Pyrrolidine Compounds

This invention relates to Pyrrolidine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and therapeutic uses of the compounds.

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 lipoprotein(a) (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 no

pharmaceutical treatment approved to lower Lp(a) levels. The physiological function of Lp(a) is complex; however, it is reported that elevated Lp(a) plasma level is an independent risk factor for CVD. There is a need for a pharmaceutical treatment for patients with elevated Lp(a)l.

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. The present invention offers another treatment option for patients suffering from CVD. There is a need for pharmaceutically acceptable compounds and treatment options to reduce plasma Lp(a) levels.

Provided is a compound of formula G :

wherein

L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, -NHSO2NH-,

R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of H and CH3; or

a pharmaceutically acceptable salt thereof.

Provided is a compound of formula I”:

a pharmaceutically acceptable salt thereof.

Provided is a compound of the Formula 1 :

or a pharmaceutically acceptable salt thereof.

An embodiment is a compound of the Formula 2:

or a pharmaceutically acceptable salt thereof.

In an embodiment, is a compound of Formula F, I”, 1, or Formula 2 wherein the compound is a pharmaceutically acceptable salt. In an embodiment, is a compound of Formula F, Formula 1, or Formula 2 wherein the compound is a hydrochloride salt. In an embodiment, a compound of Formula 1 or Formula 2 wherein the compound is a tetrahydrochloride salt.

In an embodiment, is a compound of Formula F, Formula 1, or Formula 2 wherein the compound is a hydrochloride salt selected from the group consisting of a

monohydrochloride, dihydrochloride, trihydrochloride, and tetrahydrochloride. In an embodiment is a compound of Formula 1 or Formula 2 as a zwitter ion.

Provided is a compound of Formula G wherein L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, and -NHSO2NH-; or a pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein R1 and R3 are each H; and L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, and -NHSO2NH-; or a pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein R1 and R3 are each H; R2 and R4 are each CH3; and L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, - S(O)2-, -O-, -OCH2-, -OCH2CH2O-, and -NHSO2NH-; or a

pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein R1 and R3 are each H; R2 and R4 are each H; and L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, -S(O)2-, -O-, -OCH2-, -OCH2CH2O-, and -NHSO2NH-; or a

pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein L is selected from the group

consi sting of and ; or a

pharmaceutically acceptable salt thereof.

Provided is a compound of Formula G wherein R1, R3, and R5 are each H; and L is

selected from the group consisting of and

; or a pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein R1, R3, and R5 are each H; R2, R4, and R6 are each H; or a pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein R1, R3, and R5 are each H; R2, R4, and R6 are each CFF; or a pharmaceutically acceptable salt thereof.

Provided is a compound of Formula F wherein L is

; R1, R3, and R5 are each H; R2, R4, and R6 are each CFF; or a pharmaceutically acceptable salt thereof.

In an embodiment is a pharmaceutical composition comprising a compound of Formula F, Formula I”, Formula 1, or Formula 2, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

In an embodiment is a method of treating a patient in need of treatment for cardiovascular disease, comprising administering an effective amount of a compound selected from the group consisting of Formula F, Formula 1, and 2, or a

pharmaceutically acceptable salt thereof. In an embodiment is 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 a pharmaceutically acceptable salt thereof. In an embodiment, is a method of treating a patient in need of treatment for elevated Lp(a) plasma levels, comprising administering an effective amount of a compound selected from the group consisting of Formula F, Formula 1, or Formula 2, or a pharmaceutically acceptable salt thereof. In an embodiment, is 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 a pharmaceutically acceptable salt thereof.

In an embodiment, is a compound selected from the group consisting of Formula F, Formula 1, and 2, or a pharmaceutically acceptable salt thereof, for use in therapy. In an embodiment, is a compound of Formula I”, or a pharmaceutically acceptable salt thereof, for use in therapy.

In an embodiment, is a compound selected from the group consisting of Formula F, Formula 1, and 2, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. In an embodiment, is a compound of Formula I”, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease.

In an embodiment, is a compound selected from the group consisting of Formula F, Formula 1, and 2, or a pharmaceutically acceptable salt thereof, for use in treating elevated Lp(a) plasma levels.

In an embodiment, is the use of a compound selected from the group consisting of Formula F, Formula 1, and Formula 2, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament of cardiovascular disease.

Lp(a) may exhibit both prothrombotic and antithrombotic properties, and atherothrombotic property. 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. Lp(a) plasma levels may be linked to genetic predisposition.

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) may reduce Lp(a) levels.

As used herein, the term“elevated Lp(a) plasma levels” means a plasma level 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.

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. The compounds of Formulas G, I”, 1 or Formula 2 may be a zwitterion, a mono-, di, or tri-acid addition salt. The compounds of Formulas G, I”, 1 or Formula 2 may be a mono-, di, or tri- base addition salt.

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.

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.

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. Provided is a method to treat myocardial infarction comprising administering a compound of Formula G, Formula 1, or Formula 2 to a patient in need thereof.

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

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.

Certain abbreviations are defined as follows: “Apo” refers to Apolipoprotein; “BOC” refers to tert- butoxycarbonyl;“BSA” refers to Bovine Serum Albumin;“DAD” refers to diode array detector;“DCM” refers to dichloromethane or methylene chloride; “de” refers to diasteriomeric excess;“DMEA” refers to dimethylethylamine;“DMEM” refers to Dulbecco’s Modified Eagle’s Medium;“DMF” refers to N,N-dimethylformamide;“DMSO” refers to dimethyl sulfoxide;“ee” refers to enantiomeric excess;“EACA” refers to epsilon-aminocaproic acid or 6-aminocaproic acid;“ELISA” refers to enzyme-linked immunosorbent assay;“equiv” refers to equivalents;“Et20” refers to diethyl ether;“EtOAc” refers to ethyl acetate;“EtOH” refers to ethanol or ethyl alcohol;“Ex” refers to example;“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 -hy droxy ethyl)- 1-piperazineethanesulfonic acid;“HPLC” refers to high-performance liquid

chromatography;“HRP” refers to Horseradish Peroxidase;“IC50” refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent;“min” refers to minute or minutes;“MeOH” refers to methanol or methyl alcohol;“MTBE” refers to methyl tert- butyl ether;“RP-HPLC/MS” refers to reverse-phase high performance liquid chromatography with mass spectrometry;“RT” refers to room temperature;“SFC” refers to supercritical fluid chromatography;“SPA” refers to scintillation proximity assay;“t(R>” refers to retention time;“THF” refers to

tetrahydrofuran;“TMB” refers to 3,3’,5,5’-teramethylbenzidine and“Tris” refers to tris(hydroxymethyl)aminomethane.

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.

A compound of Formula G, Formula I”, Formula 1, or Formula 2 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, z.e., removing the protecting group. Examples, reactions and conditions for salt formation are known to the skilled artisan.

The compounds selected from the group consisting of Formula F, Formula I”, Formula 1, and Formula 2, 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.

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 Formula F, I”, Formula 1, and Formula 2, or salts thereof may be prepared by using starting materials or intermediates with the corresponding desired

stereochemical configuration.

Scheme 1 depicts the preparation of intermediates which can give access to compounds of the present invention. Protected pyrrolidin-3-yl acetic acid derivative A is first converted to acyl oxazolidinone B. This is accomplished by first converting A to the acid chloride and reacting with (4S)-4-benzyloxazolidin-2-one in the presence of lithium chloride at 10 °C. Alkylation of acyl oxazolidinone B with a benzyl bromide derivative and a base such as lithium bis(trimethylsilyl)amide at 0 °C gives intermediate C in a diastereoselective fashion. It is recognized by a person of ordinary skill in the art that the stereochemistry of the oxazolidinone substitution influences the diastereoselectivity of the alkylation, and that use of an oxazolidinone derivative B of opposite or racemic stereochemical configuration in this synthesis could give either the opposite or no diastereoselectivity, respectively. Conversion of acyl oxazolidinone C to the acid intermediate D is accomplished with aqueous LiOH and H2O2 in THF at 5 to 15 °C. Acid intermediate D is optionally isolated as an ammonium salt. The acid intermediate D is protected, for example as a /c/V-butyl ester by reaction with /c/V-butyl- 1 ,3-diisopropylisourea at elevated temperature to give intermediate E.

Scheme 1 also depicts conversion of acid A to methyl ester F, which is accomplished by reacting A with iodomethane in the presence of a carbonate base.

Intermediate F is then alkylated with a benzyl bromide derivative using a base such as lithium bis(trimethylsilyl)amide at -78 °C to give intermediate G. Intermediate G is alkylated again with iodomethane using a base such as lithium bis(trimethylsilyl)amide at -78 °C, and the ester is then hydrolyzed with sodium hydroxide at elevated temperature to give acid intermediate H. The acid intermediate H is protected, for example as a tert-butyl ester by reaction with /c/V-buty 1 - 1 , 3 -di i sopropy 1 i sourea at elevated temperature to give intermediate I.

In particular, intermediates D, E, H, and I where Ra is bromine or -NO2 are particularly useful for further transformations in the preparation of compounds of Formula G. Intermediate D where Ra is -H can be prepared either by alkylation of B with benzyl bromide followed by hydrolysis of the acyl oxazolidinone, or by stirring intermediate D where Ra is bromine with palladium on carbon under a hydrogen atmosphere. When Ra is -H, deprotected of the pyrrolidine nitrogen on intermediate D gives compounds of formula I”.

Scheme 1

Scheme 2 depicts the conversion of a key intermediate (J, prepared as described in Scheme 1) into penultimate compounds of the present invention. The bromide is converted to the aldehyde K using syngas (1 : 1 CO/H2), palladium(II) acetate, butyldi-1- adamantylphosphine, and N,N,N',N'-tetramethylethylenediamine at an elevated temperature. Aldehyde K is then converted to a mixture of N and O by reductive amination of K (2 or 3 equivalents, respectively) with ammonia and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, and then N and O are separated by chromatography. Alternatively, dimeric compound O is prepared by converting aldehyde K to aldoxime L, reducing L to the amine M by flow hydrogenation using a sponge nickel catalyst at elevated temperature, and then reductive amination of amine M with aldehyde K. Intermediate P is prepared by reductive amination of dimeric intermediate O with 3-fluoro-5-methoxybenzaldehyde.

Scheme 2

Rb and Rc independently = -H or -CH3

Scheme 3 shows further use of bromide intermediate J to prepare penultimate compounds of the present invention. Bromide J is converted to boronic acid Q using tetrahydroxy diboron, chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1,1'-biphenyl)(2'-amino-l,r-biphenyl-2-yl) palladium(II), X-PHOS, and potassium acetate at an elevated temperature. Boronic acid Q is then converted to phenol T using H2O2 at 5 °C. Phenol T is coupled onto bromide J using copper(I) iodide, N,N-dimethylglycine hydrochloride, and cesium carbonate at an elevated temperature to give biphenyl ether U. Phenol T is also reacted with 1,2-dibromoethane and a carbonate base at an elevated temperature to give V. Aldehyde intermediate K (prepared from bromide J as described in Scheme 2) is reduced with sodium borohydride at 0 °C to alcohol R, which then undergoes a Mitsunobu reaction to give intermediate S.

Scheme 3

Rb and Rc independently = -H or -CH3

Scheme 4 shows further use of bromide intermediate J to prepare penultimate compounds of the present invention. Two equivalents of bromide J are coupled with potassium thioacetate using bis(dibenzylideneacetone)palladium, potassium phosphate tribasic), l,r-bis(diphenylphosphino)ferrocene to give the diphenyl sulfide W. Sulfide W is then converted to either the sulfone X or sulfoxide Y using either 1 or 2 equivalents of meta-chloroperoxybenzoic acid, respectively.

Scheme 4

Scheme 5 depicts use of nitro intermediate Z (prepared as in Scheme 1) to prepare penultimate compounds of the present invention. Nitro intermediate Z is reduced to aniline AA in the presence of a catalyst under hydrogen atmosphere. Aniline AA

undergoes reductive amination with aldehyde K (prepared as in Scheme 2) using a reducing agent such as sodium triacetoxyborohydride to give CC. Buchwald reaction between aniline AA and bromide BB (prepared as in Scheme 1) using [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1, 1 '-biphenyl)-2-(2'-amino-l, 1 ' -biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) and potassium carbonate at elevated temperature gives diphenylamine derivative DD. Two equivalents of aniline AA are also reacted with l,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) and iodine at elevated temperature to give sulfamide EE.

Scheme 5

Global deprotection of intermediates N, O, P, S, U, V, W, X, Y, CC, DD, and EE from Schemes 2 through 5 give compounds of Formula G. If the pyrrolidine protecting group (Pg1 in Schemes 1 through 5) is -BOC and the ester (Pg2 in Schemes 1 through 5) is a /c/V-butyl ester, global deprotection is accomplished in one step using a solution of HC1 in an organic solvent such as diethyl ether, dioxane, or isopropanol. Upon deprotection, the pyrrolidine nitrogen in compounds of Formula I' can be methylated by reductive amination with paraformaldehyde and sodium triacetoxyborohydride.

Preparation 1

tert-Butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-l- carboxylate

Add triethylamine (56.5 g, 77.9 mL, 559 mmol, 2.5 equiv) to a solution of 2-[(3R)- 1 -/ -butoxy carbonyl pyrrol idin-3-yl]acetic
(53.8 g, 235 mmol, 1.05 equiv) in

THF (540 mL) maintained at 10 °C. After 5 min, add pivaloyl chloride (33.7 g, 34.2 mL, 279 mmol, 1.25 equiv). After 15 min, add lithium chloride (11.8 g, 279 mmol, 1.25 equiv) in THF (540 mL) and (4S)-4-benzyloxazolidin-2-one (40.0 g, 223 mmol, 1 equiv). Allow the mixture to warm to RT and stir 24 h. After 24 h, add IN aqueous HC1 (500 mL) and separate the organic phase from the aqueous phase. Wash the organic phase with IN aqueous NaOH (500 mL) and saturated aqueous NaCl (500 mL), dry over MgSO4, filter, and concentrate the solution in-vacuo. Suspend the residue in a mixture of MeOH / water (1 :2, 575 mL) and stir at RT overnight. Filter off the solid, wash with hexanes (2 x 150 mL), and dry the solid to give the title compound (65.7 g, 76%).

ES/MS (m/z): 333 (M+H-tert-butyl), 1H NMR (400.13 MHz, CDCl3) d 7.38-7.28 (m,

3H), 7.25-7.20 (m, 2H), 4.73-4.70 (m, 1H), 4.27-4.19 (m, 2H), 3.75-3.66 (m, 1H), 3.55-3.48 (m, 1H), 3.38-3.30 (m, 2H), 3.11-2.96 (m, 3H), 2.84-2.76 (m, 1H), 2.74-2.65 (m,

1H), 2.14-2.11 (m, 1H), 1.64-1.58 (m, 1H), 1.49 (s, 9H).

Preparation 2

/v/V- Butyl (3S)-3-[2-[(4R)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-l- carboxylate

Prepare the title compound essentially as described in Preparation 1 using 2-[(3S)-1 -/f/V-butoxycarbonyl pyrrol idi n -3 -yl]aceti c acid and (4R)-4-benzyloxazolidin-2-one. Purify the product by silica gel chromatography using a gradient of 10 to 50% EtOAc in hexanes. ES/MS (m/z): 333 (M+H-tert-butyl)

Preparation 3

tert- Butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-l-carboxylate

Add iodomethane (2 mol/L in MTBE, 240 mL, 480 mmol, 1.1 equiv) to a solution of 2-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid (100g, 436 mmol) in DMF (800 mL) at RT. Add potassium carbonate (90.4 g, 654 mmol, 1.5 equiv) and stir the resulting mixture for 4 h. Add water (1.5 L) and extract with MTBE (3 L). Wash the organic phase with ice/water (3 x 500 mL), dry the organic phase over MgSO4, filter and concentrate the solution under reduced pressure to give the title compound (103 g, 97%). ¾ NMR (300 MHz, CDC13) d 3.68 (s, 3H), 3.65-3.53 (m, 1H), 3.52-3.36 (m, 1H), 3.35-3.23 (m, 1H), 3.03-2.84 (m, 1H), 2.64-2.49 (m, 1H), 2.45-2.30 (m, 2H), 2.13-1.97 (m, 1H), 1.65-1.48 (m, 1H), 1.45 (s, 9H).

Preparation 4

tert-Butyl (3R)-3-[l-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-l- carboxylate

To a solution of tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-l-carboxylate (7 g, 28 mmol) in THF (93 mL) at -78 °C, add lithium

bis(trimethylsilyl)amide (1 M solution in THF, 33.5 mL, 33.5 mmol, 1.2 equiv). Stir the mixture at -78 °C for 1 h. Add a solution of 3-bromobenzyl bromide (8.37 g, 33.5 mmol, 1.2 equiv) in THF (5 mL). Allow the mixture to warm up to RT and stir overnight.

Quench the mixture with saturated aqueous MLCl and extract with EtOAc. Wash the organics with saturated aqueous NaCl, dry over MgSO4, filter and evaporate to dryness. Purify the residue by silica gel chromatography using a gradient of 10 to 40% EtOAc in hexanes to give a mixture of diastereomers of the title compound (8.4 g, 73%) as a yellow oil. ES/MS (m/z): 356, 358 (M+H-tert-butyl).

Preparation 5

3-(3-Bromophenyl)-2-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl -propanoic acid

To a solution of tert-butyl (3R)-3-[l-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-l-carboxylate (8.4 g, 20 mmol) in THF (100 mL) under nitrogen and at -78 °C, add lithium bis(trimethylsilyl)amide (1 M solution in THF, 41 mL, 41 mmol, 2 equiv). Stir the reaction at -78 °C for 2 h. Add iodom ethane (25 mL, 410 mmol, 20 equiv) and allow the mixture to warm up to RT. Stir the mixture overnight. Add saturated aqueous M 4Cl and extract with EtOAc. Wash the organic layer with saturated aqueous NaCl and dry over MgSO4, filter and remove the solvent in-vacuo. Dissolve the residue in MeOH (80 mL) and THF (80 mL), then add sodium hydroxide (5 M solution in water, 81 mL, 410 mmol, 20 equiv) and heat the resulting mixture at 60 °C for 3 days. Allow the mixture to cool down to RT, add HC1 (1 N aqueous solution) to adjust the mixture pH to 2-3. Extract the aqueous layer with EtOAc. Dry the organic layer over MgSO4, filter and concentrate in-vacuo. Subject the residue to chiral SFC under the following parameters: column - Chiralpak® AD (25 x 3 cm, 5 pm); mobile phase -solvent A = CO2, solvent B = MeOH +0.2% v/v DMEA; gradient - isocratic 80:20 A:B; flow rate - 120 mL/min). Obtain isomer 1 (1.7 g, 27%) and isomer 2 (3.4 g, 41%) of the title compound as white solids. ES/MS (m/z): 356 / 358 (M+H-tert-butyl).

Preparation 6

ter/-Butyl (3R)-3-[(lS)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3- bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate

Add a solution of lithium bis(trimethylsilyl)amide (1M in THF, 818 mL, 818 mmol, 1.2 equiv) over 29 min to a 0 °C solution of tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-l-carboxylate (265 g, 682 mmol) in THF (1325 mL) in a 3-neck 3 L round-bottom flask in an ice bath under nitrogen with mechanical stirring. Stir the mixture for 47 min at 0.6 °C. Then add a solution of 1-bromo-3-(bromomethyl)benzene (190 g, 760 mmol, 1.12 equiv) in THF (450 mL) over 28 min, raising the reaction temperature to 5.1 °C. Allow the mixture to warm up to RT with stirring overnight. Cool the reaction mixture using an ice/water bath, then add a saturated aqueous solution of MLCl (1 L) in 4 portions at such a rate as to maintain the reaction temperature below 21 °C. Add water (1 L) to the mixture and extract with MTBE (3.5 L). Wash the organic layer with a mixture of water (1 L) and saturated aqueous NaCl (500 mL), then with saturated aqueous NaCl (500 mL). Dry the organics over NaiSO4, filter, then concentrate in-vacuo. To the residue add hexanes (1 L) and concentrate in-vacuo , then dry under high vacuum overnight to obtain the title compound as an orange oil (416 g, >100%), purity estimated at 90 wt% based on theoretical yield. ES/MS (m/z): 501/503 (M+H-ter/-buty 1 ) .

Preparation 7

ter/-Butyl (3S)-3-[(lR)-2-[(4R)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3- bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate

Prepare the title compound essentially as described for Preparation 6 using tert-butyl (3S)-3-[2-[(4R)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-l-carboxylate. ES/MS (m/z): 501, 503 (M+H-tert-butyl).

Preparation 8

fer/-Butyl (3R)-3-[(lS)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3- nitrophenyl)methyl]-2-oxo-ethyl]pynOlidine-l-carboxylate

Add lithium bis(timethylsilyl)amide (1.0 M in THF, 46 mL, 46 mmol, 1.2 equiv) to a solution of tert- butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyljpyrrolidine-l-carboxylate (15 g, 39 mmol, 1 equiv) in THF (75mL) at -20 °C. Stir the mixture at -20 °C for 20 min. Add a solution of l-(bromomethyl)-3-nitro-benzene (9.17 g, 42.5 mmol, 1.1 equiv) in THF (45 mL). Stir the solution for 2 h and allow it to warm up to RT. Dilute the mixture with MTBE and quench with a saturated aqueous solution of NH4CI. Separate the phases and extract the aqueous phase with MTBE. Combine the organic extracts and wash the organics sequentially with water and saturated aqueous NaCl. Dry over NaiSO4, filter, and concentrate the filtrate in-vacuo. Triturate the residue with a mixture of MeOEl/EhO (2: 1, 150 mL). Stir the slurry overnight. Filter to collect the solid and wash with hexanes. Dry the solid in-vacuo at 40 °C to give the title compound (19 g, 88%). ES/MS (m/z): 468 (M+H-tert-butyl).

Preparation 9

tert-Butyl (3R)-3-[(lS)-l-benzyl-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

Prepare the title compound in 76% purity essentially as described in Preparation 6 using benzyl bromide. ES/MS (m/z): 423 (M+H-tert-butyl).

Preparation 10

(2S)-3-(3-Bromophenyl)-2-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

Add a solution of hydrogen peroxide (0.88 M in water, 105 mL, 926 mmol, 1.5 equiv) in one portion to a mechanically-stirred mixture of /tvV-butyl (3R)-3-[(lS)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate (90 wt% pure, 381 g, 615 mmol) in THF (4 L) and cool to 8.6 °C in a 3 -neck 12 L round-bottom flask with an ice/water bath. Add a solution of lithium hydroxide monohydrate (38.7 g, 923 mmol, 1.5 equiv) in water (930 mL) over 25 min, raising the

reaction temperature to 12.8 °C. Stir the reaction for 2.5 h then cool to 5.7 °C. Add a solution of sodium bisulfite (129.4 g, 1244 mmol, 2.02 equiv) in water (2 L) over 40 min, raising the reaction temperature to 14.7 °C. Add an aqueous solution of NaOH (5N) to raise the pH of the reaction mixture to >12, then add water (1 L) and MTBE (4 L).

Separate the layers and extract the aqueous layer with MTBE (2 L). Combine the organics, extract with water (1 L), then add this aqueous extraction to the bulk aqueous solution. Stir the aqueous solution with MTBE (3 L) and cool the mixture to 5°C. Add an aqueous solution of hydrochloric acid (5N) to bring the pH of the mixture to 3.

Separate the layers and wash the organic layer with a mixture of saturated aqueous NaCl (1 L) and water (500 mL). Dry the organics over NaiSO4, filter, and concentrate in-vacuo at 40 °C. Dry the residue under high-vacuum to obtain the title compound (221.5 g, 90%) as a white solid. ES/MS (m/z): 342/344 (M+H-tert-butyl).

Preparation 11

Ammonium;(2S)-3-(3-bromophenyl)-2-[(3R)- l -/tv7-b utoxy carbonyl pyrrol idin-3- yljpropanoate

Mix (2S)-3-(3-bromophenyl)-2-[(3R)- l -/c/v-butoxy carbonyl pyrrol idin-3-yljpropanoic acid (237.6 g, 596.5 mmol) and MTBE (3801 mL) to give a cloudy mixture with solids. Filter the mixture over 2 glass fiber filter papers, and add ammonia (7 M) in MeOH (128 mL, 896 mmol, 1.5 equiv) to the filtrate under nitrogen with mechanical stirring. A white solid precipitates and the mixture becomes very thick. Add MTBE (800 mL) to the mixture to give a free-flowing slurry. Stir the mixture at RT for 1.5 h, then cool -5 to 0 °C in an ice/acetone bath and stir for 1.5 h. Filter the solid by vacuum filtration through a propylene mat and a 3 L glass-fritted funnel and rinse the solid with MTBE (1 L), then continue applying vacuum at RT overnight under a blanket of nitrogen. Combine the solid with two more batches of material prepared in a similar manner starting with (2S)-3-(3-bromophenyl)-2-[(3R)- l -/ -b utoxy carbonyl pyrrol idin-3-yljpropanoic acid (47.3 g, 1 13 mmol, and 53.0 g, 120 mmol). Suspend the solid in acetonitrile (4300 mL) and stir the mixture at 23 °C with mechanical stirring under nitrogen overnight. Filter the solid by vacuum filtration and wash with acetonitrile (500 mL) and MTBE (1 L), then continue applying vacuum for 4 h at RT under a blanket of nitrogen to obtain the title compound as a white powder (249.5 g, 77%). ES/MS (m/z): 342/344 (M+H-ferf-butyl).

Preparation 12

Ammonium; (2R)-3 -(3 -bromophenyl)-2- [(3 S)- 1 -/c/V-butoxy carbonyl pyrrol i di n-3 - yljpropanoate

Prepare the title compound essentially as described in Preparation 10 using tert-butyl (3 S)-3-[(lR)-2-[(4R)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate, followed by ammonium salt formation as described in Preparation 1 1. ES/MS (m/z): 342, 344 (M+H-tert-butyl).

Preparation 13

(2S)-2-[(3R)-l-tert-Butoxycarbonylpyrrolidin-3-yl]-3-(3-nitrophenyl) propanoic acid Prepare the title compound essentially as described in Preparation 10 using tert-butyl (3R)-3-[(l S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-l-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate, omitting the step of adding an aqueous solution of sodium bisulfite in the reaction workup. ES/MS (m/z): 309 (M+H -tert butyl).

Preparation 14

(2S)-2-[(3R)- l -tert-Butoxycarbonylpyrrolidin-3-yl]-3 -phenyl -propanoic acid

Prepare the title compound essentially as described in Preparation 10 using tert-butyl (3R)-3-[(l S)-l-benzyl-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-l-carboxylate. Purify the product by trituration with 1 : 1 MeOH: water. ES/MS (m/z): 264 (M+H-tert butyl).

Preparation 15

(2R)-2-[(3S)- l -tert-Butoxycarbonylpyrrolidin-3-yl]-3 -phenyl -propanoic acid

Dissolve ammonium;(2R)-3-(3-bromophenyl)-2-[(3S)-l -l rl-

butoxycarbonylpyrrolidin-3-yl]propanoate (830 mg, 2.08 mmol) in EtOH (20 mL) and add palladium on carbon (10% w/w, 222 mg, 0.208 mmol, 0.1 equiv). Stir the mixture under a balloon of hydrogen at RT overnight. Filter the reaction mixture over a pad of diatomaceous earth. Concentrate the filtrate and purify the residue by silica gel chromatography using a gradient of 10 to 40% EtOAc in hexanes with an addition of 1% acetic acid to give the title compound (560 mg, 84%) as a white solid. ES/MS (m/z): 264 (M+H-ter/-buty 1 ) .

Preparation 16

tert-Butyl (3R)-3-[(l S)-l-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

Add to a reactor ammonium;(2S)-3-(3-bromophenyl)-2-[(3R)- l -l rl-butoxycarbonylpyrrolidin-3-yl]propanoate (500 g, 1210 mmol), 2-methyltetrahydrofuran (4000 mL), and then a solution of KHSO4 (1M in water, 3000 mL). Stir the mixture for 30 min, during which time the pH is measured to be 2-3. Separate the phases of the reaction mixture and extract the aqueous layer with 2-methyltetrahydrofuran (1000 mL). Combine the organic phases and wash them with saturated aqueous NaCl. Dry the organic phase over MgSCri and filter it. Transfer the solution to a reactor and add 2-tert-butyl-l,3-diisopropylisourea (618.2 g, 3024 mmol, 2.5 equiv). Stir the mixture at 65 °C for three hours and add more 2-/c77-buty 1 - 1 ,3 -di i sopropy 1 i sourea (247.3 g, 1210 mmol, 1 equiv). Stir the mixture at 65 °C overnight. Cool the mixture to RT. Filter off the solid and wash the organic layer with saturated aqueous NaHCCte (1000 mL). Dry the organic layer over MgS04, filter and concentrate in-vacuo. Add MTBE (2000 mL) to the residue

and filter off the solid. Concentrate the filtrate to obtain the title compound (483 g, 88%) as a white solid. ES/MS (m/z): 342/344 (M+H- 2x tert-butyl)

Preparation 17

tert-Butyl (3R)-3-[l-[(3-bromophenyl)methyl]-2-tert-butoxy-l-methyl-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

To a solution of 3-(3-bromophenyl)-2-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-propanoic acid, isomer 2 (3.4 g, 8.2 mmol) in 2-methyltetrahydrofuran (33 mL) add 2-ter/-butyl-l,3-diisopropylisourea (5.1 g, 5.7 mL, 25 mmol, 3 equiv) and heat the mixture at 55 °C for 3.5 h. Add additional 2-tert-butyl-l,3-diisopropylisourea (5.1 g, 5.7 mL, 25 mmol, 3 equiv) and continue heating the reaction at 55 °C for 1.5 h. Add additional 2-tert-butyl-l,3-diisopropylisourea (2.5 g, 2.9 mL, 12 mmol, 1.5 equiv) and continue heating the reaction at 55 °C overnight. Filter off a white solid and wash with MTBE, then evaporate the filtrate to dryness. Purify the residue by silica gel

chromatography using a gradient of 0 to 100% EtOAc in hexanes to give the title compound (3.6 g, 93%) as a yellow oil. ES/MS (m/z): 356, 358 [M+H-(2xtert-butyl)].

Preparation 18

tert-Butyl (3R)-3-[(lS)-2-tert-butoxy-l-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine- 1 -carb oxy late

Prepare the title compound essentially as described in Preparation 17 using (2S)-2-[(3R)-l-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-nitrophenyl) propanoic acid and running the reaction at 80 °C in toluene as the reaction solvent. Purify the crude product by silica gel chromatography using a gradient of 5 to 20% EtOAc in hexanes. ES/MS (m/z): 309 [ M+ H -( 2 / tert-b uty 1 ) ] .

Preparation 19

te/V-Butyl (3R)-3-[(lS)-2-tert-butoxy-l-[(3-formylphenyl)methyl]-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

Add to a parr reactor a solution of /cvV-butyl (3R)-3-[(lS)-l-[(3-bromophenyl (methyl ]-2-/c77-butoxy-2-oxo-ethyl]pyrrolidine- l -carboxyl ate (300 g, 660 mmol) in toluene (3000 mL) followed by palladium(II) acetate (7.41 g, 33.0 mmol, 0.05 equiv), butyldi-l-adamantylphosphine (24.92 g, 66.02 mmol, 0.1 equiv) and N,N,N',N'-tetramethylethylenediamine (115g, 149 mL, 990 mmol, 1.5 equiv). Pressurize the mixture with 70 psi of syngas (CO/H2 1 : 1) and stir at 100 °C overnight. Cool the mixture to RT and evaporate the solvent to dryness. Dissolve the residue in EtOAc and filter through silica gel to obtain the title compound (273 g, 97%) as an orange oil. ES/MS (m/z): 426 (M+Na).

Preparation 20

/v/V-Butyl (3R)-3-[2-tert-butoxy-l-[(3-formylphenyl)methyl]-l-methyl-2-oxo- ethyl ] py rroli dine- 1 -carb oxy 1 ate

Prepare the title compound essentially as described in Preparation 19 using tert-butyl (3R)-3-[ 1 -[(3-bromophenyl) ethyl]-2-tert-butoxy- 1 -methyl -2-oxo-ethyl]pyrrolidine-l-carboxylate. Purify the crude product by silica gel chromatography using a gradient of 10 to 30% acetone in hexanes. ES/MS (m/z): 262 (M+H-tert-butyl-BOC).

Preparation 21

/v/V- Butyl (3R)-3-[( 1 S)-2-/y/7-butoxy- 1 -[[3 -[hydroxyi mi nomethyl ]phenyl]methyl ]-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

Mix tert-butyl (3R)-3-[(l S)-2-tert-butoxy-l-[(3-formylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-l-carboxylate (50 g, 105 mmol, purity 85%), EtOH (400 mL), pyridine (17.0 mL, 211 mmol, 2 equiv) and hydroxylamine hydrochloride (10.98 g, 158.0 mmol, 1.5 equiv). Stir the mixture at RT for 2 h. Evaporate the solvent, add KHSO4 (1 M solution in water, 300 mL) and MTBE (500 mL). Separate the organic layer, wash the organic layer with saturated aqueous NaHCCh, filter and dry over MgSO4. Filter through Celite® and concentrate to dryness to obtain the title compound as a yellow oil (49g, 98% yield, purity 88% w/w). ES/MS (m/z): 319 (M+H-Boc)

Preparation 22

tert-Butyl (3R)-3-[(lS)-l-[[3-(aminomethyl)phenyl]methyl]-2-tert-butoxy-2-oxo- ethy 1 ] py rroli dine- 1 -carb oxy 1 ate

Prepare a FlowCAT high pressure flow chemistry reactor (H.E.L Ltd) with a stainless steel packed-bed reactor column (1.2 cm inner diameter c 10 cm long) containing sponge nickel catalyst (2 g) and glass beads (6 g, 212 to 300 microns). The reactor is equipped with gas and liquid flow controllers and a heating jacket around the column. Equilibrate the column by flushing with MeOH and hydrogen gas with the following parameters: liquid flow rate - 4 mL/min; Eh flow rate - 60 mL/min; pressure -50 bar; reactor column jacket temperature - 120 °C (internal reaction temperature maintained at 50 °C).

We claim:

1. A compound of the formula:

wherein

L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, - S(O)-, -S(O)2-, -O-, -0CH2-, -OCH2CH2O-, -NHSO2NH-,

R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of H and CH3;

or

a pharmaceutically acceptable salt thereof.

2. A compound as claimed by Claim 1 wherein R1 is H, and R3 is H; or a

pharmaceutically acceptable salt thereof.

3. A compound a claimed by any one of Claims 1 or 2 wherein R5 is H, or a

pharmaceutically acceptable salt thereof.

4. A compound as claimed by any one of Claims 1 to 3 wherein R2 is H and R4 is H; or a pharmaceutically acceptable salt thereof.

5. A compound as claimed by any one of Claims 1 to 4 wherein R6 is H, or a pharmaceutically acceptable salt thereof.

6 A compound as claimed by any one of Claims 1 to 3 wherein R2 is CH3 and R4 is CH3; or a pharmaceutically acceptable salt thereof.

7. A compound as claimed by any one of Claims 1 to 3 wherein R2 is CH3, R4 is CH3, and R6 is CH3, or a pharmaceutically acceptable salt thereof.

8 A compound as claimed by any one of Claims 1, 2, 4 or 6 wherein L is selected from the group consisting of -CH2NHCH2-, -CH2NH-, -NH-, -S-, -S(O)-, - S(O)2-, -O-, -OCH2-, -OCH2CH2O-, and -NHSO2NH-; or a pharmaceutically acceptable salt thereof.

9. A compound as claimed by any one of Claims 1 to 3 wherein L is

; or a pharmaceutically acceptable salt thereof. 10. A compound as claimed by Claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. A compound as claimed by claim 10 wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. A compound as claimed by claim 11, wherein the compound is a hydrochloride salt.

13. A compound as claimed by Claim 12 wherein the compound is a

tetrahydrochloride salt.

14. A pharmaceutical composition comprising a compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

15. A composition as claimed by claim 14 for use in treating cardiovascular disease.

16. A composition as claimed by claim 14 for use in the treatment of elevated Lp(a) plasma levels.

17. A method for treating cardiovascular disease in a patient in need thereof,

comprising administering an effective amount of a compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a composition of Claim 14, or a pharmaceutically acceptable salt thereof.

18. A method for treating elevated Lp(a) plasma levels comprising administering an effective amount of a compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a composition of claim 14, or a pharmaceutically acceptable salt thereof.

19. A compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in therapy.

20. A compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease.

21. A compound as claimed by any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated Lp(a) plasma levels.

22. Use of a compound as claimed by any one of claims 1 to 13, or a

pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cardiovascular disease.

23. Use of a compound according to any one of Claims 1 to 13, or a

pharmaceutically acceptable salt thereof, wherein the medicament is useful in the treatment of elevated Lp(a) plasma levels.

24. A compound of the formula:

; or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound as claimed by Claim 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.