 7 g, 16.4 mmol) in DCM (66 mL). The mixture was stirred at room temperature for 1 hour, then concentrated to dryness under vacuum. MeOH (164 mL) was added and the mixture was stirred at room temperature for 3 hours, then concentrated to dryness. The mixture was loaded onto an SCX cartridge and eluted first with MeOH (x2), then with NH3 / MeOH (2 N) (x2). The NH3 / MeOH eluate was concentrated under vacuum to give the title compound as a light yellow oil (5 g, 91%). ES / MS (m / z). 337 [M+H].

[0099] Preparation 6 2-[2-tert-butoxy-1-[(3-nitrophenyl)methyl]-2-oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (mixture of isomers) To a solution of 3-(3-nitrophenyl)-2-[morpholin-2-yl]propanoic acid tert-butyl ester (mixture of isomers, 5 g, 14.9 mmol) in DCM (74 mL) was added di-tert-butyl dicarbonate (3.9 g, 17.8 mmol). The mixture was stirred at room temperature for 16-18 hours, then concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a light green oil (6.5 g, 99%). ES / MS (m / z). 459 [M+Na].

[0100] Preparation 7 2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (mixture of isomers, Isomer 1, Isomer 2, Isomer 3 and Isomer 4) To a solution of 2-[2-tert-butoxy-l-[(3-nitrophenyl)methyl]-2-oxo-ethyl]morpholine-4- carboxylic acid tert-butyl ester (6.5 g, 15 mmol) in ethanol (150 mL) was added Lindlar catalyst (20 wt% palladium, 7.9 g, 15 mmol). The mixture was stirred at room temperature under hydrogen (balloon) for 2 hours. The mixture was filtered through celite and the filtrate was concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a white solid (isomer mixture) (4.1 g, 64%). ES / MS (m / z). 407 [M+H].

[0101] After two steps of purification, the mixture of 4 isomers (3.1 g) was separated by chiral SFC: 1) Three fractions were separated by chiral SFC [column-Chiralpak IG (10 x 4.6 cm, 5 pm); mobile phase: CO2(A) / EtOH (0.2% IPA) (B); elution program: gradient from 5%B to 25%B in 2 min - hold at 25%B for 1 min, then back to 5%B in 0.5 min; flow rate - 4 mL / min] to give isomer 1 (first eluting isomer, 552 mg), isomer 2 (second eluting isomer, 644 mg) as white solids, then a mixture of isomers 3 and 4 eluting after isomers 1 and 2.

[0102] 2) The mixture of isomers 3 and 4 obtained in the previous step was separated by chiral SFC [column-Chiralpak IC (10 x 4.6 cm, 5 pm); mobile phase: CO2(A) / EtOH (0.2% IPA) (B); elution program: gradient from 5%B to 25%B in 2 min - hold at 25%B for 1 min, then back to 5%B in 0.5 min; flow rate - 4 mL / min] to give isomer 3 (first eluting isomer under these conditions, 458 mg) and isomer 4 (second eluting isomer under these conditions, 548 mg) as white solids.

[0103] 2-[l-[(3-Aminophenyl)methyl]-2-tert-butoxy-2-oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5 and isomer 6) In a separate experiment, a sample of 4 g of a mixture of the 4 isomers was prepared. Separation of the diastereomers was achieved by reverse phase purification to give two diastereomers as racemic mixtures (first and second eluting diastereomers 1.61 g and 0.93 g, respectively). The first eluting diastereomer was then subjected to chiral SFC analysis [column: Chiralpak IC (25 x 2 cm, 5 pm); mobile phase: C02(A) / IPA (0.2% dimethyl ethylamine) (B); elution program: isocratic 20% B; flow rate: 65 mL / min] to give isomer 5 (first eluting isomer from chiral SFC under these conditions, 680 mg) and isomer 6 (second eluting isomer from chiral SFC under these conditions, 693 mg).

[0104] Preparation 8 2-[2-tert-butoxy-l-[[3-[[3-[3-tert-butoxy-2-(4-tert-butoxycarbonylmorpholin-2-yl)-3-oxo- propyl]phenyl]carbamoylamino]phenyl]methyl]-2-oxo-ethyl]morpholine-4-carboxylic acid tert-butyl ester (Isomer 1, Isomer 2, Isomer 3 and Isomer 4) Isomer 1 : To a solution of 2-[l-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4- carboxylic acid tert-butyl ester (Isomer 1, 200 mg, 0.5 mmol) in 2-methyltetrahydrofuran (7.4 mL) was added 1,1'-carbonyldiimidazole (240 mg, 1.5 mmol). The mixture was stirred at 80 °C for 16-18 hours. The reaction was cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc / hexanes to give the title compound as a colorless oil (65 mg, 16%). ES / MS (m / z): 740 [M+H-BOC].

[0105] Isomer 2, Isomer 3 and Isomer 4 were prepared in a similar manner: Isomer 2: 125 mg, 30%; as a colorless oil. ES / MS (m / z): 740 [M+H-BOC]. Isomer 3: 128 mg, 28%; as a colorless oil. ES / MS (m / z): 740 [M+H-BOC]. Isomer 4: 150 mg, 36%; as a light yellow solid. ES / MS (m / z): 740 [M+H-BOC].

[0106] Preparation 9 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5) Copper bromide (18 mg, 0.080 mmol) and tert-butyl nitrite (0.2 mL, 200 mg, 2 mmol) were added to a solution of 2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo- ethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5, 632 mg, 1.555 mmol), 4- methylbenzenesulfonic acid monohydrate (330 mg, 1.72 mmol), and tetrabutylammonium bromide (1 g, 3.071 mmol) in MeCN (19 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with MeOH and concentrated to dryness under vacuum. The crude product was purified with an HLB cartridge eluting with a gradient of 0 to 100% MeCN / NH4HCO3 (pH 9) to give the title compound as a light brown oil (630 mg, 75%). ES / MS (m / z): 314, 316 (M+H- tert butyl-Boc).

[0107] Preparation 10 2-(cyclopropyl)thiazole-4-boronic acid pinacol ester Pd(dppf)Cl2(40 mg, 0.048 mmol) was added to a mixture of 4-bromo-2- cyclopropylthiazole (200 mg, 0.941 mmol), bis(pinacolato)diboron (358 mg, 1.41 mmol), potassium acetate (185 mg, 1.89 mmol), and 1,4-dioxane (5 mL). The mixture was heated at 90 °C for 16-18 h while stirring. The reaction mixture was diluted with DCM, filtered through celite, and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with a gradient of EtOAc / hexanes (0 to 90%) to give the title compound (70 mg, 28%). ES / MS m / z: m / z = 252 [M+1].

[0108] Preparation 11 2-[2-tert-butoxy-1-[[3-[3-[3-tert-butoxy-2-(4-tert-butoxycarbonylmorpholin-2-yl)-3-oxo- propyl]phenyl]phenyl]methyl]-2-oxo-ethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5) A mixture of 2-(cyclopropyl)thiazole-4-boronic acid pinacol ester (70 mg, 0.3 mmol), Pd(dppf)Cl2(12 mg, 0.01 mmol) and sodium carbonate (2 mol / L in water, 0.47 mL, 0.9 mmol) was added to a solution of 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5, 126 mg, 0.3 mmol) in 1,4-dioxane (1.5 mL). The mixture was stirred at 100 °C for 16-18 hours. The reaction was cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by reverse phase chromatography (column: Claricep C series silica bonded C 18 ) eluting with a gradient of 5% to 25% MeCN in aqueous NH4HCO3(pH 9). The resulting residue was purified by reverse phase chromatography using the following conditions: column - XBridge TM C 18 (19 x 100 mm, 5 µm); mobile phase - Solvent A = 20 mM ammonium bicarbonate in water (pH 9), Solvent B = ACN; gradient 70% to 95% A:B; flow rate - 40 mL / min; to give the title compound (25 mg, 12%) as a cross coupling by-product. ES / MS (m / z): 681 (M+H-BOC).

[0109] Preparation 12 2-[2-tert-Butoxy-2-oxo-1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5) A mixture of 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5, 100 mg, 0.2126 mmol), bis(pinacolato)diboron (81 mg, 0.32 mmol), potassium acetate (42 mg, 0.43 mmol) and 1,4-dioxane (2 mL) was heated at 90 °C. Pd(dppf)Cl2(10 mg, 0.012 mmol) was added and the mixture was heated and stirred at 90 °C for 16-18 hours to give the title compound (110 mg, 99+%) which was used without purification in 13. ES / MS m / z = 518 [M+H].

[0110] Preparation 13 2-[2-tert-butoxy-l-[[3-(2-cyclopropylthiazol-4-yl)phenyl]methyl]-2- oxoethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5) To a solution of 2-[2-tert-butoxy-2-oxo-l-[[3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]methyl]ethyl]morpholine-4-carboxylic acid tert-butyl ester (isomer 5, 110 mg) in THF (2 mL) was added 4-bromo-2-cyclopropylthiazole (45 mg, 0.212 mmol), sodium carbonate (2 M in water, 390 mg, 0.371 mL, 0.743 mmol) and Pd(dppf)Cl2(10 mg, 0.0120 mmol). The resulting mixture was heated at 90 °C for about 16-18 hours. The reaction mixture was diluted with MeOH, filtered through celite and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with 0 to 90% EtOAc / hexanes, then further purified by reverse phase HPLC to give the title compound as a colorless oil (44.4 mg, 41%). ES / MS m / z = 515 [M+H].

[0111] Preparation 14 (Z)-2-[4-benzylmorpholin-2-yl]-3-phenyl-prop-2-enoic acid ethyl ester (racemic mixture) To a solution of 2-[4-benzylmorpholin-2-yl]acetic acid ethyl ester (racemic mixture, 3000 mg, 11.39 mmol) in THF (79.76 mL) under N2atmosphere at -78 °C was added potassium bis(trimethylsilyl)amide (1 M in THF, 17.09 mL, 17.09 mmol). The mixture was stirred at this temperature for 1 hour, then benzaldehyde (1.81 g, 1.74 mL, 17.09 mmol) was added at room temperature and stirred for 16-18 hours. The reaction mixture was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with 0-90% EtOAc / hexanes, then using an SCX column as follows. First, the SCX column (5 g) was conditioned eluting twice with MeOH, then the compound was dissolved in MeOH and loaded onto the column, eluting with MeOH, then with NH3 / MeOH (2 N). The NH3 / MeOH eluate was concentrated to dryness under vacuum to give the title compound (300 mg, 5%). ES / MS m / z = 352 [M+H].

[0112] Preparation 15 2-[morpholin-2-yl]-3-phenyl-propionic acid ethyl ester (mixture of isomers) To a solution of (Z)-2-[4-benzylmorpholin-2-yl]-3-phenyl-prop-2-enoic acid ethyl ester (racemic mixture, 300 mg, 0.854 mmol) in EtOH (8.5 mL) was added palladium (3 eq, 0.2725 g, 2.561 mmol, 100 mass%) and the mixture was stirred under a hydrogen balloon at room temperature for 16-18 hours. The mixture was filtered through celite, concentrated to dryness under vacuum and purified using an SCX cartridge (5 g). The SCX cartridge was pre-eluted twice with MeOH, then the crude product was dissolved in MeOH and loaded onto the cartridge and eluted with MeOH and NH3 / MeOH (2 N). The NH3 / MeOH eluate was concentrated to dryness under vacuum to give the title compound as a colourless oil (200 mg, 71 %). ES / MS m / z: m / z = 264 [M+H].

[0113] Preparation 16 2-[1-benzyl-2-ethoxy-2-oxo-ethyl]morpholine-4-carboxylic acid tert-butyl ester (mixture of isomers) To a solution of 2-[morpholin-2-yl]-3-phenyl-propionic acid ethyl ester (mixture of isomers, 200 mg, 0.760 mmol) in THF (13.7 mL) was added di-tert-butyl dicarbonate (205 mg, 0.912 mmol) and N,N-diisopropylethylamine (196 mg, 0.265 mL). The reaction was stirred at room temperature for 16-18 hours. The mixture was diluted with MeOH and concentrated to dryness under vacuum to give the title compound as a colourless oil (200 mg, 58%) which was used in the next step without further purification. ES / MS m / z = 308 [M+H-tBu].

[0114] Preparation 17 2-[4-tert-butoxycarbonylmorpholin-2-yl]-3-phenyl-propionic acid (mixture of isomers, isomer 1, isomer 2 and isomer 3) To a solution of tert-butyl 2-[l-benzyl-2-ethoxy-2-oxoethyl]morpholine-4-carboxylate (200 mg, 0.440 mmol, 80 mass%) in MeOH (4 mL) and THF (4 mL) was added sodium hydroxide (1 M in H20, 4.40 mL, 4.40 mmol). The resulting mixture was stirred at 55 °C for ~1.5 h. The mixture was concentrated to dryness under vacuum. The crude product was dissolved in EtOAc, neutralized to pH 4 with HC1 (1 M), extracted with EtOAc (x3), washed with saturated aqueous NaCl (x2). The organics were dried over a celite column, filtered, and concentrated to dryness under vacuum to give the title compound isomeric mixture as a colorless oil (140 mg, 94.8%). ES / MS m / z = 280 [M+H-tBu].

[0115] The isomeric mixture was combined with additional similarly prepared material to give 288 mg of isomeric mixture. The mixture was subjected to SFC [Column: Chiralpak AD (2 x 25 cm, 5 µm); Mobile phase: Isocratic 7% (MeOH + 0.2% dimethylamine) / CO2; Flow rate: 65 mL / min]. Three isomers of the title compound were isolated: Isomer 1 : 17.6 mg, >98% ee Isomer 2: 31.7 mg, 93% ee Isomer 3: 14.5 mg, 71% ee.

[0116] Preparation 18 4-[l-[(3-Bromophenyl)methyl]-2-ethoxy-2-oxoethyl]piperidine-l-carboxylic acid tert-butyl ester (racemic mixture) To a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)piperidine-l-carboxylate (CAS Registry Number: 135716-09-5; 5 g, 18.42 mmol) in THF (1590 mmol, 99.9 mass%) was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 22.11 mmol) under N2atmosphere at -78 °C. The mixture was stirred at -78 °C for 20 minutes, then a solution of l-bromo-4-(bromomethyl)benzene (22.11 mmol) in THF (14 mL) was added. The mixture was allowed to warm to room temperature, then stirred at room temperature for 30 minutes. MeOH was added, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography eluting with a 10-40% MTBE / hexanes gradient to give the title compound as a colorless oil (5.2 g, 54%). ES / MS m / z = 384, 386 [M+H- tert butyl].

[0117] The compounds in Table 1 were prepared in a similar manner to that of Preparation 18 using the appropriate corresponding reagents.

[0118] Table 1 Preparation No. Name Structure ES / MS m / z: 19 4-[1-[(4-bromophenyl)methyl]-2-ethoxy-2-oxoethyl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) 384, 386 [M+H-butyl] 20 4-[2-ethoxy-2-oxo-1-(p-tolylmethyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) 320 [M+H-t-Bu] 21 4-[2-ethoxy-1-[(3-methoxyphenyl)methyl]-2-oxoethyl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) 336 [M+H-t-Bu] 22 4-[1-[(2,3-dichlorophenyl)methyl]-2-ethoxy-2-oxoethyl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture) 375 (M-Bu+H)

[0119] Preparation 23 tert-Butyl 4-[2-ethoxy-2-oxo-l-[[4-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]piperidine-l- carboxylate (racemic mixture) Trimethylsilyl acetylene (22.71 mmol) was added to a mixture of tert-butyl 4-[l-[(4- bromophenyl)methyl]-2-ethoxy-2-oxo-ethyl]piperidine-l-carboxylate (2.5 g, 5.68 mmol), copper iodide (0.57 mmol), 1,3-bis(diphenylphosphino)propane (1.14 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.5677 mmol) in TEA (339 mmol). The resulting mixture was stirred at 120 °C for 16-18 hours. The mixture was cooled to room temperature, then filtered through celite, washing with EtOAc. The solvent was removed under vacuum, and purified by silica gel chromatography eluting with a 5-20% MTBE / hexanes gradient to give the title compound as a yellow oil (900 mg, 30%). ES / MS m / z 402 (M+H- tert butyl).

[0120] Preparation 24 3-(3-methoxyphenyl)-2-(4-piperidyl)propionic acid ethyl ester (racemic mixture) Phosphoric acid (500 µL) was added slowly to a solution of tert-butyl 4-[2- ethoxy-1-[(3-methoxyphenyl)methyl]-2-oxoethyl]piperidine-1-carboxylate (racemic mixture, 50 mg, 0.1277 mmol) and methanol (1.5 mL). The reaction was heated at 100 ºC in the microwave for 30 minutes and purified by SCX purification eluting with NH3 / MeOH to give the title compound (40 mg, 80.61%). ES / MS m / z = 292 [M+H].

[0121] Preparation 25 3-(3-bromophenyl)-2-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid (isomer 1 and isomer 2) Sodium hydroxide (2 M in water, 82 mmol, 41 mL) was added to a solution of tert-butyl 4-[1-[(3-bromophenyl)methyl]-2-ethoxy-2-oxo-ethyl]piperidine-1-carboxylate (4 g, 9.08 mmol) in THF (45 mL) and MeOH (18 mL). The mixture was allowed to react at 50 °C for 21 hours. The solvent was partially concentrated, acidified with HCI (1 N) to pH 3 and extracted with EtOAc (x3). The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum. The residue was purified using silica gel chromatography eluting with EtOAc / hexanes (0% to 25% gradient) to give the title compound as a racemic mixture as a light yellow oil (1.12 g, 30%). ES / MS m / z = 356, 358 [M+H- tert butyl].

[0122] The isomeric mixture was combined with additional material prepared in essentially the same manner to give 2.29 g of a racemic mixture which was subjected to chiral SFC [Column: Chiralpak AD (2 x 25 cm, 5 µm); Mobile phase: Isocratic 15% (IPA + 0.2% dimethylamine) / CO2; Flow rate 65 mL / min] to give isomer 1 (first eluting isomer, >95% ee) and isomer 2 (second eluting isomer, >90% ee).

[0123] The compounds in Table 2 were prepared in a similar manner to that of Preparation 25 using the appropriate corresponding reagents.

[0124] Table 2 Ex. No. Name Structure ES / MS m / z 26 2-(1-tert-butoxycarbonyl-4-piperidyl)-3-(4-ethynylphenyl)propionic acid (racemic mixture) a, b ]] 302 [M+H-butyl] 27 2-(1-tert-butoxycarbonyl-4-piperidyl)-3-(2,3-dichlorophenyl)propionic acid (isomer 1 and isomer 2) c ]]> 346 [M+H-butyl] a. Using tert-butyl 4-[2-ethoxy-2-oxo-1-[[4-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]piperidine-1-carboxylate as the starting material; under the reaction conditions, the TMS group is removed. b. Chiral chromatographic analysis of the product was not performed. c. The product was subjected to chiral SFC [column: Chiralcel OD (2×25 cm, 5 µm); mobile phase: isocratic 15% MeOH / CO2; flow rate: 65 mL / min] to obtain isomer 1 (first eluting isomer) and isomer 2 (second eluting isomer).

[0125] Preparation 28 Ethyl 2-(4-piperidinyl)-3-(p-tolyl)propionate (racemic mixture) A solution of tert-butyl 4-[2-ethoxy-2-oxo-1-(p-tolylmethyl)ethyl]piperidine-1-carboxylate (racemic mixture, 148 mg, 0.394 mmol) was dissolved in DCM (5.9 mL) and HCl (4 M in 1,4-dioxane, 4.9 mL). The mixture was stirred at room temperature for 16–18 hours. The mixture was diluted with MeOH, concentrated to dryness under vacuum, and purified using an SCX column (5 g loaded). The SCX column was pre-eluted with MeOH, and the crude product dissolved in MeOH was then packed into the column and eluted with MeOH and NH3 / MeOH (2 N). The NH3 / MeOH eluent was concentrated to dryness under vacuum to give the title compound (105 mg, 87%) as a colorless oil. ES / MS m / z = 276 [M+H].

[0126] Preparation 29 Ethyl 2-(1-methyl-4-piperidinyl)-3-(p-tolyl)propionate (racemic mixture) Formaldehyde (37% by mass in water, 93 mg, 0.087 mL, 1.14 mmol) was added to a solution of ethyl 2-(4-piperidinyl)-3-(p-tolyl)propionate (racemic mixture, 105 mg, 0.381 mmol) in methanol (3.8 mL). The mixture was stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.121 g, 0.572 mmol) was added. The resulting mixture was stirred at room temperature for 16–18 hours. The reaction mixture was concentrated to dryness under vacuum and diluted with saturated NaHCO3 and DCM. The organic layer was collected using a phase separator cartridge and concentrated to dryness under vacuum to give the title compound (96 mg, 75.69%) as a colorless oil. ES / MS m / z: m / z = 290 [M+H].

[0127] Preparation 30 2-(1-Methyl-4-piperidinyl)-3-(p-Tolyl)propionic acid (racemic mixture) The title compound was prepared substantially as described in Preparation 25 using ethyl 2-(1-methyl-4-piperidinyl)-3-(p-tolyl)propionate (racemic mixture), and purified on an HLB column using 0-100% MeCH / NH4HCO3 aqueous solution (pH 9). Chiral chromatographic analysis of the racemic mixture was not performed. ES / MS m / z = 262 [M+H].

[0128] Example 1 3-[3-[[3-(2-carboxy-2-morpholin-2-yl-ethyl)phenyl]carbamoylamino]phenyl]-2-morpholin-2-yl-propionic acid; dihydrochloride (isomer 1 - Example 1a) HCl (2 mol / L in diethyl ether, 1.9 mL, 3.9 mmol) was added to a solution of 2-[2-tert-butoxy-1-[[3-[[3-[3-tert-butoxy-2-(4-tert-butoxycarbonylmorpholin-2-yl)-3-oxo-propyl]phenyl]carbamoylamino]phenyl]methyl]-2-oxo-ethyl]morpholin-4-carboxylic acid tert-butyl ester (isomer 1, 65 mg, 0.08 mmol) in DCM (1.1 mL). The mixture was stirred at room temperature for 16–18 hours. The mixture was then concentrated to dryness under N2 flow at 40 °C. The solid was ground with MTBE and sonicated. The solid was filtered, washed with MTBE, and dried under high vacuum. The solid was dissolved in a minimal amount of water, concentrated to dryness under N2 flow at 40 °C, and dried in a high vacuum oven at 45 °C to give the title compound (isomer 1, 40 mg, 77%) as a pale yellow solid. ES / MS (m / z): 527 [M+H).

[0129] The other isomers were prepared in a similar manner: Isomer 2 of the title compound (Example 1b), starting from isomer 2 of the starting material: 75 mg, 79%; a pale yellow solid. ES / MS (m / z): 527 [M+H]). Isomer 3 of the title compound (Example 1c), starting from isomer 3 of the starting material: 80 mg, 90%; a pale yellow solid. ES / MS (m / z): 527 [M+H]). Isomer 4 of the title compound (Example 1d), starting from isomer 4 of the starting material: 105 mg, 95%; a pale yellow solid. ES / MS (m / z): 527 [M+H]).

[0130] The compounds in Table 3 were prepared using appropriate BOC-protected starting materials in a manner similar to that of Example 1.

[0131] Table 3 Ex. No. Name Structure ES / MS m / z 2 3,3'-([1,1'-biphenyl]-3,3'-diyl)bis(2-(morpholin-2-yl)propanoic acid) dihydrochloride (isomer 5) a ]] 469 (M+H) 3 3-[3-(2-cyclopropylthiazol-4-yl)phenyl]-2-morpholin-2-yl-propionic acid; hydrochloride (isomer 5) b ]] 359 (M+H) 4 3-(3-aminophenyl)-2-[(2S)-morpholin-2-yl]propanoic acid; hydrochloride (isomer 1) c ]] 251 (M+H) 5 2-morpholin-2-yl-3-phenylpropionic acid; hydrochloride salt (isomer 3) d ]]> 236 (M+H) 6 3-(3-bromophenyl)-2-(4-piperidinyl)propionic acid; hydrochloride (isomer 2) e ]]> 312, 314 (M+H) 7 2-(1 -methyl-4-piperidinyl)-3-(p-tolyl)propionic acid; hydrochloride (racemic mixture) f ]] 262 (M+H) 8 3-(4-ethynylphenyl)-2-(4-piperidinyl)propionic acid; hydrochloride (racemic mixture) g ]] 258 (M+H) 10 3-(2,3-dichlorophenyl)-2-(piperidin-4-yl)propionic acid hydrochloride (isomer 1) h ]] 302 (M+H) a. Starting material used: 2-[2-tert-butoxy-1-[[3-[3-[3-tert-butoxy-2-(4-tert-butoxycarbonylmorpholin-2-yl)-3-oxo-propyl]phenyl]phenyl]methyl]-2-oxo-ethyl]morpholin-4-carboxylic acid tert-butyl ester (isomer 5) b. Starting material used: tert-butyl 2-[2-tert-butoxy-1-[[3-(2-cyclopropylthiazolyl-4-yl)phenyl]methyl]-2-oxoethyl]morpholine-4-carboxylic acid (isomer 5) c. Starting material used: tert-butyl 2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxoethyl]morpholine-4-carboxylate (isomer 1) d. Starting material used: 2-[4-tert-butoxycarbonylmorpholino-2-yl]-3-phenylpropionic acid (isomer 3) e. Starting material used: 3-(3-bromophenyl)-2-(1-tert-butoxycarbonyl-4-piperidinyl)propionic acid (isomer 2) f. Starting material used: 2-(1-methyl-4-piperidinyl)-3-(p-tolyl)propionic acid (racemic mixture); under the conditions described, no chemical transformation occurs except for the formation of an HCl salt. g. Starting material used: 2-(1-tert-butoxycarbonyl-4-piperidinyl)-3-(4-ethynylphenyl)propionic acid (racemic mixture) h. Starting material used: 2-(1-tert-butoxycarbonyl-4-piperidinyl)-3-(2,3-dichlorophenyl)propionic acid (isomer 1).

[0132] Example 11 3-(3-Methoxyphenyl)-2-(4-piperidinyl)propionic acid (racemic mixture) To a mixture of ethyl 3-(3-methoxyphenyl)-2-(4-piperidinyl)propionate (40 mg, 0.14 mmol) and THF (1.5 mL), NaOH (56 mg, 1.4 mmol) and MeOH (1.5 mL) were added. The mixture was stirred at 70°C for 12 hours, then cooled to room temperature, and HCl (1 N aqueous solution, 1.26 mL, 1.26 mmol) was added. The reaction mixture was loaded onto an SCX column (10 g), washed with MeOH and DCM, eluted with 20 mL of 2.0 M NH3 / MeOH, collected, and concentrated. The residue was purified by reversed-phase HPLC to give the title compound (14.7 mg, 41%) as a white solid. ES-MS m / z 264 (M+H).

[0133] In vitro Lp(a) assembly detection The ability of the compounds to inhibit Lp(a) particle formation in vitro was assessed using a cell-free assembly assay. Conditioned medium (supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin in DMEM) was collected from confluent wild-type HepG2 cells (the source of endogenously expressed ApoB) and from a stable HEK293 cell line expressing human Apo(a) protein with 17 Kringle repeats (selected on 1 mg / ml genistein) after 24 hours of culture at 37°C and 5% CO2. In vitro assembly assays were performed by combining equal portions of HepG2 and HEK293 conditioned medium with serially added test compounds (final concentrations 0.01–100 nM). The reaction was incubated at 37°C for 2 hours and then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Lp(a) capture antibody and HRP-labeled anti-ApoB detection antibody. ELISA was performed using TMB colorimetry, terminated with 1 N sulfuric acid, and the signal was read at 450 nm using a Molecular Devices reader. The percentage inhibition of Lp(a) formed under each experimental condition was determined by setting the assembly reaction without inhibitors (with a matched DMSO concentration of 1%) as 0% inhibition and the assembly reaction with minimal HepG2 conditioned medium (50-fold dilution) as 100% inhibition. Data were fitted to a 4-parameter curve to determine the IC50 values ​​summarized in Table 4. 50 Values. Adding the test compounds from the examples to conditioned media containing ApoB and Apo(a) resulted in concentration-dependent inhibition of in vitro Lp(a) formation as summarized in Table 4. The results indicate that these compounds inhibit the assembly of Lp(a) by Apo(a) and LDL particles.

[0134] Table 4

Claims

1. A compound of the formula: ###0001### or a pharmaceutically acceptable salt thereof; wherein Y is CH2, O, or S; A 1 is NH, A 2 is CH and A 3 is O; A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH; Z is H, C 1-4 alkyl, OH or cyclopropyl; n is 0, 1, 2, or 3; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2or a 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; halogen; R 10 selected from the group consisting of: NH2; C optionally substituted by one to four OH or OCH3 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; naphthyl; phenoxy optionally substituted with methoxy; 3,4-dihydro-2H-1 λ 2 - quinoline; m is 0 or 1; and 4-, 5- or 6-membered heterocycle, which is optionally substituted by OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl, which is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is H. R 15 is H or C 1-3 alkyl.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

7. A compound of the formula: ###0003### or a salt thereof; wherein 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q 1 is H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, or a 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein Q 2 is H or halogen. Y is CH2, O, or S; n is 0, 1, 2, or 3; R 1a is H, CH3, or a protecting group; X is OH or C 1-4 alkoxy; halogen; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2, or a 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; NH2; R 10 selected from the group consisting of: naphthyl; C optionally substituted by one to four OH or OCH3 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; phenoxy optionally substituted with methoxy; m is 0 or 1; and 3,4-dihydro-2H-1 λ 2 - quinoline; 8. A compound of the formula: ###0004### or a salt thereof; wherein 4-, 5- or 6-membered heterocycle, which is optionally substituted by OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl, which is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, which is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; Y is CH2, O, or S; R 15 is H or C 1-3 alkyl, wherein if X is OH, then R 1a must be a protecting group. n is 0, 1, 2, or 3; halogen; R 1a is H, CH3, or a protecting group; X is OH or C 1-4 alkoxy; NH2; Q 1 is -(CH2) n NR 15 (CH2) n R 10 , -B(OR 10 )2, boronic acid pinacol ester, boronic acid 1,3-propanediol ester, boronic acid 2,2-dimethyl-1,3-propanediol ester, -(CH2) n NHCONR 15 R 10 , H, halogen, C 1-2 alkyl, C 2-3 alkynyl, OCH3, NH2or a 5-membered heteroaryl optionally substituted with C 3-5 cycloalkyl; Q 2 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; naphthyl; R 10 selected from the group consisting of: phenoxy optionally substituted with methoxy; C optionally substituted by one to four OH or OCH3 1-4 alkyl; C can be optionally replaced by one or two halogens 3-6 cycloalkyl; C optionally substituted by OCH3 1-4 haloalkyl; C 2-6 alkynyl; m is 0 or 1; and 10. Use of a compound according to any one of claims 7-9, or a salt thereof, in the preparation of an oligomer. 3,4-dihydro-2H-1 λ 2 - quinoline; 11. An oligomer prepared from a compound according to any one of claims 7-9, or a salt thereof. 4-, 5- or 6-membered heterocycle, which is optionally substituted by OCH3, C 1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2) m phenyl, wherein phenyl is optionally substituted by one or two substituents selected from the group consisting of halogen and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl, optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, halogen, pyrrolidine, or benzyl or phenyl, wherein benzyl or phenyl is optionally substituted with halogen; and phenyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2) n phenyl, wherein phenyl is optionally substituted with one or two halogen; 12. The oligomer according to claim 11, comprising at least two piperidine moieties, at least two morpholine moieties, or a combination thereof. R 15 is H or C 1-3 alkyl, wherein if X is OH, then R 1a must be a protecting group.

9. The compound of claim 7 or claim 8, or a salt thereof, wherein R 1a is a protecting group and the protecting group is selected from the group consisting of: tert-butyloxycarbonyl, carboxybenzyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, tritylamine, and p-toluenesulfonamide.

13. The oligomer according to claim 11, comprising at least three piperidine moieties, at least three morpholine moieties, or a combination thereof.

14. A compound of the formula: ###0005### or a pharmaceutically acceptable salt thereof; wherein Y is, at each occurrence, independently CH2, O, or S; p is, at each occurrence, independently 0 or 1; 15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein Z is, at each occurrence, H.

16. The compound according to claim 14 or claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is, at each occurrence, CH2. A 1 is NH, A 2 is CH and A 3 is O; A 1 is O, A 2 is CH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is NH; A 1 is CH, A 2 is NH and A 3 is CH; or A 1 is CH, A 2 is N(CH3) and A 3 is CH; A 1a is NH, A 2a is CH and A 3a is O; A 1a is O, A 2a is CH and A 3a is NH; A 1a is CH, A 2a is NH and A 3a is NH; A 1a is CH, A 2a is NH and A 3a is CH; or A 1a is CH, A 2a is N(CH3) and A 3a is CH; Z is, at each occurrence, independently H, C 1-4 alkyl, OH, or cyclopropyl; 18. The compound according to any one of claims 14 to 17, or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)NH- or a bond. L is -(CH2) p NHC(O)NH(CH2) p - -(CH2) p NH(CH2) p - a bond, or ; Q 3 is H, C 1-4 alkyl, cyclopropyl, CF3, OH, C 1-4 alkoxy, O-cyclopropyl, OCF3, halogen or CN; 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. A 1b is NH, A 2b is CH and A 3b is O; A 1b is O, A 2b is CH and A 3b is NH; A 1b is CH, A 2b is NH and A 3b is NH; A 1b is CH, A 2b is NH and A 3b is CH; or A 1b is CH, A 2b is N(CH3) and A 3b is CH; and L 2 is C1-3alkylene or a bond.

21. A method of treating cardiovascular disease in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof.

22. A method of treating elevated Lp(a) plasma levels in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 14 to 16, wherein Q 3 at each occurrence is H.

23. A compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof, for use in therapy.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 14 to 18, wherein A 1 is O, A 2 is CH and A 3 is NH, and A 1a is O, A 2a is CH and A 3a is NH.

24. A compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease.

25. A compound according to any one of claims 1 to 6 or 14 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated Lp(a) plasma levels. ​ ​ ​ ​

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