Piperidine, morpholine and tetrahydro-pyridazine compounds with lp(a) lowering activity

Abstract

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

Description

Piperidine, Morpholine and Tetrahydro-Pyridazine Compounds with Lp(a) Lowering Activity FIELD OF THE INVENTION

[0001] This invention relates to piperidine, morpholine and tetrahydro-pyridazine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and therapeutic uses of the compounds, in particular their use in lowering lipoprotein(a) (Lp(a)) plasma levels. BACKGROUND OF THE INVENTION

[0002] There have been significant advances in treating cardiovascular disease (CVD). Despite treatment advances, patients continue to experience cardiovascular disease events such as angina, myocardial infarction, and stroke, which if untreated, lead to death. Lipid disorder or dyslipidemia remains a major risk factor for CVD. Lipid disorders can be divided into four general risk factors: elevated low-density lipoprotein cholesterol (LDL-c), low high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated Lp(a). There are a variety of treatment regimens targeting elevated LDL-c, low HDL-c, and elevated triglycerides. There are few approved treatment options for patients with elevated Lp(a) concentrations. In some cases, apheresis may be used to filter the blood to remove LDL and Lp(a); however, the effects are temporary and typically need to be repeated every two weeks. There is currently no pharmaceutical treatment approved specifically to lower Lp(a) levels.

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

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

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

[0006] Additional treatment options are desired for patients suffering from cardiovascular diseases and, in particular, patients suffering from lipid disorders or dyslipidemia. There is a need for additional treatment options for patients whose cardiovascular risks are not adequately managed using current standard of care therapies, such as, diet, exercise and / or the use of one or more drugs such as statins, fibrates, and niacin. More particularly, there is a need for further, alternative pharmaceutically acceptable compounds which inhibit the formation of Lp(a) and thus, reduce plasma Lp(a) levels. SUMMARY OF THE INVENTION

[0007] Accordingly, in a first aspect, there is provided a compound of Formula I:I wherein A1is NH, A2is CH and A3is O; A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH; Z is H, C1-4 alkyl, OH or cyclopropyl; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2 alkyl, C2-3 alkynyl, OCH3, NH2 or a 5-membered heteroaryl optionally substituted with C3-5cycloalkyl; Q2is H, C1-4alkyl, cyclopropyl, CF3, OH, C1-4alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3;R10is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6 cycloalkyl optionally substituted with one or two halo; C1-4haloalkyl optionally substituted with OCH3; C2-6alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4 alkoxy, C1-4 alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0008] In a second aspect, there is provided a compound of Formula II:wherein R1ais H, CH3 or a protecting group;X is OH or C1-4 alkoxy; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2alkyl, C2-3alkynyl, OCH3, NH2or a 5-membered heteroaryl optionally substituted with C3-5cycloalkyl; Q2is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R10is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6cycloalkyl optionally substituted with one or two halo; C1-4 haloalkyl optionally substituted with OCH3; C2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4alkoxy, C1-4alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3alkyl, or a salt thereof, wherein if X is OH then R1amust be a protecting group.

[0009] In a third aspect, there is provided a compound of Formula III:wherein R1ais H, CH3or a protecting group; X is OH or C1-4 alkoxy; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2 alkyl, C2-3 alkynyl, OCH3, NH2 or a 5-membered heteroaryl optionally substituted with C3-5cycloalkyl; Q2is H, C1-4alkyl, cyclopropyl, CF3, OH, C1-4alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R10is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6 cycloalkyl optionally substituted with one or two halo; C1-4haloalkyl optionally substituted with OCH3; C2-6alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3;5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4alkoxy, C1-4alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3alkyl, or a salt thereof, wherein if X is OH then R1amust be a protecting group.

[0010] In a fourth aspect, there is provided the use of a compound of Formula II or 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 III, or a salt thereof. In an embodiment, the oligomer comprises at least two piperidine, at least two morpholine moieties, or a combination thereof. In another 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:IV wherein A1is NH, A2is CH and A3is O; A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH; A1ais NH, A2ais CH and A3ais O; A1ais O, A2ais CH and A3ais NH; A1ais CH, A2ais NH and A3ais NH; A1ais CH, A2ais NH and A3ais CH; or A1ais CH, A2ais N(CH3) and A3ais CH; Z at each occurrence is independently H, C1-4 alkyl, OH or cyclopropyl; Y at each occurrence is independently CH2, O or S; L is -(CH2)pNHC(O)NH(CH2)p-, -(CH2)pNH(CH2)p-, a bond,Q3is H, C1-4alkyl, cyclopropyl, CF3, OH, C1-4alkoxy, O-cyclopropyl, OCF3, halo, or CN; p is at each occurrence independently 0 or 1; A1bis NH, A2bis CH and A3bis O; A1bis O, A2bis CH and A3bis NH; A1bis CH, A2bis NH and A3bis NH; A1bis CH, A2bis NH and A3bis CH; or A1bis CH, A2bis N(CH3) and A3bis CH; and L2is C1-3alkylene or a bond, or a pharmaceutically acceptable salt thereof.

[0013] In a seventh aspect, there is provided 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.

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

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

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

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

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

[0019] In an embodiment of a compound of Formula I, Z is H.

[0020] In an embodiment of a compound of Formula I, Y is CH2.

[0021] In an embodiment of a compound of Formula I, A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH.

[0022] In an embodiment of a compound of Formula I, Q1is H, halo, C1-2alkyl, C2-3alkynyl, OCH3, or a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl.

[0023] In an embodiment of a compound of Formula I, Q2is H or halo.

[0024] In an embodiment, there is provided a compound of Formula Ia: ,or a pharmaceutically acceptable salt thereof. Formula I encompasses Formula Ia and reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to Formula Ia.

[0025] In an embodiment, there is provided a compound of Formula Ia wherein A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH, and wherein Q1is H, halo, C1-2alkyl, C2-3alkynyl, OCH3, NH2or a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl, and Q2is H or halo.

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

[0027] In an embodiment of a compound of Formula II or III, R1ais a protecting group and the protecting group is selected from: tert-butyloxycarbonyl, carboxybenzyl, 9- fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl,trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide. In a particular embodiment, R1ais tert-butyloxycarbonyl.

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

[0029] In an embodiment of a compound of Formula IV, Y at each occurrence is CH2.

[0030] In an embodiment of a compound of Formula IV, Q3at each occurrence is H.

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

[0032] In an embodiment of a compound of Formula IV, L is A1is O, A2is CH and A3is NH, and A1ais O, A2ais CH and A3ais NH.

[0033] In an embodiment, there is provided a compound of Formula IVa:, IVa or a pharmaceutically acceptable salt thereof. Formula IV encompasses Formula IVa and reference to Formula IV below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to Formula IVa.

[0034] In an embodiment, there is provided a compound of Formula IVa wherein L is - NHC(O)NH- or a bond and wherein A1is O, A2is CH and A3is NH, and A1ais O, A2ais CH and A3ais NH.

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

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

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

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

[0039] In an 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 an 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 Lp(a) plasma levels.

[0040] The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0041] The term “C1-nalkyl” refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of a C1-4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl.

[0042] The term “C1-3alkylene” refers to a bivalent straight or branched C1-3alkyl group.

[0043] The term “C1-4 haloalkyl” refers to a C1-4 alkyl group, as defined herein, which is substituted with one or more halogen. Examples of C1-4 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.

[0044] The term “C1-4alkoxy” refers to a straight, or branched chain saturated hydrocarbon containing 1 to 4 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of C1-4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.

[0045] The term “C2-6alkynyl” refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms and at least one triple bond. The term “C2-3 alkynyl” refers to a straight or branched chain hydrocarbon containing 2 to 3 carbon atoms and at least one triple bond.

[0046] The term “C3-6 cycloalkyl” refers to a monocyclic saturated carbon ring containing between 3 and 6 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term “C3-5 cycloalkyl” refers to a monocyclic saturated carbon ring containing between 3 and 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 heteroaryls include, but are not limited to, pyrazole, triazole and thiazole. Examples of 6-membered heteroaryls include, but are not limited to, pyridine and pyridazine.

[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 heteroaryls include, but are not limited to, indole, isoindole, indazole and pyrazolopyridine. Examples of 10-membered bicyclic heteroaryls include, but are not limited to, quinoline and chromene.

[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” means a plasma level of Lp(a) that is equal to or above about 50 mg / dL. A compound provided herein may be used in treatment to reduce Lp(a) plasma levels.

[0051] As used herein, the term “oligomer” means compounds that have at least two of the piperidine or morpholine moieties set out in formula I, II or III. As used herein, “piperidine moiety” refers to an optionally substituted piperidine. As used herein, “morpholine moiety” refers to an optionally substituted morpholine. The piperidine and morpholine moieties in an oligomer may be the same or different.

[0052] The term “pharmaceutically acceptable salt” as used herein refers a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley- VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. In particular, the compounds of Formula I or II may be a zwitterion, a mono-, di, or tri-acid addition salt.

[0053] The pharmaceutical compositions for the present invention may be prepared using pharmaceutically acceptable additives. The term “pharmaceutically acceptable” refers to one or more carriers, diluents, and / or excipients that are compatible with the other components of the composition and not pharmaceutically deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation are well known to the skilled artisan, and can be found, for example, in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012.

[0054] As used herein, the term “effective amount” refers to a dosage amount that is effective in treating a disorder. The effective amount for a particular patient can be determined by a skilled health professional.

[0055] As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, reducing, preventing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, “treating cardiovascular disease” means slowing, reducing, preventing, or reversing the progression of heart or blood vessel disease.

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

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

[0058] Certain abbreviations may refer to the following: “ACN” refers to acetonitrile; “Apo” refers to Apolipoprotein; “BOC” refers to tert-butoxycarbonyl; “DCC” refers to N,N'- dicyclohexylcarbodiimide; “DCM” refers to dichloromethane; “DMA” refers dimethylacetamide; “DMAP” refers to 4-dimethylaminopyridine; “DMEA” refer to dimethylethanolamine; “DMEM” refers to Dulbecco’s Modified Eagle’s Medium; “DMF” refers to dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EACA” refers to epsilon-aminocaproic acid or 6-aminocaproic acid; “ELISA” refers to enzyme-linked immunosorbent assay; “EtOAc” refers to ethyl acetate; “FBS” refers to Fetal Bovine Serum; “HEC” refers to hydroxy ethyl cellulose; “HEK” refers to human embryonic kidney; “HepG2” refers to a human hepatoma cell line; “HEPES” refers to 4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid; “HLB” refers to hydrophilic-lipophilic balance; “h” refers to hour / hours; “HRP” refers to Horseradish Peroxidase; “IC50” refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for thatagent; “IPA” refers to isopropyl alcohol or isopropanol; “MeCN” refers to acetonitrile; “min” refers to minute / s; “MTBE” refers to methyl tert-butyl ether; “RT” refers to room temperature; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; and “TMB” refers to 3,3’,5,5’-teramethylbenzidine.

[0059] Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds listed below, by methods known to the artisan, such as selective crystallization techniques or chiral chromatography.

[0060] A compound of Formula I or IV is readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt or by the addition of a pharmaceutically acceptable base to form a base addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, i.e., removing the protecting group. Examples, reactions and conditions for salt formation are known to the skilled artisan.

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

[0062] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. Compounds of afore-depicted formulae, or salts thereof may be prepared by using starting materials or intermediates with the corresponding desired stereochemical configuration.

[0063] In Scheme 1 Step A depicts a cyclization reaction that involves 2- (benzylamino)ethanol (1) and diethyl 2-(2-iodoethylidene)propanedioate in the presence of a base such as TEA to give compound (2).

[0064] Step B shows a reaction of compound (2) with a 3-nitrobenzyl halide [compound (35), optionally substituted with Q2as defined in Formula I or Q3as defined in Formula IV, and where “Xa” is Cl, 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 HCl at elevated temperature to give compound (4).

[0066] Step D depicts converting compound (4) to compound (5) by reacting compound (4) with 2-tert-butyl-1,3-diisopropylisourea under suitable conditions, such as in the presence of a solvent such as 2-methyltetrahydrofuran.

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

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

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

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

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

[0072] In Scheme 2, Step A depicts a halogenation reaction in which aniline compound (8) (optionally substituted with Q2as defined in Formula I or Q3as defined in Formula IV) is converted to aryl bromide compound (11) by a reaction of cupric bromide in the presence of tert- butyl nitrite, tetrabutylammonium bromide as a catalyst, an acid such as methylbenzenesulfonic acid monohydrate and MeCN as a solvent.

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

[0074] Step C shows deprotection (simultaneous removal of BOC groups and tert-butyl esters) of compound (12) to give compound (13) [a compound of Formula IV] in acidic conditions. Excess HCl is used to give a HCl salt compound.

[0075] Step D depicts formation of a boronic ester compound (14) by reacting 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 a Suzuki cross coupling reaction of compound (14) with 5-membered heteroaryl boronic acids or boronic esters in the presence of a palladium catalyst such as Pd(dppf)Cl2under suitable conditions to give compound (15). “W” represents a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl.

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

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

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

[0080] Step B shows formation of compound (20) by reacting compound (19) with benzaldehyde compound (36) (Q1and Q2are as defined in Formula I) in the presence of potassium bis(trimethylsilyl)amide, and a solvent such as THF.

[0081] Step C shows debenzylation of compound (20) by use of palladium catalyst and hydrogen gas to give compound (21).

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

[0083] Step E shows hydrolysis of ethyl ester compound (22) by use of 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 the HCl salt compound (24) Scheme 4

[0085] In Scheme 4, Step A depicts formation of compound (26) by reacting compound (25) with benzyl halide (36) (wherein “Xa” is Cl, Br, or I, and Q1and Q2are 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 the acid compound (27). The reaction is carried out in a presence of an aqueous base such as NaOH, MeOH and a solvent such as THF.

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

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

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

[0090] Step F shows ester hydrolysis of compound (30) by use of 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 Sonogashira coupling between ethynyl(trimethyl)silane and cuprous iodide and compound (26) (which is possible when Q1is Cl, Br, or I) 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 desilylation of the alkynyl group in compound (32) using aqueous base (e.g. sodium hydroxide) and MeOH and THF as the solvent to give compound (33).

[0093] Step I shows the removal of the BOC protecting group from compound (33) in the presence of excess HCl in diethyl ether to give compound (34) as HCl salt. Preparation 1 Diethyl 2-[4-benzylmorpholin-2-yl]propanedioate (racemic mixture)

[0094] TEA (8.5 mL, 61 mmol) was added to a solution of diethyl 2-(2- iodoethylidene)propanedioate (19 g, 61 mmol), 2-(benzylamino)ethanol (8.7 mL, 61 mmol) in H2O (1.5 mL / mmol, 91 mL) and the mixture stirred at 100 ºC for 1 h. The reaction was cooled to RT, 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 in hexanes to give the title compound (13 g, 64%) as a pale-yellow oil. ES / MS (m / z).336 [M+H]. Preparation 2 Diethyl 2-[(3-nitrophenyl)methyl]-2-[4-benzylmorpholin-2-yl]propanedioate (racemic mixture)

[0095] Cesium carbonate (16.8 g, 51.4 mmol) was added to a solution of diethyl 2-[4- benzylmorpholin-2-yl]propanedioate (11.5 g, 34.3 mmol) in MeCN (171 mL). The mixture was stirred at RT for 10 min and then 3-nitrobenzyl chloride (8.8 g, 51.4 mmol) was added. The resulting mixture was stirred at 80 ºC for 16-18 hrs. The reaction was cooled to RT, filtered, and concentrated under vacuum to dryness. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (14 g, 80%) as a pale-yellow oil. ES / MS (m / z).471 [M+H]. Preparation 3 3-(3-Nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoic acid (mixture of isomers)

[0096] Hydrochloric acid (6 M aqueous, 298 mL) was added to a solution of diethyl 2-[(3- nitrophenyl)methyl]-2-[4-benzylmorpholin-2-yl]propanedioate (racemic mixture, 14 g, 29.8 mmol) in 1,4-dioxane (149 mL). The resulting mixture was stirred at 140 ºC for 16-18 h. The reaction was then cooled to RT and concentrate under vacuum to dryness. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (10 g, 85%) as a pale-yellow oil. ES / MS (m / z).371 [M+H].Preparation 4 tert-Butyl-3-(3-nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoate (mixture of isomers)

[0097] 2-tert-Butyl-1,3-diisopropylisourea (25 mL, 108 mmol) was added 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) The resulting mixture was stirred at 60 ºC for 16-18 h. The reaction was cooled to RT and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (7 g, 61%) as a pale-yellow oil. ES / MS (m / z).427 [M+H]. Preparation 5 tert-Butyl-3-(3-nitrophenyl)-2-[morpholin-2-yl]propanoate (mixture of isomers)

[0098] 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 tert-butyl-3-(3- nitrophenyl)-2-[4-benzylmorpholin-2-yl]propanoate (mixture of isomers, 7 g, 16.4 mmol) in DCM (66 mL). The mixture was stirred at RT for 1 h, then concentrated under vacuum to dryness. MeOH (164 mL) was added, and the mixture stirred at RT for 3 h, then concentrated to dryness. The mixture was loaded in a SCX column and eluted with MeOH (x2) and then with NH3 / MeOH (2 N) (x2). The NH3 / MeOH fractions were concentrated under vacuum to give the title compound (5 g, 91%) as a pale-yellow oil. ES / MS (m / z).337 [M+H].Preparation 6 tert-Butyl-2-[2-tert-butoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]morpholine-4-carboxylate (mixture of isomers)

[0099] di-tert-Butyl dicarbonate (3.9 g, 17.8 mmol) was added to a solution of tert-butyl-3- (3-nitrophenyl)-2-[morpholin-2-yl]propanoate (mixture of isomers, 5 g, 14.9 mmol) in DCM (74 mL). The mixture was stirred at RT for 16-18 h, then concentrated under vacuum to dryness. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (6.5 g, 99%) as a pale-green oil. ES / MS (m / z).459 [M+Na]. Preparation 7 tert-Butyl-2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4-carboxylate (mixture of isomers, Isomer 1, Isomer 2, Isomer 3, and Isomer 4)

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

[0101] The mixture of 4 isomers (3.1 g) was separated by chiral SFC after two steps of purification: 1) Isolation of 3 fractions by chiral SFC [column-Chiralpak IG (10 × 4.6 cm, 5 µm); mobile phase: CO2 (A) / EtOH (0.2% IPA) (B); elution program: gradient from 5 to 25%B in 2 min - hold 1 min at 25%B then back to 5% B in 0.5 min.; flow rate - 4 mL / min] gave 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 eluted after Isomers 1 and 2. 2) Separation of the mixture of Isomers 3 and 4 obtained in the previous step by chiral SFC [column-Chiralpak IC (10 × 4.6 cm, 5 µm); mobile phase: CO2(A) / IPA (0.2% IPA) (B); Elution program: Gradient from 5 to 25%B in 2 min - hold 1 min at 25% B then back to 5% B in 0.5 min; flow rate - 4 mL / min] gave Isomer 3 (first-eluting isomer under these conditions, 458 mg) and Isomer 4 (second-eluting isomer under these conditions, 548 mg) as white solids. tert-Butyl-2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4-carboxylate (Isomer 5 and Isomer 6)

[0102] In a separate experiment, a 4 g sample of the mixture of 4 isomers was prepared. Separation of diastereomers was accomplished by reversed-phase purification, to give the two diastereomers as racemic mixtures (1.61 g and 0.93 g respectively of the first and second-eluting diastereomers). The first-eluting diastereomer was then subjected to chiral SFC [column: Chiralpak IC (25 × 2 cm, 5 µm); mobile phase: CO2 (A) / IPA (0.2% dimethylethylamine) (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). Preparation 8 tert-Butyl 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]morpholine-4-carboxylate (Isomer 1, Isomer 2, Isomer 3, and Isomer 4)

[0103] Isomer 1: 1,1'-Carbonyldiimidazole (240 mg, 1.5 mmol) was added to a solution of tert-butyl-2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4-carboxylate (Isomer 1, 200 mg, 0.5 mmol) in 2-methyltetrahydrofuran (7.4 mL). The mixture was stirred at 80 ºC for 16-18 h. The reaction was cooled to RT and concentrated under vacuum to dryness. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give title compound (65 mg, 16%) as colorless oil. ES / MS (m / z): 740 [M+H-BOC].

[0104] 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 pale-yellow solid. ES / MS (m / z): 740 [M+H-BOC]. Preparation 9 tert-Butyl 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]morpholine-4-carboxylate (Isomer 5)

[0105] Cupric bromide (18 mg, 0.080 mmol) and tert-butyl nitrite (0.2 mL, 200 mg, 2 mmol) were added to a solution of tert-butyl-2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo- ethyl]morpholine-4-carboxylate (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 ºC. The mixture was stirred at 0 ºC for 1 h. The mixture was diluted with MeOH and concentrated to dryness under vacuum. The crude was purified with a HLBcartridge, eluted with a gradient of 0 to 100% MeCN in NH4HCO3 (pH 9) to obtain the title compound (630 mg, 75%) as a pale-brown oil. ES / MS (m / z): 314,316 (M+H- tert-butyl-Boc). Preparation 10 2-(Cyclopropyl)thiazole-4-boronic acid pinacol ester

[0106] 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 was diluted with DCM, filtered through diatomaceous earth, and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with a gradient of EtOAc in hexanes (0 to 90%) to give the title compound (70 mg, 28%). ES / MS m / z: m / z = 252 [M+1]. Preparation 11 tert-Butyl 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-carboxylate (Isomer 5)

[0107] 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 tert-butyl 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo- ethyl]morpholine-4-carboxylate (Isomer 5, 126 mg, 0.3 mmol) in 1,4-dioxane (1.5 mL). Themixture was stirred at 100 ºC for 16-18 h. The reaction was cooled to RT and concentrated to dryness under vacuum. The residue was purified by reverse phase chromatography (column: Claricep C-series silica-bound C18) eluting with a gradient of 5 to 25% MeCN in aqueous NH4CO3 (pH 9). The resulting residue was purified by reverse phase chromatography using the following conditions: column - XBridgeTMC18(19 × 100 mm, 5 µm); mobile phase - solvent A = 20 mM ammonium bicarbonate in water (pH 9), solvent B = ACN; gradient from 70% to 95% A:B; flow rate - 40 mL / min; to obtain the title compound (25 mg, 12%), which was produced as a cross-coupling by-product. ES / MS (m / z): 681 (M+H-BOC). Preparation 12 tert-Butyl 2-[2-tert-butoxy-2-oxo-1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]ethyl]morpholine-4-carboxylate (Isomer 5)

[0108] A mixture of tert-butyl 2-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo- ethyl]morpholine-4-carboxylate (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 ºC. Pd(dppf)Cl2(10 mg, 0.012 mmol) was added, the mixture was heated continually while stirring at 90 ºC for 16-18 h, to give the title compound (110 mg, 99+%) which was used without purification in Preparation 13. ES / MS m / z = 518 [M+H]. Preparation 13 tert-Butyl 2-[2-tert-butoxy-1-[[3-(2-cyclopropylthiazol-4-yl)phenyl]methyl]-2-oxo- ethyl]morpholine-4-carboxylate (Isomer 5)

[0109] tert-Butyl 2-[2-tert-butoxy-2-oxo-1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]ethyl]morpholine-4-carboxylate (Isomer 5, 110 mg) was added to 4-bromo-2- cyclopropylthiazole (45 mg, 0.212 mmol), sodium carbonate (2 M in H2O, 390 mg, 0.371 mL, 0.743 mmol) and Pd(dppf)Cl2(10 mg, 0.0120 mmol). The resulting mixture was heated at 90 ºC for about 16-18 h. The reaction was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with 0 to 90% EtOAc in hexanes, and then further purified by reverse phase HPLC to give the title compound (44.4 mg, 41 %) as a colorless oil. ES / MS m / z = 515 [M+H]. Preparation 14 Ethyl (Z)-2-[4-benzylmorpholin-2-yl]-3-phenyl-prop-2-enoate (racemic mixture)

[0110] To a solution of ethyl 2-[4-benzylmorpholin-2-yl]acetate (racemic mixture, 3000 mg, 11.39 mmol) in THF (79.76 mL) under N2atmosphere and at -78 ºC 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 h, and then benzaldehyde (1.81 g, 1.74 mL, 17.09 mmol) was added at RT and stirred for 16-18 h. The reaction was diluted with MeOH and concentrated to dryness under vacuum. The residue was purified using silica gel chromatography eluting with 0-90% EtOAc in hexane, and then using an SCX cartridge as follows. The SCX cartridge (5 g) was first conditioned eluting with MeOH twice and then the compound was dissolved in MeOH andloaded into the cartridge, eluted with MeOH and then NH3 / MeOH (2 N). The NH3 / MeOH washings were concentrated to dryness under vacuum to give the title compound (300 mg, 5%). ES / MS m / z = 352 [M+H]. Preparation 15 Ethyl 2-[morpholin-2-yl]-3-phenyl-propanoate (mixture of isomers)

[0111] To a solution of ethyl (Z)-2-[4-benzylmorpholin-2-yl]-3-phenyl-prop-2-enoate (racemic mixture, 300 mg, 0.854 mmol) in EtOH (8.5 mL) was added palladium (3 equiv., 0.2725 g, 2.561 mmol, 100 mass%), then the mixture was stirred at RT for 16-18 h under a balloon of hydrogen. The mixture was filtered through diatomaceous earth, concentrated to dryness under vacuum, and purified using SCX cartridge (5 g). The SCX cartridge was first conditioned eluting with MeOH twice and then the crude dissolved in MeOH was loaded into the cartridge, eluted with MeOH and NH3 / MeOH (2 N). The NH3 / MeOH washings were concentrated to dryness under vacuum to give the title compound (200 mg, 71%) as a colorless oil. ES / MS m / z: m / z = 264 [M+H]. Preparation 16 tert-Butyl 2-[1-benzyl-2-ethoxy-2-oxo-ethyl]morpholine-4-carboxylate (mixture of isomers)

[0112] To a solution of ethyl 2-[morpholin-2-yl]-3-phenyl-propanoate (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 RT for16-18 h. The mixture was diluted with MeOH and concentrated to dryness under vacuum to give the title compound (200 mg, 58 %) as a colorless oil, which was used in the next step without further purification. ES / MS m / z = 308 [M+H-tBu]. Preparation 17 2-[4-tert-Butoxycarbonylmorpholin-2-yl]-3-phenyl-propanoic acid (mixture of isomers, Isomer 1, Isomer 2, and Isomer 3)

[0113] To a solution of tert-butyl 2-[1-benzyl-2-ethoxy-2-oxo-ethyl]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 H2O, 4.40 mL, 4.40 mmol). The resulting mixture was stirred at 55 °C for about 1.5 h. The mixture was concentrated to dryness under vacuum. The crude was dissolved in EtOAc and neutralized with HCl (1 M) to pH 4, extracted (x3) with EtOAc, and washed (x2) with saturated aqueous NaCl. The organics were dried by passing through a diatomaceous earth cartridge, filtered, and concentrated to dryness under vacuum to give a mixture of isomers of the title compound (140 mg, 94.8 %) as a colorless oil. ES / MS m / z = 280 [M+H-tBu].

[0114] The mixture of isomers was combined with another lot of material prepared in a similar manner to give 288 mg of the isomeric mixture. The mixture was subjected to chiral SFC [column: Chralpak AD (2 × 25 cm, 5 µm); mobile phase: isocratic 7% (MeOH + 0.2% dimethylethylamine) in CO2; flow rate: 65 mL / min]. Three isomers of the title compound were obtained in the separation: Isomer 1: 17.6 mg, >98% ee Isomer 2: 31.7 mg, 93% ee Isomer 3: 14.5 mg, 71% eePreparation 18 tert-Butyl 4-[1-[(3-bromophenyl)methyl]-2-ethoxy-2-oxo-ethyl]piperidine-1-carboxylate (racemic mixture)

[0115] To a solution of tert-butyl 4-(2-ethoxy-2-oxo-ethyl)piperidine-1-carboxylate (CAS registry No.135716-09-5; 5 g, 18.42 mmol) in THF (1590 mmol, 99.9 mass%) under N2 atmosphere and at -78 °C was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 22.11 mmol). The mixture was stirred at -78 °C for 20 min and then a solution of 1-bromo-4- (bromomethyl)benzene (22.11 mmol) in THF (14 mL) was added. The mixture was allowed to reach RT and then it was stirred at RT for 30 min. MeOH was added and the solvent eliminated vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 10- 40% MTBE in hexanes to obtain the title compound (5.2 g, 54%) as a colorless oil. ES / MS m / z = 384, 386 [M+H-tert-butyl]

[0116] The compounds in Table 1 were prepared in a manner analogous to the method of Preparation 18 using the appropriate corresponding reagents.Table 1 Prep. No. Name Structure ES / MS 19 tert-Butyl 4-[1-[(4- 384, 386 [M+H-tert- bromophenyl)methyl]-2- butyl] ethoxy-2-oxo-ethyl]piperidine- 1-carboxylate (racemic mixture) 20 tert-Butyl 4-[2-ethoxy-2-oxo- 320 [M+H-t-Bu] 1-(p- tolylmethyl)ethyl]piperidine-1- carboxylate (racemic mixture) 21 tert-Butyl 4-[2-ethoxy-1-[(3- 336 [M+H-t-Bu] methoxyphenyl)methyl]-2- oxo-ethyl]piperidine-1- carboxylate (racemic mixture) 22 tert-Butyl 4-[1-[(2,3- 375 (M-tBu+H) dichlorophenyl)methyl]-2- ethoxy-2-oxo-ethyl]piperidine- 1-carboxylate (racemic mixture)Preparation 23 tert-Butyl 4-[2-ethoxy-2-oxo-1-[[4-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]piperidine-1- carboxylate (racemic mixture)

[0117] Ethynyl(trimethyl)silane (22.71 mmol) was added to a mixture of tert-butyl 4-[1-[(4- bromophenyl)methyl]-2-ethoxy-2-oxo-ethyl]piperidine-1-carboxylate (2.5 g, 5.68 mmol), cuprous 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 h. The mixture was cooled to RT and then filtered through diatomaceous earth washing with EtOAc. The solvent was eliminated under vacuum and purified by silica gel chromatography eluting with a gradient of 5-20% MTBE in hexane to give the title compound as a yellow oil (900 mg, 30 %). ES / MS m / z 402 (M+H-tert-butyl). Preparation 24 Ethyl-3-(3-methoxyphenyl)-2-(4-piperidyl)propanoate (racemic mixture)

[0118] Phosphoric acid (500 µL) was added slowly to a solution of tert-butyl 4-[2-ethoxy-1- [(3-methoxyphenyl)methyl]-2-oxo-ethyl]piperidine-1-carboxylate (racemic mixture, 50 mg, 0.1277 mmol) and MeOH (1.5 mL). The reaction was microwaved at 100 ºC for 30 min and purified by SCX, eluting with NH3 in MeOH to give the title compound (40 mg, 80.61%). ES / MS m / z = 292 [M+H].Preparation 25 3-(3-Bromophenyl)-2-(1-tert-butoxycarbonyl-4-piperidyl)propanoic acid (Isomer 1 and Isomer 2)

[0119] Sodium hydroxide (2 M aqueous, 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 h. The solvent was partially concentrated and acidified with HCl (1N) until pH 3 and extracted with EtOAc (x3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified using silica gel chromatography eluting with EtOAc in hexanes (0% to 25% gradient) to give the title compound as a racemic mixture (1.12 g, 30%) as a pale-yellow oil. ES / MS m / z = 356, 358 [M+H-tert-butyl].

[0120] The mixture of isomers was combined with another lot of 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 × 25 cm, 5 µm); mobile phase: isocratic 15% (IPA + 0.2% dimethylamine) in CO2; flow rate 65 mL / min] to give Isomer 1 (first-eluting isomer, >95% ee) and Isomer 2 (second-eluting isomer, >90% ee).

[0121] The compounds in Table 2 were prepared in a manner analogous to the method of Preparation 25 using the appropriate corresponding reagents.Table 2 Prep. No. Name Structure ES / MS 26 2-(1-tert-Butoxycarbonyl-4- 302 (M+H- piperidyl)-3-(4- tert-butyl) ethynylphenyl)propanoic acid (racemic mixture)a, b27 2-(1-tert-butoxycarbonyl-4- 346 (M+H- piperidyl)-3-(2,3- tert-butyl) dichlorophenyl)propanoic acid (Isomer 1 and Isomer 2)ca. tert-Butyl 4-[2-ethoxy-2-oxo-1-[[4-(2- trimethylsilylethynyl)phenyl]methyl]ethyl]piperidine-1-carboxylate used as starting material; TMS-group was removed under the reaction conditions. b. No chiral chromatography was performed on the product. c. Chiral SFC performed on the product [column: Chiralcel OD (2 × 25 cm, 5 µm); mobile phase: isocratic 15% MeOH in CO2; flow rate: 65 mL / min] to give Isomer 1 (first-eluting isomer) and Isomer 2 (second-eluting isomer). Preparation 28 Ethyl 2-(4-piperidyl)-3-(p-tolyl)propanoate (racemic mixture)

[0122] 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 (4M in 1,4-dioxane, 4.9 mL). The mixture was stirred at RT for 16-18 h. The mixture was diluted with MeOH, concentrated to dryness under vacuum, and purified using SCX cartridge (5 g load). The SCX cartridge was first conditioned eluting with MeOH and then the crude product dissolved in MeOH was loaded into the cartridge, eluted with MeOH and NH3 / MeOH (2 N). The NH3 / MeOH washings were concentrated to dryness under vacuum to give the title compound (105 mg, 87%) as a colorless oil. ES / MS m / z = 276 [M+H]. Preparation 29 Ethyl 2-(1-methyl-4-piperidyl)-3-(p-tolyl)propanoate (racemic mixture)

[0123] Formaldehyde (37 mass% in water, 93 mg, 0.087 mL, 1.14 mmol) was added to a solution of ethyl 2-(4-piperidyl)-3-(p-tolyl)propanoate (racemic mixture, 105 mg, 0.381 mmol) in MeOH (3.8 mL). The mixture was stirred for 15 min at RT and then sodium triacetoxyborohydride (0.121 g, 0.572 mmol) was added. The resulting mixture was stirred at RT for 16-18 h. The reaction mixture was concentrated to dryness under vacuum and diluted with saturated NaHCO3 and DCM. The organic layer was collected with 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]. Preparation 30 2-(1-Methyl-4-piperidyl)-3-(p-tolyl)propanoic acid (racemic mixture)

[0124] The title compound was prepared essentially as described in Preparation 25 using ethyl 2-(1-methyl-4-piperidyl)-3-(p-tolyl)propanoate (racemic mixture), purifying on an HLB column using 0-100% MeCH in aqueous NH4HCO3 (pH 9). No chiral chromatography was performed on the racemic mixture. ES / MS m / z = 262 [M+H]. Example 1 3-[3-[[3-(2-Carboxy-2-morpholin-2-yl-ethyl)phenyl]carbamoylamino]phenyl]-2-morpholin-2-yl- propanoic acid;dihydrochloride (Isomer 1 – Example 1a)

[0125] HCl (2 mol / L in diethyl ether, 1.9 mL, 3.9 mmol) was added to a solution tert-butyl 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]morpholine-4-carboxylate (Isomer 1, 65 mg, 0.08 mmol) in DCM (1.1 mL). The mixture was stirred at RT for 16-18 h. The mixture was then concentrated to dryness under N2 stream at 40 ºC. The solid was triturated with MTBE and sonicated. The solid was filtered, washed with MTBE, and dried under high vacuum. The solid was dissolved in the minimum amount of water, concentrated to dryness under N2stream at 40 ºC, and dried in an oven at 45 ºC under high vacuum to give title compound (Isomer 1, 40 mg, 77%) as pale-yellow solid. ES / MS (m / z): 527 [M+H).

[0126] The remaining isomers were prepared in a similar manner: Isomer 2 of the title compound (Example 1b), starting with Isomer 2 of the starting material: 75 mg, 79%; as pale-yellow solid. ES / MS (m / z): 527 [M+H]). Isomer 3 of the title compound (Example 1c), starting with Isomer 3 of the starting material: 80 mg, 90%; as pale-yellow solid. ES / MS (m / z): 527 [M+H]). Isomer 4 of the title compound (Example 1d), starting with Isomer 4 of the starting material: 105 mg, 95%; as pale-yellow solid. ES / MS (m / z): 527 [M+H]).

[0127] The compounds in Table 3 were prepared in a manner analogous to the method of Example 1 using the appropriate corresponding BOC-protected starting materials. Table 3 Ex. Name Structure ES / MS m / z No. 2 3,3'-([1,1'-Biphenyl]-3,3'- 469 [M+H] diyl)bis(2-(morpholin-2- yl)propanoic acid) dihydrochloride (Isomer 5)a3 3-[3-(2-Cyclopropylthiazol-4- 359 [M+H] yl)phenyl]-2-morpholin-2-yl- propanoic acid;hydrochloride (Isomer 5)b4 3-(3-Aminophenyl)-2-[(2S)- 251 (M+H) morpholin-2-yl]propanoic acid;hydrochloride (Isomer 1)c5 2-Morpholin-2-yl-3-phenyl- 236 (M+H) propanoic acid;hydrochloride (Isomer 3)dEx. Name Structure ES / MS m / z No. 6 3-(3-Bromophenyl)-2-(4- 312, 314 piperidyl)propanoic (M+H) acid;hydrochloride (Isomer 2)e7 2-(1-Methyl-4-piperidyl)-3- 262 (M+H) (p-tolyl)propanoic acid;hydrochloride (racemic mixture)f8 3-(4-Ethynylphenyl)-2-(4- 258 (M+H) piperidyl)propanoic acid;hydrochloride (racemic mixture)g10 3-(2,3-Dichlorophenyl)-2- 302 (M+H) (piperidin-4-yl)propanoic acid hydrochloride (Isomer 1)ha. Starting material used: tert-Butyl 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-carboxylate (Isomer 5) b. Starting material used: tert-Butyl 2-[2-tert-butoxy-1-[[3-(2-cyclopropylthiazol-4- yl)phenyl]methyl]-2-oxo-ethyl]morpholine-4-carboxylate (Isomer 5) c. Starting material used: tert-Butyl-2-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo- ethyl]morpholine-4-carboxylate (Isomer 1) d. Starting material used: 2-[4-tert-Butoxycarbonylmorpholin-2-yl]-3-phenyl-propanoic acid (Isomer 3)e. Starting material used: 3-(3-Bromophenyl)-2-(1-tert-butoxycarbonyl-4- piperidyl)propanoic acid (Isomer 2) f. Starting material used: 2-(1-Methyl-4-piperidyl)-3-(p-tolyl)propanoic acid (racemic mixture); under the conditions no chemical transformation takes place except to make the HCl salt g. Starting material used: 2-(1-tert-Butoxycarbonyl-4-piperidyl)-3-(4- ethynylphenyl)propanoic acid (racemic mixture) h. Starting material used: 2-(1-tert-butoxycarbonyl-4-piperidyl)-3-(2,3- dichlorophenyl)propanoic acid (Isomer 1) Example 11 3-(3-Methoxyphenyl)-2-(4-piperidyl)propanoic acid (racemic mixture)

[0128] To a mixture of ethyl-3-(3-methoxyphenyl)-2-(4-piperidyl)propanoate (40 mg, 0.14 mmol) and THF (1.5 mL) was added NaOH (56 mg, 1.4 mmol) and MeOH (1.5 mL). The mixture was stirred at 70 °C for 12 h, then cooled to RT and HCl (1 N aqueous, 1.26 mL, 1.26 mmol). The reaction mixture was loaded onto an SCX cartridge (10 g), flushed with MeOH and DCM, then eluted, collected, and concentrated 20 mL 2.0 M NH3 / MeOH. The residue was purified by reverse-phase HPLC to give the title compound (14.7 mg, 41%) as a white solid. ES- MS m / z 264 (M+H). In vitro Lp(a) Assembly Assay

[0129] The ability of compounds to inhibit the formation of Lp(a) particles in vitro was assessed by a cell-free assembly assay. Conditioned media (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin) was collected from confluent wild-type HepG2 cells (a source of endogenously expressed ApoB) and from a HEK293 stable cell lineexpressing human Apo(a) protein containing 17 Kringle repeats (selected on 1 mg / ml geneticin) after 24 h of culture at 37 °C and 5% CO2. An in vitro assembly assay was conducted by combining equal parts of HepG2 and HEK293 conditioned media with the test compounds added in dilution series (final concentration 0.01~100 nM). The reaction was incubated at 37 °C for 2 hrs and then stopped with the addition of 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with an anti-Lp(a) capture antibody and an HRP -conjugated anti-ApoB detection antibody. The ELISA was developed using TMB, stopped using 1 N sulfuric acid, and the signal was read at 450 nm on a Molecular Devices plate reader. The % inhibition of Lp(a) formed for each test condition was determined with an assembly reaction having no inhibitor present (with matched DMSO concentration at 1%) set to 0% inhibition, and an assembly reaction with a minimal amount of the HepG2 conditioned media present (50-fold dilution) set to 100% inhibition. Data were fitted to a 4-parameter curve to determine the IC50 values summarized in Table 4. Addition of the Example test compound to conditioned media containing ApoB and Apo(a) lead to concentration-dependent inhibition of Lp(a) formation in vitro, as summarized in Table 4. The results indicate that these compounds inhibit the assembly of Lp(a) from Apo(a) and the LDL particle. Table 4. Example IC50nM (SEM, n) 1a 2750 (291, n = 4) 1b 1170 (65.6, n = 4) 1c 2.57 (0.285, n = 4) 1d 187 (20.6, n = 4) 2 2.33 (1.32, n = 4) 3 1110 (260, n = 4) 4 4180 (1110, n = 4) 5 3370 (1750, n = 4) 6 2000 (130, n = 4) 7 3710 (163, n = 2) 8 149 (14.8, n = 3)9 9720 (1920, n = 4) 10 3410 (2090, n = 2)

Claims

CLAIMS We claim:

1. A compound of the formula:wherein A1is NH, A2is CH and A3is O; A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH; Z is H, C1-4 alkyl, OH or cyclopropyl; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2 alkyl, C2-3 alkynyl, OCH3, NH2 or a 5-membered heteroaryl optionally substituted with C3-5cycloalkyl; Q2is H, C1-4alkyl, cyclopropyl, CF3, OH, C1-4alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R10is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6 cycloalkyl optionally substituted with one or two halo; C1-4haloalkyl optionally substituted with OCH3; C2-6 alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3;5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4alkoxy, C1-4alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3alkyl, or a pharmaceutically acceptable salt thereof.

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

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

4. The compounds according to any one of claims 1 to 3, wherein A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH, or a pharmaceutically acceptable salt thereof.

5. The compounds according to any one of claims 1 to 4, wherein Q1is H, halo, C1-2 alkyl, C2-3 alkynyl, OCH3, or a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl, or a pharmaceutically acceptable salt thereof.

6. The compounds according to any one of claims 1 to 5, wherein Q2is H or halo, or a pharmaceutically acceptable salt thereof.

7. A compound of the formula:wherein R1ais H, CH3or a protecting group; X is OH or C1-4 alkoxy; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2 alkyl, C2-3 alkynyl, OCH3, NH2 or a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl; Q2is H, C1-4alkyl, cyclopropyl, CF3, OH, C1-4alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R10is selected from: halo; C1-4 alkyl optionally substituted with one to four OH or with OCH3; C3-6 cycloalkyl optionally substituted with one or two halo; C1-4haloalkyl optionally substituted with OCH3; C2-6alkynyl; NH2; naphthyl; 3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4 alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; andphenyl optionally substituted with one to three substituents independently selected from: halo, C1-4alkoxy, C1-4alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3alkyl, or a salt thereof, wherein if X is OH then R1amust be a protecting group.

8. A compound of the formula:wherein R1ais H, CH3 or a protecting group; X is OH or C1-4alkoxy; Y is CH2, O or S; Q1is -(CH2)nNR15(CH2)nR10, -B(OR10)2, a boronic acid ethylene glycol ester, a boronic acid pinacol ester, a boronic acid propylene-1,3-diol ester, a boronic acid 2,2-dimethyl-propylene-1,3- diol ester, -(CH2)nNHCONR15R10, H, halo, C1-2alkyl, C2-3alkynyl, OCH3, NH2or a 5-membered heteroaryl optionally substituted with C3-5 cycloalkyl; Q2is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; n is 0, 1, 2, or 3; R10is selected from: halo; C1-4alkyl optionally substituted with one to four OH or with OCH3; C3-6cycloalkyl optionally substituted with one or two halo; C1-4 haloalkyl optionally substituted with OCH3; C2-6 alkynyl; NH2; naphthyl;3,4-dihydro-2H-1λ2-quinoline optionally substituted with CF3; phenoxy optionally substituted with methoxy; 4-, 5- or 6- membered heterocycle optionally substituted with OCH3, C1-4alkyl, (CH2)pyridine, O(CH2)phenyl or (CH2)mphenyl, wherein the phenyl is optionally substituted with one or two substituents selected from: halo and CH3; 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with one or two substituents selected from: C1-4 alkyl, halo, pyrrolidine, or benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with halo; and phenyl optionally substituted with one to three substituents independently selected from: halo, C1-4alkoxy, C1-4alkyl, CF3, CN, OCF3, -OCH2CH2OCH3, phenoxy, pyridine, or -OCH2phenyl or -(CH2)nphenyl, wherein the phenyl is optionally substituted one or two halo; m is 0 or 1; and R15is H or C1-3alkyl, or a salt thereof, wherein if X is OH then R1amust be a protecting group.

9. The compound according to claim 7 or claim 8 wherein R1ais a protecting group and the protecting group is selected from: tert-butyloxycarbonyl, carboxybenzyl, 9- fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide, or a salt thereof.

10. Use of a compound, or a salt thereof, according to any one of claims 7 to 9 in the preparation of an oligomer.

11. An oligomer prepared from a compound, or a salt thereof, of any one of claims 7 to 9.

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

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:wherein A1is NH, A2is CH and A3is O; A1is O, A2is CH and A3is NH; A1is CH, A2is NH and A3is NH; A1is CH, A2is NH and A3is CH; or A1is CH, A2is N(CH3) and A3is CH; A1ais NH, A2ais CH and A3ais O; A1ais O, A2ais CH and A3ais NH; A1ais CH, A2ais NH and A3ais NH; A1ais CH, A2ais NH and A3ais CH; or A1ais CH, A2ais N(CH3) and A3ais CH; Z at each occurrence is independently H, C1-4 alkyl, OH or cyclopropyl; Y at each occurrence is independently CH2, O or S; L is -(CH2)pNHC(O)NH(CH2)p-, -(CH2)pNH(CH2)p-, a bond,Q3is H, C1-4 alkyl, cyclopropyl, CF3, OH, C1-4 alkoxy, O-cyclopropyl, OCF3, halo, or CN; p is at each occurrence independently 0 or 1; A1bis NH, A2bis CH and A3bis O; A1bis O, A2bis CH and A3bis NH; A1bis CH, A2bis NH and A3bis NH; A1bis CH, A2bis NH and A3bis CH; or A1bis CH, A2bis N(CH3) and A3bis CH; and L2is C1-3 alkylene or a bond, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14, wherein Z at each occurrence is H, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 14 or claim 15, wherein Y at each occurrence is CH2, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 14 to 16, wherein Q3at each occurrence is H, or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 14 to 17, wherein L is -NHC(O)NH- or a bond, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 14 to 18, wherein A1is O, A2is CH and A3is NH, and A1ais O, A2ais CH and A3ais NH, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6 or 14 to 19 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

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.

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.

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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