Inhibitors of lipoprotein(a) assembly

Abstract

Described herein are inhibitors of lipoprotein(a) (Lp(a)) assembly, methods of making such inhibitors, pharmaceutical compositions and medicaments comprising such inhibitors, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from inhibition of Lp(a) assembly.

Description

[0001] INHIBITORS OF LIPOPROTEIN(a) ASSEMBLY CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No.63 / 656,797, filed June 6, 2024, and U.S. Provisional Application No.63 / 746,087, filed January 16, 2025, the contents of which are incorporated in their entireties. FIELD OF THE INVENTION Described herein are small molecule inhibitors of lipoprotein(a) (Lp(a)) formation, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of diseases or disorders that would benefit from inhibition of Lp(a) formation. BACKGROUND OF THE INVENTION Lipoprotein(a) (Lp(a)) is a lipid-carrying particle composed of a low-density lipoprotein (LDL)-like particle containing apolipoprotein B100 (apoB100) linked by a disulfide bond to apolipoprotein(a) (apo(a)). Formation of Lp(a) occurs after apo(a) first binds to lysine residues of apoB100 through the Kringle IV type 7 and 8 (KIV7–8) domains, which contain lysine-binding sites. This non-covalent interaction is then stabilized by a disulfide bond formed between a cysteine residue in the KIV-9 domain of apo(a) and a complementary cysteine in apoB100, resulting in the mature Lp(a) particle. Lipoprotein(a) is similar to low-density lipoprotein (LDL) cholesterol, sometimes called “bad cholesterol,” but is stickier and increases the risk of blockages in arteries. Plasma concentrations of lipoprotein(a) are primarily genetically determined (approximately 70 to ≥ 90%), and its expression is controlled by the apolipoprotein(a) gene (LPA). Common LDL lowering drugs, such as statins, do not have the same lowering effect on lipoprotein(a). Diet, exercise, and other lifestyle changes are of little benefit in lowering lipoprotein(a) plasma concentrations. Epidemiologic studies over the past three decades have shown an association between higher circulating lipoprotein(a) concentrations and an increased risk of atherosclerotic cardiovascular disease, atherosclerosis, and calcific valvular aortic stenosis. Genetic evidence supports Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. However, there are no currently available pharmacologic therapies that substantially lower plasma Lp(a) or are indicated to treat patients with elevated lipoprotein(a) plasma concentrations. Accordingly, additional treatment options are desired for patients suffering from cardiovascular diseases, metabolic diseases, and lipid disorders such as dyslipidemia, hyperlipidemia, and hypercholesterolemia. There is also a need for small molecules that bind with high affinity to KIV7–8 of apolipoprotein(a) to inhibit Lp(a) formation. SUMMARY OF THE INVENTION Described herein are inhibitors of lipoprotein(a) formation for use in the treatment of cardiovascular diseases, lipid disorders, metabolic diseases or disorders, or combinations thereof. In some embodiments, the compounds described herein exhibit strong binding affinity to the Kringle IV type 7 and 8 (KIV7–8) domains of apolipoprotein(a) (apo(a)). Without being bound to any particular theory, such binding may inhibit Lp(a) formation or reduce plasma Lp(a) levels in patients more effectively than compounds with weaker affinity for these domains. Compounds described herein are inhibitors of lipoprotein(a) formation, and they lower plasma concentrations of lipoprotein(a). In some aspects, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: G is a bivalent linker, a trivalent linker that is further coupled to R1, or a tetravalent linker that is further coupled to R1and R9(e.g., G is -O-, -N(R1)-, -S-, -S(O)-, -S(O)2-, -OCH2CH2O-, - NHS(O)2NH-, -N(R8)C(O)N(R8)-, -N(CH2CH2OR1)-, -N(CH2CH2NHR1)-, - OCH2C(CH3)(CH2OR1)CH2O-, -OCH2C(CH3)(CH2OR1)NH-, -OCH2C(NH2)(CH2OR1)CH2O-, - N(CH2CH2NR1R9)-, or -OCH2C(CH2OR1)(CH2OR9)CH2O-); each L is independently alkyl, heteroalkyl, or absent, wherein each alkyl or heteroalkyl are independently optionally substituted with R2; each R2is independently hydrogen, halogen, alkyl, or haloalkyl; Group A is a cycloalkyl (e.g., multicyclic cycloalkyl or bicyclic cycloalkyl), bicyclic heterocycloalkyl, or multicyclic heterocycloalkyl; Group B is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group C is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group D is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; each of Ra, Rb, Rc, and Rfare independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, - lkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rdis independently alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Reis independently hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two Reare taken together with the atom(s) to which they are attached and any intervening atoms between the two Reto form a heterocycloalkyl; each R3and each R5is independently hydrogen, halogen, alkyl, or haloalkyl; each R4is independently hydrogen or alkyl; each R6is independently hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -S(=O)Rd, -S(=O)2Rd, or -C(=O)Rd; each R7is independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, -OC(=O)Rd, -OC(=O)ORd, - OC(=O)N(Re)2, -SRe, -S(=O)Rd, -S(=O)2Rd, -S(=O)2ORe, -S(=O)2N(Re)2, -N(Re)2, - NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, -NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, - C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently hydrogen or alkyl, or the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle; each m is independently 0 or 1; each n is independently 1, 2, or 3; each p is independently 0, 1, 2, 3, or 4; and each q is independently 0, 1, or 2. Any combination of the groups described above for the disclosed variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a subject by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a subject by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some aspects, described herein are methods of treating a cardiovascular disease or disorder, a metabolic disease or disorder, or combination thereof, in a subject in need thereof, the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, is characterized by elevated lipoprotein(a) (Lp(a)) plasma levels in the subject. In some embodiments, the cardiovascular disease or disorder is coronary artery disease, acute myocardial infarction, asymptomatic carotid atherosclerosis, stroke, atrial fibrillation, hypercholesterolemia, peripheral artery occlusive disease, cerebrovascular disease, renal artery stenosis, or hypertensive heart disease. In some embodiments, the metabolic disease or disorder is dyslipidemia, hyperlipidemia, hyperlipoproteinemia(a), hypercholesterolemia, fatty liver, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis. In some embodiments, the metabolic disease or disorder is a lipid metabolism disorder. In some embodiments, the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, comprises metabolic syndrome. In some embodiments, the disease or disorder is a cardiovascular disease or a lipid disorder. In some embodiments, the cardiovascular disease or the lipid disorder is characterized by elevated Lp(a) plasma levels. In some embodiments, the cardiovascular disease is coronary artery disease, acute myocardial infarction, asymptomatic carotid atherosclerosis, stroke, atrial fibrillation, hypercholesterolemia, or peripheral artery occlusive disease. In some embodiments, the lipid disorder is dyslipidemia, hyperlipidemia, or hypercholesterolemia. In some aspects, described herein are methods of decreasing the likelihood of having a heart attack, a stroke, aortic stenosis, or a combination thereof, in a subject comprising administering a compound as described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method results in reducing lipoprotein(a) plasma levels in the subject. In some aspects, described herein are methods of inhibiting assembly of lipoprotein(a) in a subject, comprising administering a compound as described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the subject. In some aspects, described herein are methods of reducing lipoprotein(a) plasma levels in a subject, comprising administering a compound as described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the subject. DETAILED DESCRIPTION OF THE INVENTION There have been significant advances in treating cardiovascular disease (CVD). However, despite treatment advances, patients with CVD continue to experience cardiovascular disease events such as angina, myocardial infarction, and stroke, which if untreated, can lead to death. CVDs also include coronary artery disease, acute myocardial infarction, asymptomatic carotid atherosclerosis, stroke, atrial fibrillation, hypercholesterolemia, and peripheral artery occlusive disease. Lipid disorders remain a major risk factor for CVD. Lipid disorders, such as dyslipidemia, hyperlipidemia, and hypercholesterolemia, can be divided into four general risk factors: elevated low-density lipoprotein (LDL) cholesterol, low high-density lipoprotein (HDL) cholesterol (i.e., “good” cholesterol), elevated triglycerides, and elevated Lp(a). The physiological function of Lp(a) is complex, however, and elevated Lp(a) plasma levels are known to be an independent risk factor for CVD. Currently, there is no Food and Drug Administration (FDA) approved therapeutic to lower Lp(a) plasma levels. Lipoprotein(a) forms by bonding between apolipoprotein(a) (apo(a)) and apoB100. 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 and do not vary significantly with diet and exercise. A genetic predisposition to elevated Lp(a) plasma levels may exist. Lp(a) resembles LDL cholesterol because it includes an LDL lipid core with an attendant apolipoprotein B (apoB), but unlike LDL cholesterol, Lp(a) also contains apolipoprotein(a) (apo(a)) bound to the apoB via disulfide bond. Apolipoprotein B occurs in the plasma in two main isoforms, apoB48 and apoB100. The apoB48 is synthesized by the small intestine, while apoB100 is synthesized by the liver. The largest of the apoB group of proteins is apoB100. 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. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of a metabolic disease or disorder. In some embodiments, the metabolic disease or disorder is dyslipidemia, hyperlipidemia, hyperlipoproteinemia(a), hypercholesterolemia, fatty liver, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH). In some embodiments, the metabolic disease or disorder is a lipid metabolism disorder. Non-alcoholic fatty liver disease (NAFLD) is associated with excessive fat in the liver (steatosis) due to causes other than excessive alcohol intake. In some embodiments, NAFLD is associated with obesity, type-2 diabetes, and metabolic syndrome. NAFLD can manifest as simple steatosis or steatosis with inflammation and liver injury which is classified as non- alcoholic steatohepatitis (NASH). NASH is defined by the histologic hallmarks of inflammation, cell death, and fibrosis. In some instances, primary NASH is associated with insulin resistance. In some embodiments, hyperlipoproteinemia(a) is characterized by a plasma level of lipoprotein(a) of at least 50 mg / dL (125 nmol / L). Lipoprotein(a) levels of greater than or equal to 125 nmol / L or 50 mg / dL have been correlated with an increased risk of heart attack or stroke. (https: / / www.heart.org / en / health-topics / cholesterol / genetic-conditions / lipoprotein-a). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of metabolic syndrome. Metabolic syndrome is a serious health condition that results in higher risk of heart disease, diabetes, stroke, and diseases related to fatty buildups in artery walls (atherosclerosis). Underlying causes of metabolic syndrome include overweight and obesity, insulin resistance, physical inactivity, genetic factors and increasing age. Metabolic syndrome is diagnosed when a person has three or more of the following risk factors: high blood glucose, low levels of HDL cholesterol in the blood, high levels of triglycerides in the blood, large waist circumference or “apple-shaped” body, or high blood pressure. Each of these risk factors is a risk factor for cardiovascular disease, but the chance of developing a serious cardiovascular condition increases when a person is diagnosed with metabolic syndrome. For example, high blood pressure is an important risk factor for cardiovascular disease, but when combined with high fasting blood sugar levels, and abdominal obesity (large waistline), the chance for developing cardiovascular disease is intensified. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment of cardiometabolic syndrome. Cardiometabolic syndrome (CMS) is a combination of metabolic dysfunctions mainly characterized by obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central adiposity. CMS increases in prevalence as the population becomes more obese which increases the risk for cardiovascular disease and type 2 diabetes. CMS is recognized as a disease by the World Health Organization and the American Society of Endocrinology (Srivastava AK. “Challenges in the treatment of cardiometabolic syndrome,” Indian J Pharmacol.2012;44(2):155-156). People with CMS are two times more likely to die from coronary heart disease and three times more likely to have a heart attack or stroke than those who do not have the syndrome. It is now known that central adiposity is a major contributor to increased cardiometabolic risk. Various pathophysiological cardiometabolic factors have been reported to be associated with the risk of myocardial infarction. Visceral fat is the result of an imbalance between energy intake and expenditure. Metabolically active tissues produce various proinflammatory and prothrombotic cytokines. Both fatty liver and abdominal visceral adipose tissue are correlated with CMS. In some embodiments, compounds described herein are inhibitors of lipoprotein(a) formation. In some embodiments, compounds described herein are used to lower plasma concentrations of Lp(a). In some embodiments, compounds described herein inhibit Lp(a) formation by blocking the apo(a)-apoB100 interaction. In some embodiments, compounds described herein inhibit Lp(a) formation by blocking the apo(a)-apoB100 interaction while avoiding interaction with a homologous protein, plasminogen. Compounds In some aspects, described herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: G is a bivalent linker, a trivalent linker that is further coupled to R1, or a tetravalent linker that is further coupled to R1and R9(e.g., G is -O-, -N(R1)-, -S-, -S(O)-, -S(O)2-, -OCH2CH2O-, - NHS(O)2NH-, -N(R8)C(O)N(R8)-, -N(CH2CH2OR1)-, -N(CH2CH2NHR1)-, - OCH2C(CH3)(CH2OR1)CH2O-, -OCH2C(CH3)(CH2OR1)NH-, -OCH2C(NH2)(CH2OR1)CH2O-, - N(CH2CH2NR1R9)-, or -OCH2C(CH2OR1)(CH2OR9)CH2O-); each L is independently alkyl, heteroalkyl, or absent, wherein each alkyl or heteroalkyl are independently optionally substituted with R2; each R2is independently hydrogen, halogen, alkyl, or haloalkyl; Group A is a cycloalkyl (e.g., multicyclic cycloalkyl or bicyclic cycloalkyl), bicyclic heterocycloalkyl, or multicyclic heterocycloalkyl; Group B is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group C is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group D is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; each of Ra, Rb, Rc, and Rfare independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, - C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rdis independently alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Reis independently hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two Reare taken together with the atom(s) to which they are attached and any intervening atoms between the two Reto form a heterocycloalkyl; each R3and each R5is independently hydrogen, halogen, alkyl, or haloalkyl; each R4is independently hydrogen or alkyl; each R6is independently hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -S(=O)Rd, - S(=O)2Rd, or -C(=O)Rd; each R7is independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, -OC(=O)Rd, - C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently hydrogen or alkyl, or the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle; each m is independently 0 or 1; each n is independently 1, 2, or 3; each p is independently 0, 1, 2, 3, or 4; and each q is independently 0, 1, or 2. In certain embodiments, G is a bivalent linker, a trivalent linker that is further coupled to R1, or a tetravalent linker that is further coupled to R1and R9. As will be understood to those of skill in the art, any suitable linker may be used to couple the arms of the compounds of the present disclosure. For example, in certain embodiments the linker is a nitrogen (which is trivalent) or an oxygen (which is bivalent). In certain embodiments, the linker is an alkane (e.g., a C1-6alkane, such as a C1, C2, C3, or C4alkane), which may be substituted as described herein, and which may be coupled to the arms of the compound, e.g., through an oxygen atom, a nitrogen-containing group such as an amine, amide, or urea; or a sulfur-containing group such as a sulfone or sulfonamide. In certain such embodiments, the amine is secondary; in other such embodiments the amine is tertiary and may couple to one or two arms of the compound. In certain embodiments, when the amine is tertiary and couples to one arm of the compound, the other substituent on the amine is an alkyl or heteroalkyl. Non-limiting examples of linker groups for G include, but are not limited to, -O-, -N(R1)-, -S-, -S(O)-, -S(O)2-, -OCH2CH2O-, -

[0002] In certain embodiments, the compound of Formula (I) has the following structure: pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I) has the following structure: acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): or a pharmaceutically acceptable salt thereof. In some embodiments, In some preferred embodiments, In some embodiments, the compound of Formula (I) has the structure of Formula (Ib): Formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (Ic): Formula (Ic), or a pharmaceutically acceptable salt thereof. In some such embodiments, the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle. In some embodiments, the compound of Formula (I) has the structure of Formula (Id): or a pharmaceutically acceptable salt thereof. I I In some embodiments, the compound of Formula (I) has the structure of Formula (Ie): or a pharmaceutically acceptable salt thereof. In some embodiments, In some preferred embodiments, In some embodiments, the compound of Formula (I) has the structure of Formula (If): or a pharmaceutically acceptable salt thereof. In some embodiments, In some preferred embodiments, In some embodiments, the compound of Formula (I) has the structure of Formula (Ig): or a pharmaceutically acceptable salt thereof. In some embodiments, In some preferred embodiments, In some embodiments, the compound of Formula (I) is a compound of Formula (Ih): Formula (Ih), or a pharmaceutically acceptable salt thereof. In some embodiments, In some preferred embodiments, In some embodiments, In some preferred embodiments, In some embodiments, the compound of Formula (I) has the structure of Formula (Ij): In some preferred embodiments, In some embodiments, the compound of Formula (I) has the structure of Formula (Ik): or a pharmaceutically acceptable salt thereof. I I In some embodiments, the compound of Formula (I) has the structure of Formula (Im): or a pharmaceutically acceptable salt thereof. In some embodiments, at least one L is methyl optionally substituted with R2. In some embodiments, at least one L is heteroalkyl. In some embodiments, at least one L is absent. In some embodiments, each L is independently methyl optionally substituted with R2. In some embodiments, each R2is independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl; each R3is independently hydrogen, halo, C1-C4alkyl, or C1-C4haloalkyl; and each R7 is each R7 is independently hydrogen, halogen, -CN, -OH, -ORd, -OC(=O)Rd, - OC(=O)ORd, -OC(=O)N(Re)2, -N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, - NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, C1-C4alkyl, C1-C4haloalkyl, or C1-C4heteroalkyl. In some embodiments, one or more of R2, R3, and R7are independently halo, such as F. In some embodiments, each R2is independently hydrogen, F, Cl, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, - CH2CHCl2, or -CH2CCl3; each R3 is independently hydrogen, F, -CH3, -CH2CH, -CH2F, -CHF2, - CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or - CH2CCl3; each R4is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, - CH2CH(CH3)2, or -CH2(CH3)3; and each R7is independently hydrogen, F, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. In some embodiments, each R2is independently hydrogen or -CH3; each R3is independently hydrogen or -CH3; and each R4is independently hydrogen, -CH3, or -CH2CH3. In some preferred embodiments, each R2is hydrogen; each R3is hydrogen; and each R4is hydrogen. In some embodiments, each L is absent. In some embodiments, each R3is independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl; and each R7is independently hydrogen, halogen, -CN, -OH, -ORd, -OC(=O)Rd, - OC(=O)ORd, -OC(=O)N(Re)2, -N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, - NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, C1-C4alkyl, C1-C4haloalkyl, or C1-C4heteroalkyl. In some such embodiments, each R3is independently hydrogen, F, -CH3, - CH2CH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3; each R4is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, - C(CH3)3, -CH2CH(CH3)2, or -CH2(CH3)3; and each R7is independently hydrogen, F, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3,-CH2Cl, -CHCl2, -CCl3, - CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. In some preferred embodiments, each R3is independently hydrogen or -CH3; and each R4is independently hydrogen, -CH3, or -CH2CH3. In some more preferred embodiments, each R3is hydrogen; and each R4is hydrogen. In some embodiments, the compound has the structure of Formula (II): Formula (II), or a pharmaceutically acceptable salt thereof, In some embodiments, the compound has the structure of Formula (IIa1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIa2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIa3): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIa4): In some embodiments, the compound of Formula (II) has the structure of Formula (IIa5): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIb1): In some embodiments, the compound of Formula (II) has the structure of Formula (IIb2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIc1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIc2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIc3): Formula (IIc3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IId1): Formula (IId1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIe1): Formula (IIe1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIf1): In some embodiments, the compound of Formula (II) has the structure of Formula (IIg1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIh1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIh2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIj1): Formula (IIj1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIk1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIm1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) has the structure of Formula (IIm2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIa1): or a pharmaceutically acceptable salt thereof; wherein: Group A is caged C8-C12cycloalkyl; Group B is aryl (e.g., C6-C10aryl); Group C is aryl (e.g., C6-C10aryl); each R5is, independently for each occurrence, H, halo, or C1-6alkyl; R6is H; Rais halo, C1-6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; Rbis halo, C1-6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; Rcis halo, C1-6alkyl, C1-C6haloalkyl, or C1-C6alkoxy; each m is 1; each n is 1; and each p is, independently for each occurrence, 0 or 1. In some embodiments, the compound has the structure of Formula (IIa1): or a pharmaceutically acceptable salt thereof; wherein: Group A is cubanyl Group B is aryl (e.g., C6-C10aryl); Group C is aryl (e.g., C6-C10aryl); each R5is, independently for each occurrence, H, halo, or C1-6alkyl; R6is H; Rais halo or C1-6alkyl; Rbis halo or C1-6alkyl; Rcis halo or C1-6alkyl; each m is 1; each n is 1; and each p is, independently for each occurrence, 0 or 1. In some embodiments, the compound has the structure of Formula (IIa1):

[0003] or a pharmaceutically acceptable salt thereof; wherein: Group A is cubanyl Group B is aryl (e.g., C6-C10aryl); Group C is aryl (e.g., C6-C10aryl); R5is H R6is H m and n are 1; and p is 0. In some embodiments, Group A is a caged C8-C12cycloalkyl, bridged bicyclic C5- C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, or caged C1-C12heterocycloalkyl. In some embodiments, Group A is a cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[3.2.2]octanyl. In some embodiments, Group A is a cubanyl or bicyclo[1.1.1]pentanyl. In some preferred embodiments, Group A is a cubanyl. In some preferred embodiments, Group A is a bicyclo[1.1.1]pentanyl. or closo-1,12-carboranyl. In some preferred embodiments, Group In some preferred embodiments, Group A is . In some embodiments, Group B is caged C8-C12cycloalkyl, bridged bicyclic C5- C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, caged C1-C12heterocycloalkyl, phenyl, or pyridyl. In some embodiments, Group B is cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. In some embodiments, Group B is cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. In some embodiments, Group B is cubanyl or phenyl, each optionally substituted with 1-4 Rb.

[0004] 1

[0005] In some preferred embodiments, Group B is . In some embodiments: In some embodiments:

[0006] In some embodiments, Group B and Group C are each independently caged C8- C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5- C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, caged C1-C12heterocycloalkyl, phenyl, or pyridyl. In some embodiments, Group B and Group C are each independently cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. In some embodiments, Group B and Group C are each independently cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. In some embodiments, Group B and Group C are each independently cubanyl or phenyl, each optionally substituted with 1-4 Rbor Rc. In some embodiments, Group B and Group C are each independently ,

[0007] In some embodiments, Group B and Group C are each independently , In some embodiments, Group B and Group C are each independently , In some preferred embodiments, Group B and Group C are each independently In some embodiments: In some embodiments: In some embodiments, Group B, Group C, and Group D are each independently caged C8-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, caged C1-C12heterocycloalkyl, phenyl, or pyridyl. In some embodiments, Group B, Group C, and Group D are each independently cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. In some embodiments, Group B, Group C, and Group D are each independently cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. In some embodiments, Group B, Group C, and Group D are each independently cubanyl or phenyl, each optionally substituted with 1-4 Rb,Rc, or Rf. In some embodiments, Group B, Group C, and Group D are each independently In some embodiments, Group B, Group C, and Group D are each independently In some preferred embodiments, Group B, Group C, and Group D are each independently or . In some embodiments: I In some embodiments:

[0008] In some embodiments, each R6is independently hydrogen, -CH3, -CH2CH, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH2)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. In some embodiments, each R6is independently hydrogen, -CH3, -CH2CH, -CH2CH2CH3, or -CH2CH(CH3)2. In some preferred embodiments, each R6is hydrogen. In some preferred embodiments, each m is 1; and each n is 1. In some embodiments, the compound has the structure of Formula (IIIa1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa3): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa4): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa5): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa6): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa7): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or Formula (II) has the structure of Formula (IIIa8): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa9): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIa10): or a pharmaceutically acceptable salt thereof.In some embodiments, the compound has the structure of Formula (IIIb1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIb2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIb3): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIc1): Formula (IIIc1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIc2): Formula (IIIc2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIc3): Formula (IIIc3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIc4): Formula (IIIc4), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIh1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIh2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIk1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIk2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIk3): Formula (IIIk3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIk4): or a pharmaceutically acceptblae salt thereof. In some embodiments, the compound has the structure of Formula (IIIm1): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIm2): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIm3): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIm4): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (IIIm5): or a pharmaceutically acceptable salt thereof.

[0009] In some preferred embodiments, each R5is independently hydrogen, F, or -CH3. In some preferred embodiments, the compound has the following structure:

[0010] pharmaceutically acceptable salt thereof. In some embodiments, each Ra, Rb, Rc, and Rfare independently hydrogen, F, Cl, Br, I, - CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, - CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CD3, -CN, -NH2, -NH(CH3), -N(CH3)2, -CO2H, -CO2(C1- C4alkyl), -C(=O)(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), or -C(=O)N(C1-C4alkyl)2. In some embodiments, each Ra, Rb, Rc, and Rfare independently hydrogen, F, Cl, Br, I, - CH3, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, or -CN. In some embodiments, the compound has the following structure: each R5is independently H, -CH3, or F.

[0011] In some embodiments, the compound has the following structure: each R5is independently H, -CH3, or F; and each Rbis independently, H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: Rband Rcare each independently H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: each R5is independently H, -CH3, or F. In some embodiments, the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rbis H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: wherein: each R5is independently H, -CH3, or F; and Rbis H, -CH3, -OCH3, or F.

[0012] In some embodiments, the compound has the following structure: each R5is independently H, -CH3, or F; and Rband Rcare each independently H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: each R5is independently H, -CH3, or F; and Rcand Rfare each independently H, -CH3, -OCH3, or F.

[0013] In some embodiments, the compound has the following structure: Rcand Rfare each independently, H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rcis H, -CH3, -OCH3, or F. In some embodiments, the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rband Rcare each independently H, -CH3, -OCH3, or F. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is:

[0014]

[0015]

[0016] ,

[0017] ,

[0018] ,

[0019] ,

[0020]

[0021] , , , , ,

[0022] pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is:

[0023] pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain such embodiments, the compound of Formula (I) is: pharmaceutically acceptable salt thereof. In certain embodiments, compound of Formula (I), or pharmaceutically acceptable salt thereof, is selected from a compound in Table 1. Table 1:

[0024] In certain embodiments, compound of Formula (I), is selected from a compound in Table 2. Table 2:

[0025] Further Forms of Compounds In some aspects, compounds described herein are in the form of pharmaceutically acceptable salts. The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure disclosed herein. In an embodiment, the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In other embodiments, resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as D- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like. In some embodiments, resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. In some embodiments, when compounds described herein contain a chiral center, unless otherwise indicated, the compounds can be any of the possible stereoisomers. In some embodiments, an asterisk (*) at a chiral center indicates a compound having either an (R)- configuration or an (S)-configuration at the indicated chiral center, but absolute stereochemistry of the chiral center has not been determined. In some embodiments, the compounds provided herein have the (R)-configuration. In other embodiments, the compounds have the (S)- configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S). In some embodiments, the compounds disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compounds disclosed herein exists in the R configuration. In some embodiments, the compound disclosed herein exists in the S configuration. Those of skill in the art will appreciate that, where a compound is drawn with specific stereochemistry, variants of that compound that are racemic at any or all of the stereocenters may also be envisioned, and such partially or fully racemic compounds are also contemplated herein. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, rectus (R), sinister (S), entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure. In other embodiments, compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone–enol pairs, amide - imidic acid pairs, lactam–lactim pairs, enamine–imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4- triazole, 1H- and 2H- isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, if a compound name or structure described the 9H tautomer, it would be understood that the 7H tautomer is also encompassed). In some embodiments, the compounds disclosed herein comprise stable isotopes of hydrogen, carbon, nitrogen, and oxygen in amounts greater than their natural abundance. For example, one or more hydrogen atoms may be enriched with2H in an amount greater than about 0.015% (e.g., 1.2-1.5%, 1.5-2%, 2-10%, or more than 10%). For example, one or more carbon atoms may be enriched with13C in an amount greater than about 1.1% (e.g., 1.2-1.5%, 1.5-2%, 2-10%, or more than 10%). One or more nitrogen atoms may be enriched with15N in an amount greater than about 0.4% (e.g., 0.5-1%, 1-2%, 2-10%, or greater than 10%). Likewise, one or more oxygen atoms may be enriched with16O in an amount greater than about 0.24% (e.g., 0.25-0.5%, 0.5-1%, 1-2%, 2-10%, or greater than 10%). Recitation of “hydrogen” or “H” should be understood to encompass1H (protium),2H (deuterium), and3H (tritium) unless otherwise specified. In some embodiments, compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. In the compounds provided herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. In some embodiments, substitution with heavier isotopes such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in somecircumstances. (A. Kerekes et.al. J. Med. Chem.2011, 54, 201-210; R. Xu et.al. J. LabelCompd. Radiopharm. 2015, 58, 308-312). Unless otherwise stated, when a position isdesignated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). In embodiments, the compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Synthesis of Cubane Building Blocks Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, and HPLC are employed. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc.; R. Larock, Comprehensive Organic Transformations, 2nd Ed. Wiley-VCH (1999); P.G.M. Wuts, Greene’s Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Hoboken, NJ (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995); M.P. Wiesenfeldt, et al. “General access to cubanes as benzene bioisosteres.” Nature 618, 513–518 (2023); O.L. Garry, et al. “Rapid Access to 2‑Substituted Bicyclo[1.1.1]pentanes” Journal of the American Chemical Society 2023145 (5), 3092-3100; S.B. Beil, et al. “Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis.” Accounts of Chemical Research 202255 (23), 3481-3494. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. Suitable cubane building blocks used to prepare compounds of Formula (I) are commercially available or can be prepared as described herein. For example, monosubstituted cubanes that are commercially available include: cubane-1-carboxylic acid, (cuban-1- yl)methanol, and 1-(bromomethyl)cubane. Disubstituted cubanes that are commercially available include: cubane-1,4-dicarboxylic acid, dimethyl cubane-1,4-dicarboxylate, 4-(methoxycarbonyl)cubane-1-carboxylic acid, 4-((tert- butoxycarbonyl)amino)cubane-1-carboxylic acid, methyl 4-((tert-butoxycarbonyl)amino)cubane- 1-carboxylate, methyl 4-aminocubane-1-carboxylate, 4-(hydroxymethyl)cubane-1-carboxylate, 4- (hydroxymethyl)cubane-1-carbonitrile, 4-cyanocubane-1-carboxylic acid, methyl 4-cyanocubane- 1-carboxylate, methyl 4-(2-bromoacetyl)cubane-1-carboxylate, 4-chlorocubane-1-carboxylic acid, 4-(hydroxymethyl)cubane-1-carboxylic acid, cubane-1,4-diyl)dimethanol, methyl (1S,2R,3R,8S)-4-formylcubane-1-carboxylate, 4-(methylcarbamoyl)cubane-1-carboxylic acid, 4- (dimethylcarbamoyl)cubane-1-carboxylic acid, methyl 4-chlorocubane-1-carboxylate, methyl (1S,2R,3R,8S)-4-iodocubane-1-carboxylate, methyl (1S,2R,3R,8S)-4-bromocubane-1- carboxylate, 4-(aminomethyl)cubane-1-carboxylic acid, methyl (2R,3R,4S,5S)-4- carbamoylcubane-1-carboxylate, 4-phenylcubane-1-carboxylic acid, methyl 4-phenylcubane-1- carboxylate, methyl 4-(bromomethyl)cubane-1-carboxylate, 1,4-bis(iodomethyl)cubane, 4- (bromomethyl)cubane-1-carboxylic acid, methyl 4-(aminomethyl)cubane-1-carboxylate, methyl 4-acetylcubane-1-carboxylate, 1,4-bis(bromomethyl)cubane, 4-iodocubane-1-carboxylic acid, 4- bromocubane-1-carboxylic acid, 4-(fluoromethyl)cubane-1-carboxylic acid, methyl 4- (fluoromethyl)cubane-1-carboxylate, 4-fluorocubane-1-carboxylic acid, and methyl 4- fluorocubane-1-carboxylate. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000). Chemistry terms used herein are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985). All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, gerbils, etc.) and rodents (e.g., mice and rats). “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount. “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbon atoms in the chain. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term “amide”, as used herein, refers to a group , wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group , wherein R9and R10independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The terms “carbocyclic” or “carbocycle” refer to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms, and may be unsubstituted or substituted. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom that is different from carbon. In some embodiments, carbocycles are monocyclic (i.e., a single ring), bicyclic (i.e., two rings), or multicyclic (i.e., three or more rings). In some embodiments, a carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, one of the two rings of a bicyclic carbocycle is aromatic, and the point of attachment to the remainder of the compound is at a carbon atom of the aromatic ring. In some embodiments, one of the two rings of a bicyclic carbocycle is aromatic, and the point of attachment to the remainder of the compound is at a carbon atom of the non-aromatic ring. In some embodiments, a bicyclic carbocycle is a fused bicyclic carbocycle. In some embodiments, both rings of a fused bicyclic carbocycle are aromatic (i.e., an aryl). The terms “carbocyclic” or “carbocycle” include cycloalkyl and aryl. In some embodiments, a carbocycle can have 3-14 ring members, such as 3-12 ring members. In other embodiments, a carbocycle can have 3-10 ring members. The term “cycloalkyl” refers to a cyclic saturated aliphatic hydrocarbon, and may be unsubstituted or substituted. In some embodiments, cycloalkyl is a monocyclic cycloalkyl (i.e., a single ring), bicyclic cycloalkyl (i.e., two rings), or multicyclic cycloalkyl (i.e., three or more rings). In some embodiments, cycloalkyl is a monocyclic cycloalkyl. In some embodiments, cycloalkyl is a bicyclic cycloalkyl. In some embodiments, cycloalkyl is a multicyclic cycloalkyl. In some embodiments, a cycloalkyl can have 3-14 ring members, such as 3-12 ring members. In other embodiments, a cycloalkyl can have 3-10 ring members. The term “monocyclic cycloalkyl” refers to a cycloalkyl that is a single ring. Monocyclic cycloalkyls include from 3 to 10 carbon atoms in the ring (i.e., a monocyclic C3-C10cycloalkyl). Monocyclic cycloalkyls that include 3 to 10 carbon atoms in the ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecanyl. In some embodiments, a monocyclic cycloalkyl is a monocyclic C3-C6cycloalkyl. Monocyclic C3- C6cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “bicyclic cycloalkyl” refers to a ring system containing two cycloalkyls that are joined together. In some embodiments, the bicyclic cycloalkyl is a spiro bicyclic (spirocyclic) cycloalkyl, a fused bicyclic cycloalkyl, or a bridged bicyclic cycloalkyl. In some embodiments, a bicyclic cycloalkyl has 5 to 12 carbon atoms (i.e., a bicyclic C5-C12cycloalkyl). The term “spiro bicyclic cycloalkyl” refers to a ring system containing two cycloalkyls that are joined together and share a single carbon atom. In some embodiments, a spiro bicyclic cycloalkyl has 5 to 12 carbon atoms (i.e., a spiro bicyclic C5-C12cycloalkyl). Non-limiting examples of spiro bicyclic cycloalkyls include: spiro[2.2]pentyl, spiro[3.2]hexyl, spiro[3.3]heptyl, spiro[4.3]octyl, spiro[4.2]heptyl, spiro[5.3]nonyl, spiro[5.4]decanyl, spiro[5.5]undecanyl, spiro[5.2]octyl, spiro[6.3]decanyl, spiro[6.4]undecanyl, and spiro[6.5]dodecanyl. The term “fused bicyclic cycloalkyl” refers to a ring system containing two cycloalkyls that are joined together and share two adjacent carbon atoms. In some embodiments, a fused bicyclic cycloalkyl has 5 to 12 carbon atoms (i.e., a fused bicyclic C5-C12cycloalkyl). In some embodiments, a fused bicyclic cycloalkyl has 6 to 10 carbon atoms (i.e., a fused bicyclic C6- C10cycloalkyl). Non-limiting examples of fused bicyclic cycloalkyls include: bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[4.2.0]octane, bicyclo[4.1.0]heptane, bicyclo[3.3.0]octane, and bicyclo[3.1.0]hexane. The term “bridged bicyclic cycloalkyl” refers to a ring system containing two cycloalkyls that are joined together and share three or more carbon atoms. In some embodiments, a bridged bicyclic cycloalkyl has 5 to 12 carbon atoms (i.e., a bridged bicyclic C5-C12cycloalkyl). In some embodiments, a bridged bicyclic cycloalkyl has 5 to 8 carbon atoms (i.e., a bridged bicyclic C5-C8cycloalkyl). Non-limiting examples of bridged bicyclic cycloalkyls include: (bicyclo[1.1.1]pentanyl), (bicyclo[2.1.1]hexanyl), (bicyclo[3.1.1]heptanyl), (bicyclo[2.2.1]heptanyl), (bicyclo[2.2.2]octanyl), (bicyclo[3.2.2]octanyl), , (bicyclo[4.2.2]dodecanyl), (bicyclo[3.3.2]dodecanyl), (bicyclo[3.2.2]nonanyl), (bicyclo[3.3.3]undecanyl), a (bicyclo[3.1.1]heptanyl). Carbon numbers of bicyclo[1.1.1]pentanyl (BCP) for naming purposes is based on the following: . The term “multicyclic cycloalkyl” refers to a ring system containing three or more cycloalkyls joined together and wherein each cycloalkyl shares at least one carbon atom with at least one other cycloalkyl. In some embodiments, a multicyclic cycloalkyl has 8 to 12 carbon atoms (i.e., a multicyclic C8-C12cycloalkyl). Multicyclic cycloalkyls include caged cycloalkyls, spiro cycloalkyls, fused cycloalkyls, bridged cycloalkyls, or a combination thereof. In some embodiments, a multicyclic cycloalkyl is a caged cycloalkyl. Non-limiting examples of multicyclic cycloalkyls include: (cubane; pentacyclo[4.2.0.02,5.03,8.04,7]octane), (adamantane; tricyclo[3.3.1.13,7]decane), (cuneane; pentacyclo[3.3.0.02,4.03,7.06,8]octane), (tricyclo[3.2.2.02,4]nonane),(tricyclo[5.2.1.02,6]decane), The term “caged cycloalkyl” refers to a subset of multicyclic cycloalkyls having a three- dimensional enclosed structure with each ring forming a face of the three-dimensional structure. Non-limiting examples of caged cycloalkyls include: (cubane), (adamantane), and Carbon numbers for naming purposes is based on the following: . The term “cycloalkenyl” refers to a type of non-aromatic cycloalkyl group in which at least one carbon-carbon double bond is present, and may be unsubstituted or substituted. In some embodiments, a cycloalkenyl has 5 to 12 carbon atoms (i.e., a C5-C12cycloalkenyl). In some embodiments, a cycloalkenyl is a monocyclic cycloalkenyl, a bicyclic cycloalkenyl, or a multicyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a monocyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a bicyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a multicyclic cycloalkenyl. In some embodiments, a monocyclic cycloalkenyl has 5 to 12 carbon atoms (i.e., a C5- C12cycloalkenyl). In some embodiments, a monocyclic cycloalkenyl has 5 to 8 carbon atoms (i.e., a C5-C12cycloalkenyl). Non-limiting examples of cycloalkenyls include: ,, , , , , , , , and .The term “bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together, wherein at least one of the cycloalkyls has at least one carbon-carbon double bond. In some embodiments, the bicyclic cycloalkenyl is a spiro bicyclic cycloalkenyl, a fused bicyclic cycloalkenyl, or a bridged bicyclic cycloalkenyl. In some embodiments, a bicyclic cycloalkenyl has 5 to 12 carbon atoms (i.e., a bicyclic C5-C12cycloalkenyl). The term “spiro bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share a single carbon atom and at least one of the cycloalkyls has at least one carbon- carbon double bond. In some embodiments, a spiro bicyclic cycloalkenyl has 6 to 12 carbon atoms (i.e., a spiro bicyclic C6-C12cycloalkenyl). Non-limiting examples of spiro bicyclic cycloalkenyls include: The term “fused bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share two adjacent carbon atoms and at least one of the cycloalkyls has at least one carbon-carbon double bond. In some embodiments, a fused bicyclic cycloalkenyl has 6 to 12 carbon atoms (i.e., a fused bicyclic C5-C12cycloalkenyl). In some embodiments, a fused bicyclic c iting The term “bridged bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share three or more carbon atoms and at least one of the cycloalkyls has at least one carbon-carbon double bond. In some embodiments, a bridged bicyclic cycloalkenyl has 6 to 12 carbon atoms (i.e., a bridged bicyclic C6-C12cycloalkenyl). In some embodiments, a bridged bicyclic cycloalkenyl has 6 to 8 carbon atoms (i.e., a bridged bicyclic C5-C8cycloalkenyl). Non- limiting examples of bridged bicyclic cycloalkenyls include: , , , , The term “carbonate” is art-recognized and refers to a group -OCO2R9, wherein R9represents a hydrocarbyl group. The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H. The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. The terms “halo” and “halogen” as used herein mean halogen and include chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refer to an alkyl group substituted with a heteroyl group. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl (when linked through a carbon atom), carbocycle, heterocycle (when linked through a carbon atom), alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The term “sulfate” is art-recognized and refers to the group –OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae , wherein R9and R10independently represents hydrogen or hydrocarbyl. The term “sulfoxide” is art-recognized and refers to the group -S(O)R9, wherein R9represents a hydrocarbyl group-. The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group –S(O)2R9, wherein R9represents a hydrocarbyl group. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more atoms of the moiety. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the substituents on the moiety can themselves be substituted, if appropriate. In certain embodiments, a moiety described as “substituted” has one to six substituents preferably one to four, and most preferably one to three. It is understood that a substituent may itself be further substituted. For example, a non-limiting set of substituted cubanyl groups is provided below:

[0026] ,

[0027] 

[0028] . The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SR9or –SC(O)R9wherein R9represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term “urea” is art-recognized and may be represented by the general formula ,wherein R9and R10independently represent hydrogen or a hydrocarbyl. The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity. The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients. The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by formulas I, II, or III. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono- , di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of formulas I, I, II, or III are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of formulas I, I, II, or III for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by formulas I’, I, II, or III or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include, but are not limited to, indolizinyl, indolyl, benzofuranyl, benzothiophenyl, benzofurazanyl, benzothiazolyl, benzoxazolyl, indazolyl, benzimidazolyl, purinyl, quinolizinyle, quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, furopyridinyl and pteridinyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring system. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 1 O atom, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atom, and 1 S atoms in the ring system. In some embodiments, a heteroaryl has 5-10 ring members. In some embodiments, a monocyclic heteroaryl has 5-6 ring members. In some embodiments, a monocyclic heteroaryl has 5 members. In some embodiments, a bicyclic heteroaryl has 6-10 ring members. A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group where at least one or more ring carbon atoms has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, heterocycloalkyl is a monocyclic heterocycloalkyl (i.e., a single ring), bicyclic heterocycloalkyl (i.e., two rings), or multicyclic heterocycloalkyl (i.e., three or more rings). In some embodiments, heterocycloalkyl is a monocyclic heterocycloalkyl. In some embodiments, heterocycloalkyl is a bicyclic heterocycloalkyl. In some embodiments, heterocycloalkyl is a multicyclic heterocycloalkyl. In some aspects, a heterocycloalkyl has 3-12 ring members. In another aspect, a heterocycloalkyl has 4-12 ring members. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring system. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring system. The term “monocyclic heterocycloalkyl” refers to a heterocycloalkyl that is a single ring. Monocyclic heterocycloalkyls can include from 2 to 10 carbon atoms in the ring for a total of 3 to 12 atoms in the ring. Monocyclic heterocycloalkyls that include 2 to 10 carbon atoms in the ring include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, thietanyl, thioxanyl, oxazolidinonyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, dihydropyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5- dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, thiazolidin-2-onyl, pyrrolin-2-yl, pyrrolin- 3-yl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. In some embodiments, monocyclic heterocycloalkyls that include 2 to 8 carbon atoms in the ring include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and homopiperidinyl. In some embodiments, a monocyclic heterocycloalkyl 3-10 ring members. In other embodiments, a monocyclic heterocycloalkyl has 4-10 ring members. In some embodiments, a monocyclic heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a monocyclic heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. The term “bicyclic heterocycloalkyl” refers to a ring system containing two cycloalkyl rings that are joined together and share at least one atom, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, the bicyclic cycloalkyl is a spiro bicyclic (spirocyclic) heterocycloalkyl, a fused bicyclic heterocycloalkyl, or a bridged bicyclic heterocycloalkyl. In some embodiments, a bicyclic heterocycloalkyl has 5-12 ring members. The term “spiro bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share one atom, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a spiro bicyclic heterocycloalkyl has 5 to 12 ring members. Non-limiting The term “fused bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share two adjacent atoms, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a fused bicyclic heterocycloalkyl has 5 to 125-12 ring members. In some embodiments, a fused bicyclic heterocycloalkyl has 6 to 10 ring members. Non-limiting examples of fused bicyclic heterocycloalkyl include: , , The term “bridged bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share three or more atoms, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a bridged bicyclic heterocycloalkyl has 5 to 12 ring atoms. In some embodiments, a bridged bicyclic heterocycloalkyl has 5 to 8 ring atoms. Non-limiting The term “multicyclic heterocycloalkyl” refers to three or more cycloalkyl rings that are joined together, where at least one ring carbon atom of any one of the cycloalkyl rings has been replaced by one or more heteroatoms, e.g. selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, multicyclic heterocycloalkyls include caged heterocycloalkyls, spiro heterocycloalkyls, fused heterocycloalkyls, bridged heterocycloalkyls, or a combination thereof. In some embodiments, a multicyclic heterocycloalkyl is a caged heterocycloalkyl. In some embodiments, a multicyclic heterocycloalkyl has 3 to 12 ring members. Non-limiting examples of The term “caged heterocycloalkyl” refers to a subset of multicyclic heterocycloalkyls having a three-dimensional enclosed structure with each ring forming a face of the three- dimensional structure. Non-limiting examples of caged heterocycloalkyls include: carborane, As used herein, “carborane” refers closo-1-carb C2B10H12; closo-1,2-carborane), closo-1,7-carborane), C2B10H12; closo-1,12-carborane), where the symbol is CH and the remaining atoms are BH. A “heterocycloalkenyl” refers to a “heterocycloalkyl” that has at least one double bond in the ring. In some embodiments, heterocycloalkenyl is a monocyclic heterocycloalkenyl (i.e., a single ring), bicyclic heterocycloalkenyl (i.e., two rings), or multicyclic heterocycloalkenyl (i.e., three or more rings). In some embodiments, heterocycloalkenyl is a monocyclic heterocycloalkenyl. In some embodiments, heterocycloalkenyl is a bicyclic heterocycloalkenyl. In some embodiments, heterocycloalkenyl is a multicyclic heterocycloalkenyl. The term “monocyclic heterocycloalkenyl” refers to a non-aromatic “monocyclic heterocycloalkyl” that has at least one double bond. The term “bicyclic heterocycloalkenyl” refers to a non-aromatic “bicyclic heterocycloalkyl” that has at least one double bond. The term “spiro bicyclic heterocycloalkenyl” refers to a non-aromatic “spiro bicyclic heterocycloalkyl” that has at least one double bond. The term “fused bicyclic heterocycloalkenyl” refers to a non-aromatic “fused bicyclic heterocycloalkyl” that has at least one double bond. The term “bridged bicyclic heterocycloalkenyl” refers to a non-aromatic “bridged bicyclic heterocycloalkyl” that has at least one double bond. The term “multicyclic heterocycloalkenyl” refers to a non-aromatic “multicyclic heterocycloalkyl” that has at least one double bond. The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In some embodiments, a haloalkyl is a C1-C6haloalkyl. In some embodiments, a haloalkyl is a C1-C6fluoroalkyl. In some embodiments, a haloalkyl is a C1- C6chloroalkyl. In some embodiments, a haloalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, difluorochloromethyl, trichloromethyl, dichloromethyl, chloromethyl, 2,2,2-trichloroethyl, and the like. The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In some embodiments, a fluoroalkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The term “chloroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a chlorine atom. In some embodiments, a chloroalkyl is a C1-C6chloroalkyl. In some embodiments, a chloroalkyl is selected from trichloromethyl, dichloromethyl, chloromethyl, 2,2,2-trichloroethyl, and the like. The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, sulfur, sulfoxide, sulfone, or nitrogen (e.g., -NH-, -N(alkyl)-), or combinations thereof. A heteroalkyl is attached to the parent molecule at a carbon atom of the heteroalkyl. In some aspects, a heteroalkyl is a C1- C6heteroalkyl. The compounds and / or compositions of the disclosure can be used alone or conjointly with other therapeutic agents, or in combination with other types of treatment. For example, these other therapeutically useful agents may be administered in a single formulation, simultaneously or sequentially with the compound of the present disclosure according to the methods of the disclosure. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use. The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter. Pharmaceutical Compositions In some aspects, described herein are pharmaceutical compositions comprising a compound described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions may be formulated in a conventional manner using one or more inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. Methods of Dosing and Treatment Regimens In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from lowering of Lp(a) levels. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of a compound as disclosed herein, a pharmaceutical composition that includes at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to said mammal. In some aspects, described herein is a method of treating a cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, in a subject comprising administering a compound as described herein, such as a compound of Formula (I) or pharmaceutically acceptable salt thereof. In some embodiments, the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, is characterized by elevated lipoprotein(a) plasma levels. In some embodiments, the cardiovascular disease or disorder is coronary artery disease, acute myocardial infarction, asymptomatic carotid atherosclerosis, stroke, atrial fibrillation, hypercholesterolemia, peripheral artery occlusive disease, cerebrovascular disease, renal artery stenosis, or hypertensive heart disease. In some embodiments, the metabolic disease or disorder is dyslipidemia, hyperlipidemia, hyperlipoproteinemia(a), hypercholesterolemia, fatty liver, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis. In certain embodiments, hyperlipoproteinemia(a) is characterized by a plasma level of lipoprotein(a) of at least 50 mg / dL. Methods for determining the plasma level of lipoprotein(a) are known in the art, and any suitable method may be used. In some embodiments, hyperlipidemia is heterozygous familial hypercholesterolemia (HeFH). In some embodiments, the metabolic disease or disorder is lipid metabolism disorder. In some embodiments, the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, comprises metabolic syndrome. In other aspects, described herein is a method of decreasing the likelihood of having a heart attack, a stroke, aortic stenosis, or a combination thereof, in a subject comprising administering a compound as described herein, such as a compound of Formula (I), or pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the method results in reducing lipoprotein(a) plasma levels. In other aspects, described herein is a method of reducing the risk of coronary heart disease death (CHD death), myocardial infarction, stroke, or urgent coronary revascularization. In further aspects, described herein is a method of inhibiting lipoprotein(a) assembly in a subject, comprising administering a compound as described herein, such as a compound of Formula (I), or pharmaceutically acceptable salt thereof, to the subject. In still other aspects, described herein is a method of reducing lipoprotein(a) plasma levels in a subject, comprising administering to the subject a compound as described herein, such as a compound of Formula (I) or pharmaceutically acceptable salt thereof. Combination Therapies Among other things, provided compounds and compositions thereof may be administered or delivered to a subject who previously was administered or delivered any of the additional therapeutic agents described herein. The disclosure also provides pharmaceutical compositions comprising a compound of the disclosure or pharmaceutically acceptable salts thereof, and one or more other therapeutic agents disclosed herein, mixed with pharmaceutically suitable carriers or excipient(s) at doses to treat or prevent a disease or condition as described herein. The pharmaceutical compositions of the disclosure can also be administered in combination with other therapeutic agents or therapeutic modalities simultaneously, sequentially, or in alternation. A “pharmaceutical composition” is a formulation containing the compounds of the disclosure in a form suitable for administration to a subject. A compound of the disclosure and one or more other therapeutic agents described herein each can be formulated individually or in multiple pharmaceutical compositions in any combinations of the active ingredients. In some embodiments, the present invention provides a compound as disclosed above or herein, or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutical or therapeutic agents for co-administration. In some embodiments, the present invention provides one or more additional pharmaceutical or therapeutic agents wherein the one or more additional pharmaceutical or therapeutic agent is selected from hypolipidemic agents, niacin and analogs thereof, bile acid sequestrants, a thyroid hormone mimetic, thyroid hormone receptor (THR) P-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitor, a Niemann Pick Cl-like 1 (NPC1-L 1) inhibitor, an agonist of ATP Binding Cassette (ABC) proteins G5 or G8, an inhibitory nucleic acid targeting PCSK9 protein expression, an inhibitory nucleic acid targeting Lp(a) protein expression, an inhibitory nucleic acid targeting apoB 100, apoA-I up-regulator / inducer, ABCA 1 stabilizer or inducer, phospholipid transfer protein (PL TP) inhibitor, fish oil, anti-diabetic agent, antiobesity agent, agonists of peroxisome proliferator-activator receptors, ATP citrate lyase (ACL) inhibitor, and anti-hypertensive agents, an antibody targeting PCSK9, a monoclonal antibody targeting PCSK9, a small interfering RNA molecule (siRNA) targeting PCSK9, a small molecule targeting PCSK9, an immune checkpoint inhibitor, and combinations thereof. In some embodiments, the additional pharmaceutical or therapeutic agent is selected from an inhibitory nucleic acid targeting PCSK9 protein expression, an inhibitory nucleic acid targeting Lp(a) protein expression, an inhibitory nucleic acid targeting apoB 100, apoA-I up- regulator / inducer, ABCA 1 stabilizer or inducer, phospholipid transfer protein (PL TP) inhibitor, fish oil, anti-diabetic agent, anti-obesity agent, agonists of peroxisome proliferator-activator receptors, ATP citrate lyase (ACL) inhibitor, and anti-hypertensive agents, an antibody targeting PCSK9, an immune checkpoint inhibitor and combinations thereof. In some embodiments, the additional pharmaceutical or therapeutic agent is selected from an inhibitory monoclonal antibodies targeting the PCSK9 protein. In some embodiments, the additional pharmaceutical or therapeutic agent is selected from a small interfering RNA (siRNA) molecule targeting PCSK9 protein expression. In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co- administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. In some embodiments, the present invention provides a method of treating a cardiovascular disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is a low- density lipoprotein cholesterol (LDL-C)-lowering therapeutic agent. In some embodiments, the present invention provides a method of treating a cardiovascular disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is selected from: i) a statin, ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor, iv) a P2Y12 inhibitor, v) a citrate lyase inhibitor; vi) anti-hypertensive drugs, and (vii) PCSK9 inhibitor. In some embodiments, provided are pharmaceutical composition (for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a cardiovascular disease or condition) comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from: i) a statin, ii) a cholesterol absorption inhibitor; iii) a SGLT2 inhibitor, iv) a P2Y12 inhibitor, v) a citrate lyase inhibitor; vi) anti-hypertensive drugs, and (vii) PCSK9 inhibitor. In some embodiments, the statin is selected from atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin or Simvastatin. In some embodiments, the cholesterol absorption inhibitor is Ezetimibe (Ezetrol). In some embodiments, the SGLT2 inhibitor is selected from Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin etabonate, Sergliflozin etabonate, Sotagliflozin or Tofogliflozin. In some embodiments, the P2Y12 inhibitor is selected from Ticagrelor and Clopidogrel (Plavix). In some embodiments, the citrate lyase inhibitor is Bempedoic acid (Nexletol). In some embodiments, the antihypertensive drug is selected from Valsartan (Diovan), Metoprolol (Lopressor), HCTZ (Hydrochlorothiazide), Olmesartan (Benicar), Lisinopril (Prinivil, Zestril), Amlodipine besylate (Norvasc), Candesartan, or a calcium channel blocker or a combination thereof. In some embodiments there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient for use in the simultaneous, separate or sequential treatment of a cardiovascular disease or condition. In some embodiments, the PCSK9 inhibitor is selected from Alirocumab (Praluent®), Evolocumab (Repatha®), and Inclisiran (Leqvio®). In some embodiments, the PCSK9 inhibitor is Alirocumab (Praluent®). In some embodiments, the PCSK9 inhibitor is selected from Alirocumab, Evolocumab, and Inclisiran. In some embodiments, the PCSK9 inhibitor is Alirocumab. In some embodiments, the PCSK9 inhibitor is selected from Praluent®, Repatha®, and Leqvio®. In some embodiments, the PCSK9 inhibitor is Praluent®. In some embodiments, the PCSK9 inhibitor is Repatha®. In some embodiments, the PCSK9 inhibitor is Leqvio®. In some embodiments, the PCSK9 inhibitor is selected from Bococizumab, MK-0616, AZD0780, NNC0385-0434. In some embodiments, the PCSK9 inhibitor is MK-0616. In some embodiments, the PCSK9 inhibitor is AZD0780. In some embodiments, the PCSK9 inhibitor is NNC0385-0434. In some embodiments, the PCSK9 inhibitor is selected from those described in WO 2020 / 150473, WO 2020 / 150474, WO 2024 / 013209, WO2024062090, WO 2023 / 084449, WO 2024 / 078620, WO 2025 / 021188, WO 2025 / 045777, and WO 2025 / 067126, all of which are incorporated herein by reference in their entireties. Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept®and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L- DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), glatiramer acetate (Copaxone®), and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers (including TNF-α inhibitors), IL-1 RA, IL-23 inhibitors, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti- Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), pirfenidone (Esbriet®), nintedanib (Ofev®), intravenous immunoglobulins, bosentan (Tracleer®), nifedipine (Procardia XL®), sildenafil (Revatio®), losartan (Cozaar®), iloprost (Ventavis®), topical nitroglycerin, N-acetylcysteine, antiacid therapy, and agents for treating immunodeficiency disorders such as gamma globulin. Included herein are methods of treatment in which a compound described herein is administered in combination with an agent for treatment of an inflammatory disease or condition. Examples of agents for treatment of an inflammatory disease or condition that can be used in combination with compounds described herein, include alpha-fetoprotein modulators; adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 gene inhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPase inhibitors; beta adrenoceptor antagonists; BTK inhibitors; calcineurin inhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors; CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3 antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists; chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagen modulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics; eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; FIFO ATP synthase modulators; farnesoid X receptor agonists; fecal microbiota transplantation (FMT); fractalkine ligand inhibitors; free fatty acid receptor 2 antagonists; GATA 3 transcription factor inhibitors; glucagon-like peptide 2 agonists; glucocorticoid agonists; Glucocorticoid receptor modulators; guanylate cyclase receptor agonists; HIF prolyl hydroxylase inhibitors; histone deacetylase inhibitors; HLA class II antigen modulators; hypoxia inducible factor-1 stimulator; ICAM1 gene inhibitors; IL-1 beta ligand modulators; IL-12 antagonists; IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23 antagonists; IL-23A inhibitors; IL-6 antagonists; IL-7 receptor antagonists; IL-8 receptor antagonists; integrin alpha-4 / beta-1 antagonists; integrin alpha-4 / beta-7 antagonists; integrin antagonists; interleukin ligand inhibitors; interleukin receptor 17A antagonists; interleukin-1 beta ligands; interleukin 1 like receptor 2 inhibitors; IL-6 receptor modulators; JAK tyrosine kinase inhibitors; Jak1 tyrosine kinase inhibitors; Jak3 tyrosine kinase inhibitors; lactoferrin stimulators; LanC like protein 2 modulators; leukocyte elastate inhibitors; leukocyte proteinase-3 inhibitors; MAdCAM inhibitors; melanin concentrating hormone (MCH-1) antagonist; melanocortin agonists; metalloprotease-9 inhibitors; microbiome-targeting therapeutics; natriuretic peptide receptor C agonists; neuregulin-4 ligands; NLPR3 inhibitors; NKG2 D activating NK receptor antagonists; NR1H4 receptor (FXR) agonists or modulators; nuclear factor kappa B inhibitors; opioid receptor antagonists; OX40 ligand inhibitors; oxidoreductase inhibitors; P2X7 purinoceptor modulators; PCSK9 inhibitors; PDE 4 inhibitors; Pellino homolog 1 inhibitors; PPAR alpha / delta agonists; PPAR gamma agonists; protein fimH inhibitors; P-selectin glycoprotein ligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1 kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors; sphingosine 1 phosphate phosphatase 1 stimulators; sphingosine-1-phosphate receptor-1 agonists; sphingosine-1-phosphate receptor-5 agonists; sphingosine-1-phosphate receptor-1 antagonists; sphingosine-1-phosphate receptor-1 modulators; stem cell antigen-1 inhibitors; superoxide dismutase modulators; SYK inhibitors; TLR-3 antagonists; TLR-4 antagonists; Toll- like receptor 8 (TLR8) inhibitors; TLR-9 agonists; TNF alpha ligand inhibitors; TNF ligand inhibitors; TNF alpha ligand modulators; TNF antagonists; TPL-2 inhibitors; tumor necrosis factor 14 ligand modulators; tumor necrosis factor 15 ligand inhibitors; Tyk2 tyrosine kinase inhibitors; type I IL-1 receptor antagonists; vanilloid VR1 agonists; and zonulin inhibitors, and combinations thereof. In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic. Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart. In one embodiment, the present invention provides a composition comprising a provided compound and one or more additional therapeutic agents. The therapeutic agent may be administered together with a provided compound, or may be administered prior to or following administration of a provided compound. Suitable therapeutic agents are described in further detail below. In certain embodiments, a provided compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent. The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered. In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 ^g / kg body weight / day of the additional therapeutic agent can be administered. The amount of one or more other therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is provided for dosing per the FDA label insert. The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXAMPLES The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example A-1: Synthesis of tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl) phenyl]-1-(tert- b Step 1: tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl}pyrrolidine-1-carboxylate (3). The raw material [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]acetic acid (65.00 g, 283.50 mmol, 1.0 equiv.) was dissolved in THF (1.2 L) , cooled to 0°C, add TEA (71.72 g, 708.75 mmol, 2.5 equiv.) , stirred at 0°C for 5 minutes. Add 2,2-dimethylpropanoyl chloride (41.02 g, 340.20 mmol, 1.2 equiv.), the temperature does not exceed 10 °C during the addition, and after stirring for 15 minutes, add LiCl (14.42 g, 340.20 mmol, 1.2 equiv.) and (4S)-4-benzyl-1,3-oxazolidin-2- one (50.24 g, 283.50 mmol, 1.0 equiv.) in THF (300 mL). The reaction solution was warmed to 25 °C and stirred for 16 hours.2M aqueous hydrochloric acid (500 mL) was added, the organic phase was separated and concentrated, and the residue was purified by silica gel column chromatography, eluted with PE / EA (PE~2:1, UV=254 nm) to afford tert-butyl (3R)-3-{2-[(4S)-4- benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate (73.5 g, 66.7% yield) as a colorless solid. LCMS: ESI-MS m / z = 389.2 [M+H]+; Calculated: 388.2. NMR:1H NMR (400 MHz, Chloroform-d) δ 7.37 – 7.18 (m, 5H), 4.72 – 4.64 (m, 1H), 4.26 – 4.16 (m, 2H), 3.72 – 3.65 (m, 1H), 3.51 – 3.43 (m, 1H), 3.37 – 3.26 (m, 2H), 3.11 – 2.95 (m, 3H), 2.84 – 2.73 (m, 1H), 2.72 – 2.61 (m, 1H), 2.21 – 2.07 (m, 1H), 1.65 – 1.54 (m, 1H), 1.47 (s, 9H). Step 2: tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3- bromophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5). To a stirred solution of tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl} pyrrolidine-1-carboxylate (70.00 g, 180.19 mmol, 1.0 equiv.) in THF (700 mL) were added 1M LiHMDS in THF (216 mL, 216.23 mmol, 1.2 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0 °C under nitrogen atmosphere. To the above mixture was added the solution of 1-bromo-3-(bromomethyl) benzene (50.00 g, 200.05 mmol, 1.1 equiv.) in THF (300 mL) dropwise at 0 °C. The resulting mixture was stirred for additional 12 hours at 25 °C. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (PE~1:1, UV=220 nm) to afford tert-butyl (3R)-3-[(2S)-1- [(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3-bromophenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (19.00 g, 18.9% yield) as a colorless oil. LCMS: ESI-MS m / z = 557.1;559.0 [M+H]+; Calculated: 556.1;558.1. Step 3: (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl) pyrrolidin-3-yl]propanoic acid (6). To a stirred solution of tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]- 3-(3-bromophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (18.00 g, 32.28 mmol, 1.0 equiv.) in THF (200 mL) were added H2O2 (5.49 g, 48.43 mmol, 1.50 equiv., 30%) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 5 minutes at 0 °C under nitrogen atmosphere. To the above mixture was added the solution of LiOH.H2O (1.16 g, 48.43 mmol, 1.5 equiv.) in H2O (50 mL) dropwise over 5 minutes at 0 °C. The resulting mixture was stirred for additional 2h at 10 °C. The reaction was monitored by LCMS. The reaction was quenched with NaHSO3(aq.) at 0 °C. The mixture was basified to pH 12 with 5M NaOH(aq.). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with CH2Cl2 (3 x 200 mL). The combined organic layers were washed with brine (2x100 mL). The aqueous extraction was diluted with EtOAc (200 mL) and acidified to pH 4 with 4M HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (PE~CH2Cl2, UV=220 nm) to afford (2S)-3-(3- bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (11.9 g, 92.5% yield) as a colorless oil. LCMS: ESI-MS m / z = 342.0;344.0 [M-Boc+H]+; Calculated: 397.1;399.1. NMR:1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.52 – 7.12 (m, 4H), 3.56 – 3.42 (m, 1H), 3.37 (d, J = 10.0 Hz, 1H), 3.20 – 3.07 (m, 1H), 2.97 (q, J = 9.4 Hz, 1H), 2.76 (q, J = 7.3, 5.6 Hz, 2H), 2.61 – 2.52 (m, 1H), 2.36 – 2.18 (m, 1H), 1.90 – 1.80 (m, 1H), 1.68 – 1.53 (m, 1H), 1.39 (d, J = 3.2 Hz, 9H). Step 4: tert-butyl (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (8). To a stirred mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin- 3-yl]propanoic acid (11.50 g, 28.87 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (100 mL) was added N,N'-diisopropyltert-butoxymethanimidamide (34.70 g, 173.23 mmol, 6.0 equiv.) at 20 °C under nitrogen atmosphere. The resulting mixture was stirred for 16h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with THF (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (PE~2:1, UV=220 nm) to afford tert-butyl (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (12.70 g, 96.8% yield) as a colorless oil. LCMS: ESI-MS m / z = 454.1;456.1 [M+H]+; Calculated: 453.1;455.1. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 7.7 Hz, 2H), 7.28 – 7.16 (m, 2H), 5.75 (s, 1H), 3.57 – 3.46 (m, 1H), 3.40 – 3.34 (m, 1H), 3.22 – 3.09 (m, 1H), 3.00 (t, J = 10.0 Hz, 1H), 2.83 – 2.64 (m, 2H), 2.35 – 2.21 (m, 1H), 1.89 – 1.77 (m, 1H), 1.59 (t, J = 11.8 Hz, 1H), 1.40 (s, 9H), 1.24 (s, 9H). Step 5: tert-Butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyanophenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (9). To a stirred mixture of tert-butyl (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (4.00 g, 8.80 mmol, 1.0 equiv.) and CuCN (1.58 g, 17.60 mmol, 2.0 equiv.) in dioxane (40 mL) was added Pd2(dba)3(806.09 mg, 0.880 mmol, 0.10 equiv.), dppf (972.4 mg, 1.76 mmol, 0.20 equiv.) and Cs2CO3(5.74 g, 17.60 mmol, 2.0 equiv.) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (200 mL). at 0 °C. The layers were washed with NH4Cl (aq.) (3 x 200 mL) and brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyanophenyl)-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (3.00 g, 85.0% yield) as a brown oil. LCMS: ESI-MS m / z = 201.24 [M-Boc-Boc+H]+; Calculated: 400.24. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.70 – 7.66 (m, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 3.56 – 3.45 (m, 1H), 3.39 – 3.32 (m, 1H), 3.21 – 3.09 (m, 1H), 3.05 – 2.96 (m, 1H), 2.89 – 2.71 (m, 2H), 2.62 – 2.52 (m, 1H), 2.29 (s, 1H), 1.85 (q, J = 6.4 Hz, 1H), 1.58 (q, J = 11.0, 10.4 Hz, 1H), 1.40 (s, 9H), 1.21 (s, 9H). Step 6: tert-Butyl (3R)-3-[(2S)-3-[3-(aminomethyl) phenyl]-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (10). To a stirred solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyanophenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (1.50 g, 3.74 mmol, 1.0 equiv.) and Raney-Ni (1.00 g, 11.67 mmol, 3.12 equiv.) in MeOH (15 mL) was added NH3.H2O (3 mL) at 25°C under hydrogen atmosphere. The resulting mixture was stirred for an additional 1h at 25°C. The resulting mixture was filtered; the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% NH3.H2O), 40% to 60% gradient in 30 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1- (tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.00 g, 66.0% yield) as a white solid. LCMS: ESI-MS m / z = 405.2 [M+H]+; Calculated: 404.2. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.33 – 7.10 (m, 4H), 3.89 (s, 2H), 3.52 (q, J = 9.6 Hz, 1H), 3.36 (t, J = 9.5 Hz, 1H), 3.21 – 3.06 (m, 1H), 3.02 – 2.91 (m, 1H), 2.74 (d, J = 8.8 Hz, 2H), 2.48 (s, 1H), 2.27 (d, J = 13.5 Hz, 1H), 1.90 – 1.75 (m, 1H), 1.59 (q, J = 9.3, 7.5 Hz, 1H), 1.40 (s, 9H), 1.25 (s, 9H). Step 7: tert-Butyl (3R)-3-[(2S)-3-[3-(aminomethyl) phenyl]-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate hydrochloride (11). To a stirred solution of tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)- 1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.00 g, 2.47 mmol, 1.0 equiv.) in EA (10 mL) was added conc. HCl (0.93 mL, 3.70 mmol, 1.5 equiv.) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for an additional 1h at 0°C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl (3R)- 3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate hydrochloride (1.02 g, 93.5% yield, 97.3% purity at 220nm, ee=100%) as a white solid. LCMS: ESI-MS m / z = 405.15 [M-HCl+H]+; Calculated: 440.24. NMR:1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 3H), 7.40 – 7.14 (m, 4H), 3.96 (d, J = 5.3 Hz, 2H), 3.53 (q, J = 8.9 Hz, 1H), 3.42 – 3.36 (m, 1H), 3.22 – 3.09 (m, 1H), 3.02 – 2.93 (m, 1H), 2.80 – 2.68 (m, 2H), 2.48 (s, 1H), 2.29 (s, 1H), 1.85 (d, J = 7.5 Hz, 1H), 1.67 – 1.51 (m, 1H), 1.40 (s, 9H), 1.26 (s, 9H). Example A-2: di-tert-butyl 3,3'-((2S,2'S)-((azanediylbis(methylene))bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) (22). Step 1: tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyanophenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (26). A solution of tert-butyl (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (1000 g, 2203.53 mmol, 1.0 equiv.); Zn(CN)2 (517.446 g, 4407.08 mmol, 2 equiv.) and Pd(PPh3)4(254.52 g, 222.3 mmol, 0.1 equiv.) in DMF ( 10 L) was stirred at 120°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and then 5 L ice water was added, and the aqueous layer was extracted with EtOAc (3 x 10 L). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (3R)-3-[(2S)-1- (tert-butoxy)-3-(3-cyanophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (657 g, 74.40% yield, 95% purity) as a light-yellow oil. LCMS: (ES, m / z): [M-112+H]+=289.201HNMR: (400 MHz, Chloroform-d) δ 7.54 – 7.45 (m, 2H), 7.44 – 7.35 (m, 2H), 3.65 (dd, J = 10.6, 7.3 Hz, 1H), 3.50 (t, J = 9.6 Hz, 1H), 3.26 (td, J = 10.4, 6.8 Hz, 1H), 3.02 (t, J = 9.8 Hz, 1H), 2.92 – 2.77 (m, 2H), 2.50 – 2.34 (m, 2H), 2.00 – 1.91 (m, 1H), 1.72 – 1.62 (m, 1H), 1.47 (s, 9H), 1.28 (s, 9H). Step 2: tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl) phenyl]-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (22). A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyanophenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (300 g, 749.025 mmol, 1.0 equiv.) and Raney-Ni (150 g, 1277.8 mmol, 0.68 equiv.) in MeOH (4.5 L) was stirred at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (1 L). Add NaBH4 (56.925g, 1498.05 mmol, 2.0 equiv.) to the above solution for 1h reaction. The filtrate was concentrated under reduced pressure. The mixture was allowed to cool down to room temperature and then 5 L ice water was added and the aqueous layer was extracted with EtOAc (3 x 10 L). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (3R)-3-[(2S)-3- [3-(aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate 22 (200 g, 66.7% yield, 95.5% purity) as a light-yellow oil. LCMS:(ES, m / z): [M+H]+=792.91HNMR: (300 MHz, DMSO-d6) δ 7.25 – 7.12 (m, 6H), 7.03 (d, J = 6.9 Hz, 2H), 3.63 (d, J = 2.7 Hz, 1H), 3.58 (s, 1H), 3.57 – 3.45 (m, 2H), 3.41 – 3.29 (m, 3H), 3.14 (dd, J = 10.7, 7.2 Hz, 2H), 2.97 (t, J = 10.0 Hz, 2H), 2.72 (d, J = 8.3 Hz, 4H), 2.50 (h, J = 5.0, 3.4 Hz, 4H), 2.27 (t, J = 7.3 Hz, 2H), 1.90 – 1.78 (m, 2H), 1.58 (d, J = 10.6 Hz, 2H), 1.40 (s, 18H), 1.22 (s, 18H). Example A-3: Synthesis of tert-Butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)- 1-oxopropan-2-yl)pyrrolidine-1-carboxylate (13).

[0029] Step 1: tert-Butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3- bromophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5). Into a 3 L three-necked round-bottom flask were added tert-butyl (3R)-3-{2-[(4S)-4- benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl} pyrrolidine-1-carboxylate (100.00 g, 257.424 mmol, 1.0 equiv.) and tetrahydrofuran (1 L). To the above mixture was added LiHMDS (310 mL, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for additional 1 hour. To the above mixture was added 1-bromo-3-(bromomethyl)benzene (77.21 g, 308.909 mmol, 1.2 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for additional 4 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford tert-butyl(3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3-bromophenyl)-1- oxopropan-2-yl] pyrrolidine-1-carboxylate (130 g, 90.59% yield, 90% purity) as a yellow oil. ESI, m / z: [M-100+H]+=457.05 Step 2: (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert-butoxycarbonyl) pyrrolidin-3-yl]propanoic acid (6). Into a 3 L three-necked round-bottom flask were added tert-butyl (3R)-3- [(2S)-1-[(4S)-4- benzyl-2-oxo-1,3 -oxazolidin-3-yl]-3-(3-bromophenyl)-1-oxopropan-2-yl] pyrrolidine-1- carboxylate (130.0 g, 233.190 mmol, 1.0 equiv.) and tetrahydrofuran (1 L). To the above mixture was added H2O2(19.83 g, 582.975 mmol, 2.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for additional 5 min. To the above mixture was added LiOH.H2O (24.46 g, 582.975 mmol, 2.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 3 hours. The reaction was quenched with sat. NaHSO3(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (2S)-3-(3-bromophenyl)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (100 g, crude) as a yellow oil. LCMS: ESI-MS m / z = [M-56+H]+= 342.00 Step 3: tert-Butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl)pyrrolidine-1-carboxylate (8). Into a 2 L three-necked round-bottom flask were added (2S)-3-(3-bromophenyl)-2-[(3R)- 1-(tert-butoxycarbonyl) pyrrolidin-3-yl] propanoic acid (100.00 g, 251.069 mmol, 1.0 equiv.), KHSO4 (85.46 g, 627.673 mmol, 2.5 equiv.) and 2-methyltetrahydrofuran (1 L). The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added N,N'-diisopropyltert-butoxymethanimidamide (125.74 g, 627.673 mmol, 2.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 65 °C for additional overnight. The resulting mixture was filtered. The filter cake was washed with 2-methyltetrahydrofuran (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford tert-butyl (3R)-3-[(2S)-3-(3- bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl] pyrrolidine-1-carboxylate (58 g, 50.84% yield, 80% purity) as a yellow oil. LCMS: ESI-MS, m / z = [M+H]+= 454.15 Step 4: tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl)phenyl)-1-oxopropan-2- yl)pyrrolidine-1-carboxylate (12). Into a 1 L 3-necked round-bottom flask were added tert-butyl (3R)-3- [(2S)-3-(3- bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl] pyrrolidine-1-carboxylate (50.00 g, 110.034 mmol, 1.0 equiv.), XPhos Pd G3(18.63 g, 22.007 mmol, 0.2 equiv.), (Tributylstannyl)methanol (70.66 g, 220.068 mmol, 2.0 equiv.) and 1,4-dioxane (500 mL). The resulting mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The reaction was quenched with sat. KF (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford tert-butyl (3R)-3-[(2S)-1- (tert-butoxy)-3-[3-(hydroxymethyl) phenyl]-1-oxopropan-2-yl] pyrrolidine-1-carboxylate (38 g, 85.16% yield, 90% purity) as a yellow oil. LCMS: ESI-MS m / z = [M+H]+=406.25 Step 5: tert-Butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2- yl)pyrrolidine-1-carboxylate (13). Into a 1 L three-necked round-bottom flask were added tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-[3-(hydroxymethyl)phenyl]-1-oxopropan-2-yl] pyrrolidine-1-carboxylate (38.00 g, 93.703 mmol, 1.0 equiv.), triphenylphosphine (24.58 g, 93.703 mmol, 1.0 equiv.) and DCM (500 mL). To the above mixture was added tetrabromomethane (31.07 g, 93.703 mmol, 1.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 2 hours. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl) phenyl]-1-(tert-butoxy)-1-oxopropan- 2-yl] pyrrolidine -1-carboxylate (10.98 g, 25.02% yield, 98.9% purity) as a white semi-solid. LCMS: ESI-MS m / z = 470.20 [M+H]+. NMR:1H NMR (400 MHz, DMSO-d6): δ 7.31 – 7.23 (m, 3H), 7.18 – 7.10 (m, 1H), 4.65 (s, 2H), 3.60 – 3.45 (m, 1H), 3.41 – 3.35 (m, 1H), 3.23 – 3.08 (m, 1H), 2.99 (t, J = 10.0 Hz, 1H), 2.81 – 2.66 (m, 2H), 2.55 – 2.51 (m, 1H), 2.36 – 2.21 (m, 1H), 1.89 – 1.78 (m, 1H), 1.66 – 1.50 (m, 1H), 1.40 (s, 9H), 1.22 (s, 9H). Example A-4: tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formyl-5-methylphenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: The raw material [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]acetic acid (120 g, 523.387 mmol, 1.00 equiv.) was dissolved in THF (3500 mL), cooled to 0°C, add Et3N (181.88 mL, 1308.467 mmol, 2.50 equiv.) stirred at 0°C for 5 minutes. Add 2,2-dimethylpropanoyl chloride (1300 mL, 3980.859 mmol, 1.20 equiv.) the temperature does not exceed 10oC during the addition, and after stirring for 15 minutes, add LiCl (26.62 g, 627.978 mmol, 1.20 equiv.) and (4S)-4-benzyl-1,3-oxazolidin-2-one (97.38 g, 549.539 mmol, 1.05 equiv.) in THF (1500 mL). The reaction solution was warmed to 25oC and stirred for 16 hours.2M aqueous hydrochloric acid (1000 mL) was added, the organic phase was separated and concentrated, and the residue was purified by silica gel column chromatography, eluted with PE / EA=2:1 to afford tert-butyl (3R)-3- {2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate (150 g, 73.7% yield) as a colorless solid LCMS: ESI-MS m / z = 333.1 [M-tBu+H]+; NMR:1H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J = 8.0, 6.3 Hz, 2H), 7.31 – 7.28 (m, 1H), 7.24 – 7.18 (m, 2H), 4.68 (ddt, J = 10.4, 7.0, 3.3 Hz, 1H), 4.27 – 4.16 (m, 2H), 3.68 (dd, J =10.8, 7.3 Hz, 1H), 3.48 (s, 1H), 3.36 – 3.25 (m, 2H), 3.01 (ddd, J = 17.6, 10.2, 7.2 Hz, 3H), 2.78 (dd, J = 13.4, 9.5 Hz, 1H), 2.66 (dq, J = 14.7, 7.4 Hz, 1H), 2.11 (dtd, J = 12.9, 6.7, 3.7 Hz,1H), 1.59 (dq, J = 12.4, 8.6 Hz, 1H), 1.46 (s, 9H). Step 2: To a stirred solution of tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl}pyrrolidine-1-carboxylate (90 g, 231.682 mmol, 1.00 equiv.) in THF (900 mL) were added LiHMDS (1.0 M in THF) (46 g, 278.018 mmol, 1.20 equiv.) dropwise at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0oC under nitrogen atmosphere. To the above mixture was added the solution of 1-bromo-3-(bromomethyl)-5-methylbenzene (67 g, 254.849 mmol, 1.10 equiv.) in THF (600 mL) dropwise at 0oC. The resulting mixture was stirred for additional 12 h at 25oC. The reaction was monitored by LCMS. The reaction was quenched with sat.NH4Cl (aq.) at 0oC. The resulting mixture was diluted with water (1000 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (1:1, UV=220 nm) to afford tert-butyl (3R)-3-[(2S)-1- [(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3-bromo-5-methylphenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (40 g, 30.2% yield, 95% purity) as a colorless oil. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 7.1 Hz, 2H), 7.19 (d, J = 5.9 Hz, 3H), 7.09 (d, J = 4.8 Hz, 1H), 6.85 (d, J = 6.3 Hz, 2H), 4.66 (s, 1H), 4.31 – 4.21 (m, 2H), 4.03 (td, J =12.6, 11.3, 4.3 Hz, 1H), 3.43 (dt, J = 28.5, 9.8 Hz, 1H), 3.17 – 3.06 (m, 1H), 2.92 (dt, J = 24.4, 14.8 Hz, 3H), 2.79 (d, J = 13.7 Hz, 1H), 2.41 (s, 1H), 2.24 (s, 3H), 1.99 (s, 1H), 1.90 (s, 1H),1.64 (s, 1H), 1.39 (s, 9H). Step 3: To a stirred solution of tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]- 3-(3-bromo-5-methylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (70 g, 122.482 mmol, 1.00 equiv.) in THF (700 mL) were added H2O2(20 g, 183.723 mmol, 1.50 equiv, 30%) at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 5 min at 0oC under nitrogen atmosphere. To the above mixture was added the solution of LiOH.H2O (8 g, 183.723 mmol, 1.50 equiv.) in H2O (175 mL) dropwise over 5 min at 0oC. The resulting mixture was stirred for additional 2h at 10oC. The reaction was monitored by LCMS. The reaction was quenched with NaHSO3(aq.) at 0oC. The mixture was basified to pH 12 with 5M NaOH(aq.). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (2x100 mL). The aqueous extraction was diluted with EtOAc (2000 mL) and acidified to pH 4 with 4M HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1, UV=220 nm) to afford (2S)-3-(3-bromo-5- methylphenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (35 g, 69.3%yield, 95%purity) as a colorless oil LCMS: ESI-MS m / z = 356;358 [M-tBu+H]+Step 4: To a stirred mixture of (2S)-3-(3-bromo-5-methylphenyl)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (60 g, 145.517 mmol, 1.00 equiv.) in 2- Methyltetrahydrofuran (600 mL) was added (E)-(tert-butoxy)-N',N-bis(propan-2- yl)methanimidamide (174 g, 873.102 mmol, 6.00 equiv.) at 20oC under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 60oC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with THF (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / PE (1:2, UV=220 nm) to afford tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methylphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (45 g, 66.0% yield, 95%purity) as a colorless oil. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J = 16.8 Hz, 2H), 7.00 (s, 1H), 3.51 (ddd, J = 14.4, 10.3, 7.4 Hz, 1H), 3.35 (ddd, J = 10.5, 8.4, 2.0 Hz, 1H), 3.15 (tq, J = 17.4, 10.4, 8.6 Hz,1H), 2.99 (t, J = 10.0 Hz, 1H), 2.68 (tt, J = 13.5, 7.2 Hz, 2H), 2.46 (dt, J = 9.8, 4.6 Hz, 1H), 2.25 (s, 4H), 1.82 (dt, J = 12.4, 6.3 Hz, 1H), 1.57 (q, J = 12.6, 11.7 Hz, 1H), 1.40 (s, 10H), 1.25(s, 9H). Step 5: To a mixture of tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methylphenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (15 g, 32.022 mmol, 1.00 equiv.) and N,N,N',N'- Tetramethylethylenediamine (7 g, 64.044 mmol, 2.00 equiv.) in Toluene (150 mL) were added Pd(OAc)2 (720 mg, 3.202 mmol, 0.10 equiv.) and di(1-adamantyl)-N-butylphosphine (2 g, 6.404 mmol, 0.20 equiv.) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 20 h at 100 °C under 10 atm of syngas (CO / H2,1:1). The reaction was monitored by LCMS. Cool the mixture to 25 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 50% to 70% gradient in 20 min; detector, UV 254 nm. The pure fraction was lyophilized to afford tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formyl-5- methylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3.0096 g, 22.5%yield, 98.5%purity) as a off-white semi-solid. LCMS: ESI-MS m / z = 262.15 [M-tBu-Boc+H]+NMR:1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.55 (d, J = 12.1 Hz, 2H), 7.37 (s, 1H), 3.52 (dd, J = 13.8, 8.5 Hz, 1H), 3.36 (ddd, J = 10.6, 8.4, 2.1 Hz, 1H), 3.16 (dd, J = 13.9, 8.4 Hz, 1H), 3.01 (t, J = 10.0 Hz, 1H), 2.78 (q, J = 13.3 Hz, 2H), 2.53 (s, 1H), 2.36 (s, 3H), 2.30 (s, 1H), 1.87 – 1.80 (m, 1H), 1.62 – 1.52 (m, 1H), 1.40 (s, 9H), 1.21 (s, 9H). Example A-5: tert-butyl (R)-3-((S)-3-(3-(aminomethyl)-5-methylphenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: To a stirred mixture of tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methylphenyl)-1-(tert-butoxy)- 1-oxopropan-2-yl]pyrrolidine-1-carboxylate (10 g, 21.348 mmol, 1.00 equiv.) and CuCN (3.82 g, 42.696 mmol, 2.00 equiv.) in dioxane (100 mL) was added Pd2(dba)3 (1.95 g, 2.135 mmol, 0.10 equiv.), Dppf (2.37 g, 4.270 mmol, 0.20 equiv.) and Cs2CO3 (13.91 g, 42.696 mmol, 2.00 equiv.) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (500 mL). at 0oC. The layers were washed with NH4Cl (aq.) (3 x 200 ml) and brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 20 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyano-5-methylphenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (6 g, 67.8%yield, 95%purity) as a white oil. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 14.8 Hz, 2H), 7.37 (s, 1H), 3.52 (dq, J = 16.2, 8.8 Hz, 1H), 3.37 (d, J = 9.4 Hz, 1H), 3.24 – 3.08 (m, 1H), 3.01 (d, J = 11.5 Hz, 1H), 2.74 (dt, J = 24.3, 10.3 Hz, 2H), 2.54 (s, 1H), 2.31 (s, 4H), 1.84 (d, J = 8.3 Hz, 1H), 1.57 (q, J = 13.8, 13.0 Hz, 1H), 1.40 (s, 9H), 1.23 (s, 9H). Step 2: To a stirred solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyano-5-methylphenyl)- 1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5.5 g, 13.268 mmol, 1.00 equiv.) and raney nickel (2.34 g, 39.804 mmol, 3.00 equiv.) in MeOH (60 mL) was added Ammonium hydroxide (11 mL, 28%) at 25°C under hydrogen atmosphere. The resulting mixture was stirred for additional 1h at 25°C. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% NH3.H2O), 40% to 60% gradient in 30 min; detector, UV 220 nm. The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)-5-methylphenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3.0365 g, 54.6%yield, 99.1%purity) as a white oil. LCMS: ESI-MS m / z = 419.30 [M+H]+; NMR:1H NMR (400 MHz, DMSO-d6) δ 6.97 (s, 1H), 6.91 (s, 1H), 6.81 (s, 1H), 3.63 (s, 2H), 3.57 – 3.45 (m, 1H), 3.34 (ddd, J = 10.7, 8.5, 2.2 Hz, 1H), 3.19 – 3.08 (m, 2H), 2.96 (dd, J = 10.6, 9.3 Hz, 1H), 2.68 (d, J = 8.5 Hz, 2H), 2.43 (d, J = 8.7 Hz, 2H), 2.27 (s, 1H), 2.23 (s, 3H), 1.82 (dd, J = 9.8, 4.7 Hz, 1H), 1.57 (q, J = 11.4, 10.7 Hz, 1H), 1.40 (s, 9H), 1.26 (s, 9H). Example A-6: tert-butyl (3R)-3-(3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-2-methyl-1- o Step 1: A solution of [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]acetic acid (100.0 g, 436.156 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (300 mL) was treated with KHSO4(178 g, 1308.468 mmol, 3.0 equiv.) at room temperature for 30 min under nitrogen atmosphere followed by the addition of (E)-N,N'-diisopropyltert-butoxymethanimidamide (262.0 g, 1308.468 mmol, 3.0 equiv.) dropwise at room temperature. The resulting mixture was stirred at 65 °C for additional overnight. The resulting mixture was washed with 1x1 L of NaHCO3. The aqueous layer was extracted with EtOAc (1x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100:1) to afford tert-butyl (3R)-3-[2-(tert-butoxy)-2- oxoethyl]pyrrolidine-1-carboxylate (57 g, 50% yield, 95% purity) as an off white solid. Step 2: A solution of tert-butyl (3R)-3-[2-(tert-butoxy)-2-oxoethyl]pyrrolidine-1-carboxylate (50.0 g, 173.010 mmol, 1.0 equiv.) in THF (1200 mL) was treated with LiHMDS (1M in THF) (260 mL, 1.5 equiv.) at 0 °C for 1 h under nitrogen atmosphere followed by the addition of 1-bromo-3- (bromomethyl)benzene (85.0 g, 346.020 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched by the addition of water (1000 mL) at room temperature. The aqueous layer was extracted with EtOAc (1 x 300 mL), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford tert-butyl (3R)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine- 1-carboxylate (60 g, 70 % yield, 92% purity) as a brown oil. LC-MS (ES, m / z): 342.10[M-56-56+H] Step 3: A solution of tert-butyl (3R)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (50.0 g, 110.034 mmol, 1.0 equiv.) in THF (500 mL) was treated with LDA (1M in THF) (220 mL, 2.0 equiv.) at 0 °C for 30 min under nitrogen atmosphere followed by the addition of CH3I (31.0 g, 220.068 mmol, 2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of water (100 mL) at room temperature. The aqueous layer was extracted with EtOAc (1 x 100 mL), dried over anhydrous Na2SO4and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl (3R)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]pyrrolidine- 1-carboxylate (30 g, 58.20% yield, 80% purity) as a brown oil. LC-MS (ES, m / z):356.05 [M-56-56+H] Step 4: A solution of tert-butyl (3R)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-methyl-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (10.0 g, 21.348 mmol, 1.0 equiv.), Pd(PPh3)4 (4.93.0 g, 4.270 mmol, 0.2 equiv.) and Zn(CN)2 (5.01 g, 42.696 mmol, 2.0 equiv.) in DMF (100 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was washed with 1 x 100 mL of water. The aqueous layer was extracted with EtOAc (1x50 mL), dried over anhydrous Na2SO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford tert-butyl (3R)-3-[1-(tert-butoxy)-3- (3-cyanophenyl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3.0 g, 33.90% yield, 80% purity) as a yellow oil. LC-MS (ES, m / z): 259.10[M-56-100+H] Step 5: A solution of tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-cyanophenyl)-2-methyl-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (3.0 g, 7.237 mmol, 1.0 equiv.) and Raney-Ni (0.08 g, 1.447 mmol, 0.2 equiv.) in MeOH (30mL) was stirred at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (1 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl (3R)-3-{3-[3- (aminomethyl)phenyl]-1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl}pyrrolidine-1-carboxylate (1.5 g, 45% yield, 94.3% purity) as a light green oil. LC-MS: (ES, m / z): 419.45[M+H]+. NMR:1H NMR (300 MHz, DMSO-d6) δ 7.20 – 7.16 (m, 2H), 7.15 – 7.10 (m, 1H), 7.07 – 6.96 (m, 1H), 3.69 – 3.72 (m, 2H), 3.40 – 3.35 (m, 1H), 3.25-3.20 (m, 1H), 3.20 – 3.12 (m, 1H), 3.08 – 2.96 (m, 2H), 2.68 – 2.54 (m, 1H), 2.48 – 2.39 (m, 1H), 1.86 – 1.49 (m, 2H), 1.39 – 1.34 (m, 18H), 0.92 (s, 3H). Example A-7: tert-butyl (3S)-3-(3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-2-fluoro-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: In a 250-mL round bottom flask, to a solution of tert-butyl (3R)-3-[3-(3-bromophenyl)-1- (tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (10.00 g, 22.007 mmol, 1.0 equiv) in THF (100 mL) was added dropwise n-butyllithium solution (2 M in THF, 22 mL, 44.014 mmol) at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for about 30 mins. Then a solution of N-(benzenesulfonyl)-S-phenylfluoranesulfonamido (20.82 g, 66.021 mmol, 3.0 equiv) in 50 mL THF was added dropwise; the mixture was stirred for 16 hours at about room temperature. The reaction was quenched with sat. NH4Cl (100 mL), and then the mixture was extracted with EtOAc (2 x 100mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure.^The crude product was purified by reverse phase flash chromatography with the following conditions (0.5 % FA in ACN) to afford tert-butyl (3S)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (3.1 g, 29.82% yield, 91% purity) as a yellow oil. LCMS (ES, m / z): [M-56-56+H]+=360.05 Step 2: A solution of tert-butyl (3S)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (3.10 g, 6.562 mmol, 1.0 equiv),^Pd(pph3)4 (0.76 g, 0.656 mmol, 0.1 equiv) and Zn(CN)2 (1.54 g, 13.124 mmol, 2.0 equiv) in dry^DMF (31 mL) was stirred at 120 °C for 2^h under nitrogen atmosphere.^The mixture was allowed to cool down to room temperature.^The reaction was quenched with ice water (100 mL) at RT.^The resulting mixture was extracted with EtOAc (20^mL). The combined organic layers were washed with brine (50^mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.^The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-cyanophenyl)-2-fluoro-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (2 g, 72.82% yield, 89% purity) as a yellow oil. LCMS: (ES, m / z): [M-56-56+H]+=307.20 Step 3: A solution of tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-cyanophenyl)-2-fluoro-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (2.00 g, 4.779 mmol, 1.0 equiv.) and Raney-Ni (0.20 g, 3.408 mmol, 0.71 equiv.) in MeOH (50 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (0.5% FA in ACN) to afford tert-butyl (3S)-3-(3- [3-(aminomethyl)phenyl]-1-(tert-butoxy)-2-fluoro-1-oxopropan-2-ylpyrrolidine-1-carboxylate (1 g, 49.52% yield, 98.1% purity) as a light-yellow oil. LCMS:(ES,m / z): 423.30[M+H]+. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.26 – 7.18 (m, 2H), 7.14 (s, 1H), 7.02 – 6.89 (m, 1H), 3.68 (s, 2H), 3.55 – 3.49 (m, 1H), 3.46 – 3.36 (m, 2H), 3.19 – 2.96 (m, 4H), 2.81 – 2.74 (m, 1H), 2.61 – 2.52 (m, 1H), 2.22 – 1.79 (m, 1H), 1.40 (s, 9H), 1.31 (s, 9H). 19F NMR (376 MHz, DMSO) δ -170.903 –-171.808. Example A-8: tert-butyl (R)-3-((S)-3-(3-(aminomethyl)-5-fluorophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0030] Step 1: Into a 500mL 3-necked round-bottom flask were added tert-butyl (3R)-3-{2-[(4S)-4- benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate (25.0 g, 64.356 mmol, 1.0 equiv.) and THF (250 mL) at 0°C. To the above mixture was added LiHMDS (1.0 M in THF) (130.0 mL, 128.712 mmol, 2.0 equiv.) dropwise over 30min at 0°C. The resulting mixture was stirred at 0°C for additional 50min and then a solution of 1-bromo-3-(bromomethyl)-5- fluorobenzene (25.86 g, 96.534 mmol, 1.5 equiv.) in THF (100 mL) was added dropwise over 30min at 0°C. The resulting mixture was stirred at 0°C for another 4h. The reaction was quenched by the addition of water (50 mL) at 0°C. The aqueous layer was extracted with EtOAc (3x50 mL), washed with 1x20 mL of brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3- (3-bromo-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (25 g, 67.50%yield) as a yellow oil. LCMS: (ES, m / z): [M-100]+=477.15 Step 2: Into a 500mL 3-necked round-bottom flask were added tert-butyl (3R)-3-[(2S)-1-[(4S)-4- benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3-bromo-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (25.0 g, 43.442 mmol, 1.0 equiv.) and THF (300 mL) at room temperature. To the above mixture was added H2O2 (30%, 250 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 10min. To the above mixture was added LiOH.H2O (3.65 g, 86.884 mmol, 2.0 equiv.) in 30mL H2O dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 2h. The reaction was quenched by the addition of sodium hydrogen sulfite (20mL) at room temperature. The aqueous layer was extracted with EtOAc (3x50 mL). The organic extracts was washed with 1x20 mL of brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product (2S)-3-(3-bromo-5-fluorophenyl)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (13 g, 71.88%yield) as a yellow oil. Step 3: Into a 500mL 3-necked round-bottom flask were added (2S)-3-(3-bromo-5-fluorophenyl)- 2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (13.0 g, 31.228 mmol, 1.0 equiv.) and 2-methyltetrahydrofuran (200 mL) at room temperature. To the above mixture was added KHSO4(12 g, 88.235 mmol, 2.83 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for additional 30min. To the above mixture was added (E)-N,N'- diisopropyltert-butoxymethanimidamide (18.77 g, 93.684 mmol, 3 equiv.) dropwise 10min at room temperature. The resulting mixture was stirred at 65°C for additional overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (6 g, 40.67% yield, 80% purity) as a yellow oil. Step 4: Into a 100mL 3-necked round-bottom flask were added tert-butyl (3R)-3-[(2S)-3-(3- bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5.0 g, 10.584 mmol, 1.0 equiv.), Pd(PPh3)4(2.45 g, 2.117 mmol, 0.2 equiv.) and Zn(CN)2(2.49 g, 21.168 mmol, 2.0 equiv.) in DMF (50 mL) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyano-5-fluorophenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (4.0 g, 90.30%yield, 95% purity) as a yellow oil. Step 5: Into a 100mL round-bottom flask were added tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- cyano-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (4.0 g, 9.558 mmol, 1.0 equiv.) and Nickel (0.11 g, 1.912 mmol, 0.2 equiv.) in MeOH (40 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (40 mL) (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The mixture was concentrated under reduced pressure and basified to pH 7 with saturated NaHCO3(aq.). The mixture was extracted with EtOAc (3 x mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-[(2S)-3-[3- (aminomethyl)-5-fluorophenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (980 mg, 24.27%yield, 97.9%purity) as a yellow oil. LCMS: (ES, m / z): [M+H]+= 423.35 NMR:1H NMR (300 MHz, DMSO-d6) δ 7.07 – 6.88 (m, 2H), 6.92 – 6.79 (m, 1H), 4.18 – 4.01 (m, 1H), 3.67 (s, 2H), 3.58 – 3.40 (m, 1H), 3.39 – 3.06 (m, 2H), 2.98 (t, J = 10.0 Hz, 1H), 2.81 – 2.65 (m, 2H), 2.35 – 2.20 (m, 1H), 1.89 – 1.74 (m, 1H), 1.69 – 1.52 (m, 1H), 1.40 (s, 9H), 1.24 (d, J = 2.1 Hz, 9H).19F NMR (377 MHz, DMSO-d6) δ -114.70 – -114.88. Example A-9: tert-butyl (R)-3-((S)-3-(3-(aminomethyl)-5-methoxyphenyl)-1-(tert-butoxy)-1- o Step 1: A solution of 1-bromo-3-methoxy-5-methylbenzene (60.0 g, 300 mmol, 1.0 equiv.) in CCl4(600 mL) was treated with NBS (58.42g, 330 mmol, 1.1 equiv.), AIBN (4.92 g, 30 mmoL, 0.1 equiv.) at room temperature under nitrogen atmosphere. The mixture was stirred at 80 °C for 5 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product1-bromo-3-(bromomethyl)-5-methoxybenzene (86 g) as a yellow solid was used in the next step directly without further purification. Step 2: A solution of tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl}pyrrolidine-1-carboxylate (54.24 g, 139.631 mmol, 1.0 equiv.) in THF (100 mL) was treated with LiHMDS (1.0 M in THF) (35.05 g, 209.446 mmol, 1.5 equiv.) at -20 °C for 0.5 h under nitrogen atmosphere followed by the addition of 1-bromo-3-(bromomethyl)-5- methoxybenzene (43 g, 153.594 mmol, 1.1 equiv.) which dissolved in THF (100 mL) dropwise at -20 °C. The mixture was stirred at room temperature for overnight under nitrogen atmosphere. The reaction was poured into sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3-bromo- 5-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30 g, 36.57% yield, 80% purity) as a yellow oil. LCMS: (ES, m / z): [M-100+H]+=487 Step 3: A solution of tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(3- bromo-5-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (33.0 g, 56.169 mmol, 1.0 equiv.) in THF (300 mL) was treated with H2O2(9.55 g, 84.254 mmol, 1.5 equiv., 30%) at 0 °C followed by the addition of LiOH.H2O (2.02 g, 84.254 mmol, 1.5 equiv.) which dissolved in H2O (60 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 4 h under air atmosphere. The mixture was acidified to pH 3 with HCl (aq.1 mol / L). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.05% FA), 45% to 100% gradient in 20 min; detector, UV 220 nm. This resulted in (2S)-3-(3-bromo-5-methoxyphenyl)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (18 g, 74.82% yield, 95% purity) as a light-yellow oil. LCMS: (ES, m / z): [M-100+H]+=328 Step 4: A solution of (2S)-3-(3-bromo-5-methoxyphenyl)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (16.0 g, 37.355 mmol, 1.0 equiv.) in 2- methyltetrahydrofuran (160 mL) was treated with KHSO4 (17.80 g, 130.742 mmol, 3.5 equiv.) at room temperature under nitrogen atmosphere followed by the addition of (E)-N,N'- diisopropyltert-butoxymethanimidamide (26.19 g, 130.742 mmol, 3.5 equiv.) in portions at room temperature. The mixture was stirred at 65 °C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with 2-methyltetrahydrofuran (160 mL) (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 45% to 100% gradient in 20 min; detector, UV 220 nm. This resulted in tert-butyl (3R)-3- [(2S)-3-(3-bromo-5-methoxyphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5.3 g, 29.29% yield, 95% purity) as a light-yellow oil. LCMS: (ES, m / z): [M-156+H]+=328 Step 5: A solution of tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methoxyphenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (4.0 g, 8.257 mmol, 1.0 equiv.) and Zn(CN)2 (1.16 g, 9.908 mmol, 1.2 equiv.), Pd(PPh3)4 (0.95 g, 0.826 mmol, 0.1 equiv.) in DMF (40 mL) was stirred at 120°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 40% to 100% gradient in 20 min; detector, UV 220 nm. This resulted in tert- butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyano-5-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (3 g, 84.39% yield, 95% purity) as a brown oil. LCMS: (ES, m / z): [M+H]+=431 Step 6: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-cyano-5-methoxyphenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (3.0 g, 6.968 mmol, 1.0 equiv.) in methanol (90 mL) was treated with Raney-Ni (0.3 g, 5.111 mmol, 0.73 equiv.) at room temperature for overnight under H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with THF (90 mL) (3x50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 20% to 70% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)-5-methoxyphenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (950.0 mg, 31.37% yield) as a yellow oil. LCMS: (ES,m / z): 435.4[M+H]+. NMR:1H NMR (400 MHz, DMSO-d6) δ 6.76 (t, J = 1.8 Hz, 1H), 6.70 (s, 1H), 6.58 (s, 1H), 3.71 (s, 3H), 3.64 (s, 2H), 3.50 (d, J = 10.9 Hz, 1H), 3.14 (d, J = 8.7 Hz, 2H), 2.97 (t, J = 10.0 Hz, 1H), 2.69 (d, J = 8.2 Hz, 2H), 2.46 (d, J = 8.7 Hz, 1H), 2.26 (s, 2H), 1.88 – 1.78 (m, 1H), 1.64 – 1.53 (m, 1H), 1.40 (s, 9H), 1.26 (s, 9H). Example A-10: tert-butyl (3R)-3-(3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: A solution of tert-butyl (3R)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-methyl-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (10.0 g, 21.348 mmol, 1.0 equiv.), XPhos Pd G3 (3.61 g, 4.27 mmol, 0.2 equiv.) and (tributylstannyl)methanol (13.7 g, 42.6 mmol, 2.0 equiv.) in dioxane (100 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction was quenched with potassium fluoride (aq) at room temperature. The aqueous layer was extracted with EtOAc (1x50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford tert-butyl (3R)- 3-[1-(tert-butoxy)-3-[3-(hydroxymethyl)phenyl]-2-methyl-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (6.0 g, 66.99% yield, 80% purity) as a yellow oil. LCMS: (ES, m / z):320.30 [M-100+H]+. Step 2: A solution of tert-butyl (3R)-3-[1-(tert-butoxy)-3-[3-(hydroxymethyl)phenyl]-2-methyl-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (4.0 g, 9.53 mmol, 1.0 equiv.) and triphenylphosphine (2.50 g, 9.53 mmol, 1.0 equiv.) in DCM (40 mL) was added CBr4 (3.57 g, 10.766 mmol, 1.2 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was washed with 1 x 30 mL of water. The aqueous layer was extracted with CH2Cl2 (2 x 10mL). The crude product was purified by Prep-HPLC with the following conditions (column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl (3R)-3-{3- [3-(bromomethyl)phenyl]-1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl}pyrrolidine-1-carboxylate (3.0 g, 65.2% yield, 99.3%purity) as a colorless oil. LCMS: (ES, m / z): 482.15[M+H]+. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.33 – 7.19 (m, 3H), 7.13 – 7.10 (m, 1H), 4.65 (s, 2H), 3.49 – 3.36 (m, 2H), 3.22 – 2.96 (m, 3H), 2.70 – 2.54 (m, 1H), 2.45 – 2.42 (m, 1H), 2.00 – 1.50 (m, 2H), 1.40 (s, 18H), 0.92 (s, 3H). Example A-11: tert-butyl (3S)-3-(3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-2-fluoro-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: A solution of tert-butyl (3S)-3-[3-(3-bromophenyl)-1-(tert-butoxy)-2-fluoro-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (7.0 g, 14.818 mmol, 1.0 equiv.), (tributylstannyl)methanol (9.52 g, 29.636 mmol, 2.0 equiv.) and X-Phos Pd G3 (2.51 g, 2.964 mmol, 0.2 equiv.) in dioxane (100 mL) was stirred at 100°C for 1 h under nitrogen atmosphere. The resulting mixture was washed with potassium fluoride (aq.) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under reduced pressure and then purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl (3S)-3-[1-(tert-butoxy)-2-fluoro-3-[3-(hydroxymethyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (3.1 g, 49.40%yield, 89%purity) as a light-yellow oil. LCMS:(ES, m / z): [M+H]+=424.25 Step 2: To a stirred solution of tert-butyl (3S)-3-[1-(tert-butoxy)-2-fluoro-3-[3- (hydroxymethyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3.8 g, 8.972 mmol, 1.0 equiv.) and PPh3(2.82 g, 10.766 mmol, 1.2 equiv.) in DCM (50 mL) was added CBr4(3.57 g, 10.766 mmol, 1.2 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was washed with 50 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl (3S)-3-(3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-2-fluoro-1-oxopropan- 2-ylpyrrolidine-1-carboxylate (1.5 g, 34.37% yield, 95.10% purity) as a light-yellow oil. LCMS: (ES,m / z): 486.30 [M+H]+. NMR:1H NMR (400 MHz, DMSO-d6) δ 7.44 – 7.24 (m, 3H), 7.15 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 3.61 – 3.48 (m, 1H), 3.46 – 3.36 (m, 1H), 3.24 – 3.04 (m, 4H), 2.88 – 2.66 (m, 1H), 1.92 – 1.72 (m, 2H), 1.44 – 1.36 (m, 9H), 1.29 (s, 9H).19F NMR (376 MHz, DMSO) δ -170.88 – -171.69. Example A-12: tert-butyl (R)-3-((S)-3-(3-(bromomethyl)-5-fluorophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: Into a 100mL 3-necked round-bottom flask were added tert-butyl (3R)-3-[(2S)-3-(3- bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (6.00 g, 12.701 mmol, 1.0 equiv.), (tributylstannyl)methanol (8.16 g, 25.402 mmol, 2.0 equiv.) and XPhos Pd G3 (2.15 g, 2.540 mmol, 0.2 equiv.) in Dioxane (100 mL) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was washed with 1x10 mL of saturated KF(aq.). The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford tert-butyl (3R)- 3-[(2S)-1-(tert-butoxy)-3-[3-fluoro-5-(hydroxymethyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (4 g, 74.36%yield, 95%purity) as a yellow oil. LCMS: (ES, m / z): [M+H]+=424.35 Step 2: Into a 100mL round-bottom flask were added tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[3- fluoro-5-(hydroxymethyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (4.00 g, 9.445 mmol, 1.0 equiv.) and PPh3(2.48 g, 9.445 mmol, 1.0 equiv.) in DCM (40 mL) at room temperature. To the above mixture was added CBr4(3.13 g, 9.445 mmol, 1.0 equiv.) in DCM (40 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 1h. The reaction was quenched with water at room temperature. The aqueous layer was extracted with CH2Cl2 (3x10 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)-5-fluorophenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (975 mg, 20.68% yield, 96.2% purity) as an off-white solid. LCMS: (ES, m / z): [M+H]+=486.25 NMR:1H NMR: (400 MHz, DMSO-d6) δ 7.16 – 7.10 (m, 2H), 7.01 (d, J = 10.2 Hz, 1H), 4.65 (s, 2H), 3.41 – 3.31 (m, 1H), 3.40 – 3.34 (m, 1H), 3.23 – 3.08 (m, 1H), 3.00 (t, J = 10.0 Hz, 1H), 2.84 – 2.64 (m, 2H), 2.59 – 2.50 (m, 1H), 2.34 – 2.19 (m, 1H), 1.90 – 1.76 (m, 1H), 1.68 – 1.45 (m, 1H), 1.40 (s, 9H), 1.24 (s, 9H).19F NMR (377 MHz, DMSO-d6) δ -113.42 – -113.93. Example A-13: tert-butyl (R)-3-((S)-3-(3-(bromomethyl)-5-methoxyphenyl)-1-(tert-butoxy)- 1-oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: A solution of tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methoxyphenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (4.0 g, 8.281 mmol, 1.0 equiv.) and (Tributylstannyl)methanol (5.33 g, 16.563 mmol, 2 equiv.), XPhos Pd G3 (1.40 g, 1.656 mmol, 0.2 equiv.) in Dioxane (40 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 25% to 100% gradient in 25 min; detector, UV 220 nm. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[3- (hydroxymethyl)-5-methoxyphenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3 g, 83.10% yield, 95% purity) as a yellow oil. LCMS: (ES, m / z): [M+H]+=436 Step 2: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(hydroxymethyl)-5- methoxyphenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3.0 g, 6.888 mmol, 1.0 equiv.) in DCM (30 mL) was treated with tetrabromomethane (4.57 g, 13.781 mmol, 2.00 equiv.), PPH3 (3.61 g, 13.781 mmoL, 2.0 equiv.) at 0 °C. The mixture was stirred at room temperature for 0.5 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to100% gradient in 25 min; detector, UV 220 nm. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)-5- methoxyphenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.1 g, 32.04% yield, 97.1% purity) as an off-white oil. LCMS: (ES,m / z): 498.15[M+H]+. NMR:1H NMR (400 MHz, DMSO-d6) δ 6.88 – 6.80 (m, 2H), 6.72 (s, 1H), 4.61 (s, 2H), 3.73 (s, 3H), 3.58 – 3.43 (m, 1H), 3.15 (h, J = 9.9 Hz, 1H), 2.99 (t, J = 10.0 Hz, 1H), 2.77 – 2.63 (m, 2H), 2.27 (s, 1H), 1.84 (s, 1H), 1.66 – 1.50 (m, 1H), 1.40 (s, 9H), 1.25 (s, 9H). Example A-14: tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate. Step 1: A solution of tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl}pyrrolidine-1-carboxylate (30.0 g, 77.227 mmol, 1.0 equiv.) in THF (300 mL) was treated with LiHMDS (1.0 M in THF) (155 mL, 154.454 mmol, 2.0 equiv.) at 0 °C for 1 h under nitrogen atmosphere followed by the addition of 1-(benzyloxy)-3-(bromomethyl)benzene (42.81 g, 154.454 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was quenched with water. The aqueous layer was extracted with EtOAc (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford tert-butyl (3R)-3-[(2S)-1- [(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[3-(benzyloxy)phenyl]-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (32.0 g, 70.87% yield, 80% purity) as a light brown oil. LCMS: (ES, m / z):529.20 [M+H]+. Step 2: A solution of tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[3- (benzyloxy)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (32.0 g, 54.728 mmol, 1.0 equiv.) and 30% H2O2 (3.72 g, 109.456 mmol, 2.0 equiv.) in THF (300 mL) was stirred at 0 °C for 5 min. To the above mixture was added LiOH.H2O (4.59 g, 109.456 mmol, 2 equiv.) in H2O (60 mL) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with sat. NaHSO3(aq.) at room temperature. The aqueous layer was extracted with EtOAc (1x100 mL), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to afford (2S)-3-[3-(benzyloxy)phenyl]-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]propanoic acid (20 g, 85.88% yield, 80% purity) as an orange oil. LCMS: (ES, m / z):326.05 [M-100+H]+. Step 3: A solution of (2S)-3-[3-(benzyloxy)phenyl]-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl]propanoic acid (20.0 g, 47.001 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (200 mL) was treated with KHSO4 (19.20 g, 141.003 mmol, 3.0 equiv.) at room temperature for 30 min followed by the addition of (E)-N,N'-diisopropyltert-butoxymethanimidamide (28.25 g, 141.003 mmol, 3.0 equiv.) in portions at room temperature. The resulting mixture was stirred at 65 °C for additional overnight. The resulting mixture was washed with 1 x 200 mL of NaHCO3. The resulting mixture was extracted with EtOAc (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30:1) to afford tert-butyl (3R)-3-[(2S)-3- [3-(benzyloxy)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (15 g, 66.26% yield) as a yellow oil. LCMS: (ES, m / z): 326.20[M-100-56+H]+. Step 4: A solution of tert-butyl (3R)-3-[(2S)-3-[3-(benzyloxy)phenyl]-1-(tert-butoxy)-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (15.0 g, 31.144 mmol, 1.0 equiv.) and Pd / C (0.66 g, 6.229 mmol, 0.2 equiv.) in MeOH (150 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (10 g, 82.01% yield, 90% purity) as a colorless oil. LCMS: (ES, m / z): 280.20[M-56-56+H]+. Step 5: To a stirred solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (10.0 g, 25.542 mmol, 1.0 equiv.), PPh3(13.40 g, 51.084 mmol, 2.0 equiv.) and benzyl N-(2-hydroxyethyl)carbamate (9.97 g, 51.084 mmol, 2.0 equiv.) in THF (100 mL) was added DIAD (10.33 g, 51.084 mmol, 2.0 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was washed with 1 x 100 mL of water. The aqueous layer was extracted with EtOAc (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford tert-butyl (3R)-3-[(2S)-3-[3-(2-{[(benzyloxy)carbonyl]amino}ethoxy)phenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5 g, 34.42% yield, 90% purity) as a yellow oil. LCMS: (ES, m / z): 469.30[M-100+H]+. Step 6: A solution of tert-butyl (3R)-3-[(2S)-3-[3-(2-{[(benzyloxy)carbonyl]amino}ethoxy)phenyl]- 1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (2.2 g, 2.110 mmol, 1.0 equiv.) and Pd / C (0.04 g, 0.422 mmol, 0.2 equiv.) in MeOH (30 mL) was stirred at room temperature for overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl (3R)-3-[(2S)-3-[3-(2-aminoethoxy)phenyl]-1-(tert-butoxy)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (950 mg, 60% yield, 96.1% purity) as a colorless oil. LCMS: (ES, m / z):435.35 [M+H]+NMR:1H NMR (400 MHz, DMSO-d6) δ 7.18 – 7.15 (m, 1H), 6.76 – 6.73 (m, 3H), 3.94 – 3.83 (m, 2H), 3.52– 3.49 (m, 1H), 3.31 – 3.23 (m, 1H), 3.19 – 3.09 (m, 2H), 2.99 – 2.90 (m, 1H), 2.88 – 2.79 (m, 2H), 2.80 – 2.75 (m, 2H), 2.31 – 2.27 (m, 1H), 1.87 – 1.84 (m, 1H), 1.67 – 1.50 (m, 1H), 1.40 (s, 9H), 1.24 (s, 9H). Example A-15: Chiral SFC tert-Butyl(3R)-3-[1-(tert-butoxy)-3-[3-(methoxycarbonyl)cuban-1-yl]-1-oxopropan-2- yl]pyrrolidine-1-carboxylate 19a / b (5 g, 10.879 mmol, 1 equiv.) was purified by Prep-Chiral-SFC with the following conditions Column: XA-CHIRAL ART Cellulose-SC, 3*25cm 5um; Mobile Phase A: CO2, Mobile Phase B: IPA: HEX=1:1 (1% 2M NH3-MeOH); Flow rate: 80 mL / min;Gradient (B%): isocratic 30% B; Column Temperature (°C): 35; Back Pressure (bar): 100;Wavelength: 220 nm; Retention Time-1(4.7 min); Retention Time-2(5.8 min); Sample Solvent:IPA; Injection Volume: 1 mL. The collected fractions were dried by lyophilization to afford 19ayellow oil tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(methoxycarbonyl)cuban-1-yl]-1-oxopropan- 2-yl]pyrrolidine-1-carboxylate (1.75 g, 35 % yield, 95% purity) and 19b yellow oil tert-butyl (3R)- 3-[(2R)-1-(tert-butoxy)-3-[3-(methoxycarbonyl)cuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (2 g, 40 % yield, 96% purity). Example B-1: Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3- yl)ethyl)cuban-1-yl)methyl)azanediyl)bis(methylene))bis1-phenylene))bis(2-((R)-pyrrolidin- 3-yl)prpanoic acid) tetrahydrochloride (001).

[0031] Step 1: To a vial containing cubane ester 14 (10 mmol, 1 eq.) in anhydrous THF (0.08 M) at 0 °C under N2was added borane dimethyl sulfide complex (11.5 mmol, 1.15 eq.) dropwise. The reaction mixture was then warmed to RT and stirred for 1 hour. The reaction was quenched by the slow addition of water (2 mL), diluted with water (18 mL) and the mixture was then concentrated to remove the THF. The residue was diluted with water (80 mL) and extracted with DCM (3 x 30 mL). The combined organics were dried over MgSO4 and concentrated to give crude material which was purified by flash column chromatography (0-100% EtOAc / hexane) to afford the cubane alcohol 15 as an oil (97%). LCMS: ESI-MS: [M+H]+ = 193.1; Calculated: 192.1 Step 2: To a vial containing cubane alcohol 15 (12.8 mmol, 1 eq.), imidazole (35.7 mmol, 2.8 eq.) and 2-(diphenylphosphaneyl)pyridine (33.1 mmol, 2.6 eq.) was added anhydrous THF (0.1 M) and the resulting solution cooled to 0 °C. To this solution was added iodine (33.1 mmol, 2.6 eq.) over 3 minutes and the resulting mixture was stirred at 0 °C for 15 min. The reaction mixture was then warmed to RT and stirred for 1.5 hour. The mixture was then quenched by the addition of sat. aq. Na2S2O4and stirred for 15 minutes and then extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSO4 and concentrated to dryness and purified by flash column chromatography (0-50% EtOAc / hexane) to afford compound 16 as a white solid (73%). NMR:1H NMR (CDCl3) 3.50 (s, 2 H), 3.68-3.72 (s, 4 H), 3.77-3.87 (m, 2 H), 3.91-4.04 (m, 2 H), 4.23 (td, J = 5.0, 2.5 Hz, 1 H) Step 3: To a vial containing ester 17 (5.05 mmol, 1 eq.) in anhydrous THF (0.2 M) at −78 °C was added KHMDS (1.15 eq.) and stirred for 30 min. Following this, a solution of 16 (7.57 mmol, 1.5 eq.) in anhydrous THF (0.8 M) was added at −78 °C. The reaction vessel and dry ice bath was insulated with cotton wool and the reaction mixture was allowed to warm to RT slowly overnight. The reaction mixture was then quenched with sat. aq. NH4Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The organics were then dried over MgSO4and concentrated to dryness to give crude material which was purified by flash column chromatography (0-100% EtOAc / hexane) to afford compound 19 as a sticky foam oil (82%). Compound 19 was purified according to Example A-15 described herein. Chirally enriched material was arbitrarily assigned as compound 19a (first eluting isomer) and compound 19b (second eluting isomer). The first eluting isomer was characterized and used for the next step. LCMS: ESI-MS m / z: [M+H]+ = 460.3; Calculated: 459.3 NMR:1H NMR (400 MHz, DMSO-d6) δ 4.16 (tq, J = 4.8, 2.3 Hz, 1H), 3.91 (d, J = 3.7 Hz, 2H), 3.81 (m, 2H), 3.70 (m, 1H), 3.61 (s, 3H), 3.44 (dd, J = 10.3, 6.7 Hz, 1H), 3.11 (d, J = 10.0 Hz, 1H), 2.87 (d, J = 9.2 Hz, 1H), 2.19 (s, 2H), 2.01-1.87 (m, 1H), 1.80 (s, 1H), 1.58 (m, 2H), 1.39 (m, 18H), 1.36 -1.21 (m, 1H). The following steps can also be performed using chirally enriched material compound 19b. Step 4: To a vial containing cubane ester 19a (2.43 mmol, 1 eq.) and LiBH4 (7.28 mmol, 3 eq.) under N2, was added anhydrous Et2O (0.1 M) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was then quenched with sat. aq. NH4Cl (20 mL), stirred for 10 minutes and then extracted with EtOAc (3 x 20 mL). The organics were then dried over MgSO4 and concentrated to dryness to afford compound 20a as a white solid (69%) which was used in the next step without further purification. LCMS: ESI-MS; m / z: [M+H]+= 432.3; Calculated: 431.3. Step 5: To a vial containing sulfur trioxide pyridine complex (3.66 mmol, 3 eq.) in DCM (0.133 M) at 0 °C was added DMSO (0.4 M) and DIPEA (7.94 mmol, 6.5 eq.). This mixture was stirred at 0 °C for 1 hour before adding cubane alcohol 20a (1.22 mmol, 1 eq.) in DCM (1.25 M). The reaction mixture was gradually warmed to RT overnight. The reaction mixture was quenched with aq.1 M HCl (10 mL) and extracted with DCM (3 x 10 mL) and dried over Na2SO4and concentrated to dryness to give crude material. The crude material was purified by flash column chromatography (0-70% EtOAc / hexane) to afford compound 21a as a clear and colorless oil (88%). LC-MS: MS m / z [C16H19NO3+H]+274.2, [C17H19NO5+H]+318.1, [C20H27NO3+H]+330.2, [C21H27NO5+H]+374 LCMS: ESI-MS; m / z: [M+H]+= 429.3; Calculated: 430.3 Step 6: To a vial containing cubane aldehyde 21a (0.26 mmol, 1 eq.) and amine 10 (0.39 mmol, 1.5 eq.) was added anhydrous DCE (0.2 M) followed by DIPEA (0.39 mmol, 1.5 eq.). To this mixture was added NaBH(OAc)3 (0.78 mmol, 3 eq.) in one portion at RT and the resulting mixture was stirred at 35 °C overnight. The reaction mixture was quenched with aq.1 M NaOH (10 mL) and extracted with DCM (3 x 10 mL) and dried over Na2SO4 and concentrated to dryness to give crude material. The crude material was purified by reverse phase column chromatography (C18, 10-100% MeCN / water with 0.1% formic acid) to afford compound 26a as a clear and colorless oil (70%). LC-LCMS: ESI m / z [M+H]+818.4 Step 7: To a vial containing 26a (0.04 mmol, 1 eq.) and bromide 13 (0.04 mmol, 1 eq.) was added K2CO3(0.09 mmol, 2.5 eq.) and anhydrous acetone (0.1 M). The reaction mixture was then stirred at 50 °C overnight. The reaction mixture concentrated to dryness and purified by reverse phase chromatography (C18, 30-100% MeCN / water with 0.1% formic acid) to afford compound 23a as a clear and colorless oil (93%).LC-MS: MS m / z [M+H]+1205.7 Step 8: To a vial containing 23a (0.03 mmol, 1 eq.) was added anhydrous 1,4-dioxane (0.1 M) followed by the addition of aq.6 M HCl (80 eq.) at RT. The reaction mixture was then stirred at RT for 4 days. The reaction mixture was then concentrated to dryness, redissolved in MeOH and filtered to remove insoluble material. The filtrate was then concentrated to dryness to afford compound 001 as a white solid (93%).LC-MS: MS m / z [M+H]+737.3 NMR:1H NMR (CD3OD) 1.67-1.75 (m, 1 H), 1.82-1.90 (m, 2 H), 1.91-1.95 (m, 1 H), 1.98-2.04 (m, 1 H), 2.18-2.23 (m, 2 H), 2.24-2.28 (m, 1 H), 2.47-2.51 (m, 1 H), 2.52-2.58 (m, 1 H), 2.58- 2.63 (m, 2 H), 2.87 (br s, 2 H), 2.98 (d, J = 8.6 Hz, 4 H), 3.00-3.06 (m, 1 H), 3.16 (t, J = 10.6 Hz, 2 H), 3.23-3.31 (m, 4 H), 3.35 (s, 2 H), 3.36-3.38 (m, 2 H), 3.40-3.45 (m, 4 H), 3.54-3.59 (m, 2 H), 3.80-3.83 (m, 1 H), 3.83-3.87 (m, 2 H), 3.88-3.94 (m, 2 H), 4.08-4.11 (m, 1 H), 4.19-4.32 (m, 4 H), 7.36-7.39 (m, 2 H), 7.39-7.44 (m, 4 H), 7.52-7.60 (m, 2 H) Example B-2: Synthesis of (2S,2'S)-3,3'-(((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3- yl)ethyl)cuban-1-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) tetrahydrochloride (002). Step A: A solution of tert-butyl (3R)-3-[(2R)-1-(tert-butoxy)-3-[3-(methoxycarbonyl)cuban-1-yl]-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (2 g, 4.134 mmol, 1 equiv, 95%) in diethyl ether (40 mL) was treated with lithium borohydride (4.0M in THF) (0.27 g, 12.402 mmol, 3 equiv.) in portions at 0 °C for 5 min under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2h under nitrogen atmosphere. The reaction mixture was then quenched with sat. aq. NH4Cl (20 mL), stirred for 10 min and then extracted with EtOAc (3 x 50 mL). The organics were then dried over Na2SO4 and concentrated to dryness to afford the title compound tert-butyl (3R)- 3-[(2R)-1-(tert-butoxy)-3-[3-(hydroxymethyl)cuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (2 g) as a white solid which was used in the next step without further purification. LCMS: (ES, m / z): [M+H]+=432.3; Calculated:431.3. Step B: To a solution of pyridine; sulfonylideneoxidane (2.10 g, 13.206 mmol, 3 equiv.) in DCM (40 mL) at 0 °C was added DMSO (8.36 g, 106.969 mmol, 24.3 equiv.) and DIEA (3.70 g, 28.627 mmol, 6.50 equiv.) under nitrogen atmosphere. This mixture was stirred at 0 °C for 1 h before adding tert-butyl (3R)-3-[(2R)-1-(tert-butoxy)-3-[3-(hydroxymethyl)cuban-1-yl]-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (2 g, 4.402 mmol, 1 equiv, 95%) in DCM (10 mL). The reaction mixture was gradually warmed to RT overnight. The reaction mixture was quenched with aq.1 M HCl (20 mL) and extracted with DCM (3 x 50 mL) and dried over Na2SO4 and concentrated to dryness to give crude material. The crude material was purified by flash column chromatography (0-80% THF / PE) to afford the title compound tert-butyl (3R)-3-[(2R)-1-(tert- butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.6 g) as a clear colorless oil. Step 1: A solution of tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (3.89 g, 9.606 mmol, 1.5 equiv.) and tert-butyl (3R)-3- [(2S)-3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (3 g, 6.404 mmol, 1.00 equiv.), DIEA (2.48 g, 19.212 mmol, 3 equiv.) in MeCN (50 mL) was stirred at room temperature for 2h under nitrogen atmosphere. The reaction mixture concentrated to dryness and purified by flash column chromatography (0-80% THF / PE) to afford the title compound tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (4.3 g) colorless oil. Step 2: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (829.77 mg, 1.047 mmol, 1.5 equiv.) ,tert-butyl (3R)-3- [(2R)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (300 mg, 0.698 mmol, 1.00 equiv.) in DCE (6 mL) was stirred at room temperature for 20 mins under nitrogen atmosphere. Then the STAB (444.05 mg, 2.094 mmol, 3 equiv.) was added at room temperature .The resulting mixture was stirred for 2h .The reaction mixture was quenched with aq.1 M NaOH (10 mL) and extracted with DCM (3 x 50 mL) and dried over Na2SO4 and concentrated to dryness to give crude material. The crude material was purified by reverse phase column chromatography (C18, 10-100% MeCN / water with 0.1% formic acid) to afford the title compound tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2R)-3-(tert-butoxy)-2- [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (23b) (450 mg, 53.44%yield, 95%purity) as a colorless oil. LCMS: (ES, m / z): [M+H]+= 1205.8 Calculated:1204.8 Step 3: A solution of 23b (1200 mg, 0.995 mmol, 1 equiv.) and trifluoroacetic acid (3.6 mL, 0.032 mmol, 0.03 equiv.) in DCM (9.8 mL) was stirred at room temperature for 12h .The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with HCl in (dioxane)(10 mL), stirred at room temperature for 10 mins and concentrated. This procedure was repeated twice. This resulted in (2R)-3-(3-{[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (002) (300 mg, 58.53%yield) as a light-yellow solid. LCMS: (ES, m / z): [M+H]+=737.5; Calculated: 736.4. NMR:1H NMR (300 MHz, Methanol-d4) δ 7.58 (d, J = 18.3 Hz, 2H), 7.40 (m, 6H), 4.31 (m, 4H), 4.09 (m, 1H), 3.91 (m, 2H) 3.81 (m, 3H), 3.57 (m, 2H), 3.33 (m, 6H), 3.26 (m, 3H), 3.17 (m, 2H), 2.99 (m, 5H), 2.87 (m, 2H), 2.55 (m, 4H), 2.18 (m, 3H), 1.88 (m, 4H), 1.83 (m, 1H). Example B-3: Synthesis of (2S)-3-(3-([bis((3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenylmethyl)amino]methylcuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (003). Step 1: di-tert-butyl 3,3'-((2S,2'S)-(((((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane- 1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (23). The synthesis of starting materials 21a and 22 can be found in Example B-1 and Example A-2. Diastereomers were separated by chiral SFC chromatography, see e.g., Example A-15. A solution of 21a (1.7 g crude) and 22 (1.3 g, 1.659 mmol, 1.5 equiv.) in DCE (20 mL) was stirred at room temperature for 20 mins under nitrogen atmosphere. Then NaHB(OAc)3(703 mg, 3.318 mmol, 3 equiv.) was added at room temperature. The resulting mixture was stirred for 2 hours. The reaction mixture was quenched with NaOH (10 mL, aq.1 M) and extracted with DCM (3 x 50 mL) and dried over Na2SO4 and concentrated to dryness to give crude material. The crude material was purified by reverse phase column chromatography (C18, 10-100% MeCN / water with 0.1% formic acid) to afford 23a (1.1 g, 78 % yield, 95% purity) as a white oil. LCMS: ESI-MS, m / z: [M+H]+= 1205.8 Calculated:1204.8 Step 2: (2S)-3-(3-([bis((3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenylmethyl)amino]methylcuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (003). A solution of 23a (700 mg, 0.581 mmol, 1 equiv.) and trifluoroacetic acid (2 mL, 0.018 mmol, 0.03 equiv.) in DCM (6 mL) was stirred at room temperature for 12h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with HCl / MeOH (10 mL), stirred at room temperature for 10 mins and concentrated. This procedure was repeated twice. The crude product was dissolved in a small amount of methanol (4 mL) and transfer the solution into a centrifuge tube. Then add cold diethyl ether (40 mL) to the tube and shake for 1 minute to precipitate the product. Then centrifuge at 3500 r / min for 2 minutes. Discard the supernatant. Repeat the washing and centrifugation progress 3-5 times. Collect the white solid precipitate and dissolve it in methanol (10 mL). Then concentrate the solution and dry the product fully under reduced pressure to remove the diethyl ether and the methanol. This resulted in 003 (308 mg, 60% yield, 95% purity) as a light-yellow solid. LCMS: ESI-MS, m / z: [M+H]+= 737.5; Calculated:736.4 NMR:1H NMR (300 MHz, Methanol-d4) δ 7.58 (d, J = 18.3 Hz, 2H), 7.40 (m, 6H), 4.31 (m, 4H), 4.09 (m, 1H), 3.91 (m, 2H) 3.81 (m, 3H), 3.57 (m, 2H), 3.33 (m, 6H), 3.26 (m, 3H), 3.17 (m, 2H), 2.99 (m, 5H), 2.87 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.18 (m, 3H), 1.99 (m, 1H), 1.83 (m, 4H) Example B-4: (2S,2'S)-3,3'-(((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(5-methyl-3,1-phenylene))bis(2-((R)-pyrrolidin-3- Step 1: To a stirred mixture of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formyl-5-methylphenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.207 mmol, 1.00 equiv.), tert-butyl (R)-3- ((S)-3-(3-(aminomethyl)-5-methylphenyl) -1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (87 mg, 0.208 mmol, 1.00 equiv.) and STAB (64 mg, 0.302 mmol, 1.5 equiv.) in DCE (2.0 mL) was added at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The residue was purified by Prep-TLC (PE:EA=5:3) to afford di-tert-butyl 3,3'- ((2S,2'S)-((azanediylbis(methylene))bis(5-methyl-3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (130 mg, 70.59%yield) as a transparent oil. LCMS: (ES, m / z): [M+H]+=820.7; Calculated: 819.5. Step 2: The synthesis of 21b can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 8-mL vial, was placed with a mixture of di-tert-butyl 3,3'-((2S,2'S)- ((azanediylbis(methylene))bis(5-methyl-3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2- diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (30 mg, 0.037 mmol, 1 equiv.), tert-butyl (3R)-3- ((2R)-1-(tert-butoxy)-3-((1S,2S,5R,6S)-3-formylcuban-1-yl)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (15.7 mg, 0.037 mmol, 1 equiv) and STAB (19.38 mg, 0.092 mmol, 2.5 equiv) in DCE (1.0 mL). The reaction mixture was stirred at 25 °C for 2 hours. Then was purified by Prep- HPLC with the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile Phase A: Water (0.05% NH3.H2O); Mobile Phase B: ACN; Gradient: 42% B to 86% B in 15 min; Flow rate: 60 mL / min; Wavelength: 254 nm. The collected fractions were dried by lyophilization. This resulted di-tert-butyl 3,3'-((2S,2'S)-(((((3-((R)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)cuban-1-yl)methyl)azanediyl)bis(methylene))bis(5- methyl-3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) (20 mg, 44.32%yield, 95% purity) as white solid. LCMS: (ES, m / z): [M+H]+=1233.8; Calculated: 1232.8. Step 3: To a stirred mixture of di-tert-butyl 3,3'-((2S,2'S)-(((((3-((R)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)cuban-1-yl)methyl)azanediyl)bis(methylene))bis(5- methyl-3,1-phenylen e))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) (10 mg, 0.008 mmol, 1 equiv.), HCL (3.0 mL), THF (3.0 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture were concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted (2S,2'S)-3,3'-(((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methyl ene))bis(5-methyl-3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (004) (14.8 mg, 78.69%yield, 96.2%purity) as a white solid. LCMS (ES, m / z): [M+H]+=765.5; Calculated:764.5. NMR:1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.45 (d, J = 36.1 Hz, 5H), 7.30 (dd, J = 11.4, 6.4 Hz, 4H), 7.12 (s, 2H), 4.07 (s, 5H), 3.85 (s, 2H), 3.72 (t, J = 4.7 Hz, 4H), 3.14 (d, J = 26.5 Hz, 11H), 3.01 – 2.62 (m, 10H), 2.35 (d, J = 7.1 Hz, 4H), 2.29 (s, 4H), 2.13 – 1.94 (m, 3H), 1.90 – 1.73 (m, 2H), 1.71 – 1.57 (m, 2H).

[0032] Example B-5: (2S,2'S)-3,3'-(((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3- Step 1: A solution / mixture of tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)-5-fluorophenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (150 mg, 0.355 mmol, 1 equiv.), DIEA (137.65 mg, 1.065 mmol, 3 equiv.) and tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)-5- fluorophenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (172.68 mg, 0.355 mmol, 1 equiv.) in MeCN (2 mL) was stirred at 0 °C for 1h.The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA(1:1) to afford tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- {[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5- fluorophenyl}methyl)amino]methyl}-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (150 mg, 51.03%yield) as a white solid. LCMS: (ES, m / z): [M+H]+=828.1; Calculated: 827.5. Step 2: The synthesis of 21b can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. A solution of tert-butyl (3R)-3-[(2R)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2- yl]pyrrolidine-1-carboxylate 21b (30 mg, 0.070 mmol, 1 equiv.), tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]-5-fluorophenyl}methyl)amino]methyl}-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (57.83 mg, 0.070 mmol, 1 equiv.) and STAB (22.20 mg, 0.105 mmol, 1.5 equiv.) in DCE (1 mL) was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (20% CH3CN up to 60% in 10 min); Detector, UV 220&254 nm. The collected fractions were dried by lyophilization. The result in tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]-5-fluorophenyl}methyl)({3-[(2R)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]methyl}-5-fluorophenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (25 mg, 28.83%yield) as a white solid. Desired product could be detected by LCMS. LCMS: (ES, m / z): [M+H]+=1241.7; Calculated: 1240.7. Step 3: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)({3-[(2R)-3-(tert-butoxy)- 2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]methyl}-5- fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (25 mg, 0.020 mmol, 1 equiv.) and HCl (0.5 mL, 0.004 mmol, 0.22 equiv.) in THF (0.5 mL) was stirred at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted in (2R)-3-(3-{[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]-5- fluorophenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (005) (15 mg, 96.38%yield, 91.9%purity) as a yellow solid. LCMS (ES, m / z): [M+H]+=773.5; Calculated: 772.4. NMR:1H NMR (300 MHz, Methanol-d4) δ 7.46 (s, 2H), 7.28 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.4 Hz, 2H), 4.29 (s, 4H), 4.10 (s, 1H), 3.99 – 3.76 (m, 5H), 3.66 – 3.52 (m, 2H), 3.49 – 3.36 (m, 6H), 3.18 (t, J = 10.5 Hz, 2H), 2.94 (dt, J = 34.0, 8.1 Hz, 7H), 2.70 – 2.42 (m, 4H), 2.22 (s, 3H), 2.05 – 1.58 (m, 6H).

[0033] Example B-6: (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(5-methyl-3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (006). Step 1: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 40-mL round-bottom flask, was placed tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- {[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5- methylphenyl}methyl)amino]methyl}-5-methylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30 mg, 0.037 mmol, 1 equiv.), tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[(1S,2S,5R,6S)-3- formylcuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate 21a (23.57 mg, 0.055 mmol, 1.5 equiv.), STAB (23.26 mg, 0.111 mmol, 3.0 equiv.), and DCE (1.0 mL) . The resulting reaction mixture was stirred for 16 h at 25oC. The mixture was concentrated under reduced pressure. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.1% FA) and CH3CN (10% CH3CN up to 80% in 15 min); Detector, UV 220&254 nm. The collected fractions were dried by lyophilization. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5- methylphenyl}methyl)({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]cuban-1-yl}methyl)amino]methyl}-5-methylphenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (25 mg) as a white solid. LCMS: (ES, m / z): [M+H]+=1233.7; Calculated:1232.8. Step 2: To a stirred mixture of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-methylphenyl}methyl)({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butox ycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]methyl}-5-methylphenyl)-1-oxopropan-2-yl]pyrro lidine-1-carboxylate (20 mg, 0.016 mmol, 1 equiv.) ,HCl (3.0 mL) ,THF (3.0 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture were concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted (2S)-3-(3-{[bis({3- [(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]-5-methylphenyl}methyl)amino]methyl}cuban-1-yl)-2- [(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (006) (12.4 mg, 82.6%yield, 95.9%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=765.5; Calculated:764.5. NMR:1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.48 (d, J = 28.3 Hz, 6H), 7.30 (t, J = 9.4 Hz, 4H), 7.12 (s, 2H), 4.22 – 3.96 (m, 6H), 3.84 (s, 2H), 3.76 – 3.69 (m, 4H), 3.26 – 3.04 (m, 9H), 2.98 – 2.70 (m, 10H), 2.36 (d, J = 7.5 Hz, 3H), 2.29 (s, 6H), 2.08 – 1.91 (m, 3H), 1.76 (d, J = 6.4 Hz, 1H), 1.62 (dd, J = 12.3, 8.8 Hz, 2H). Example B-7: (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (007). Step 1: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)amino]methyl}-5- fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (40 mg, 0.048 mmol, 1 equiv.), tert- butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20.75 mg, 0.048 mmol, 1.00 equiv.), STAB (12.29 mg, 0.058 mmol, 1.2 equiv.) in DCE (0.5 mL) was stirred at 25°C for 1 h. Then add HCl (2.0 mL), The resulting mixture was stirred for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (20% CH3CN up to 60% in 10 min); Detector, UV 220&254 nm. The collected fractions were dried by lyophilization. The result in tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]-5-fluorophenyl}methyl)({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]methyl}-5-fluorophenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (30 mg, 50.02%yield) as a white solid. LCMS: (ES, m / z): [M+H]+=1241.6; Calculated: 1240.7. Step 2: A solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-fluorophenyl}methyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]methyl}-5-fluorophenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (23 mg, 0.019 mmol, 1 equiv.) and HCl (0.5 mL, 0.004 mmol, 0.24 equiv.) in THF (0.5 mL) was stirred at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted in (2S)-3-(3-{[bis({3-[(2S)-2-carboxy-2-[(3R)- pyrrolidin-3-yl]ethyl]-5-fluorophenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3- yl]propanoic acid (007) (14 mg, 97.78%yield, 96.7%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=773.5; Calculated: 772.4. NMR:1H NMR (300 MHz, Methanol-d4) δ 7.47 (s, 2H), 7.30 (d, J = 9.1 Hz, 2H), 7.14 (d, J = 9.5 Hz, 2H), 4.30 (s, 4H), 4.11 (s, 1H), 3.87 (d, J = 29.7 Hz, 5H), 3.57 (q, J = 8.7, 7.4 Hz, 3H), 3.37 (s, 6H), 3.25 – 3.13 (m, 3H), 3.09 – 2.81 (m, 6H), 2.74 – 2.42 (m,41H), 2.20 (s, 3H), 2.05 – 1.57 (m, 6H). Example B-8: (2S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)((3-((S)-2- carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1-yl)methyl)amino)ethoxy)phenyl)-2-((R)- Step 1: Into a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-3-[3- (bromomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.213 mmol, 1 equiv.) , tert-butyl (3R)-3-[(2S)-3-[3-(2-aminoethoxy)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (139.16 mg, 0.320 mmol, 1.50 equiv.) ,ACN (2.6 mL), DIEA (82.77 mg, 0.639 mmol, 3.00 equiv.) ,tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[(2-{3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenoxy}ethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (120 mg, 68.38%yield, 95.0%purity) . The reaction mixture was stirred at 25 °C for 2h. The residue was applied on a silica gel column and eluted with PE / THF (5 / 3) to afford tert-butyl (3R)-3-[(2S)- 1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]cuban-1-yl}methyl)({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 22.29%yield, 95.1%purity) ,as a yellow oil. Step 2: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- {[(2-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenoxy}ethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (50 mg, 0.061 mmol, 1 equiv.) ,tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (39.19 mg, 0.091 mmol, 1.50 equiv.) ,DCE (1.0 mL) . The reaction mixture was stirred at 25 °C for 15min. Then added STAB (38.67 mg, 0.183 mmol, 3 equiv.) at 0°C .The reaction mixture was stirred at 25 °C for 2h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({2-[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20 mg, 22.29%yield, 95.1%purity)tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)(2-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenoxy}ethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 26.61%yield, 95%purity) ,as a yellow oil. Step 3: In to a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- {[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)(2-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenoxy}ethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 0.016 mmol, 1 equiv.),THF (0.25 mL, 1.00 equiv.) ,HCl (0.15 mL 6mol / L) . The reaction mixture was stirred at 25 °C for 3h. Then added HCl (0.15 mL 10mol / L) .The reaction mixture was stirred at 25 °C for 16h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in (2S)-3-(3- {[(2-{3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy}ethyl)({3-[(2S)-2-carboxy-2-[(3R)- pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (008) (12.0 mg, 81.22%yield, 94.6%purity) as a white solid. LCMS:(ES, m / z): [M+H]+=767.4; Calculated: 766.4. NMR:1H NMR (400 MHz, Methanol-d4) δ 7.57 (s, 1H), 7.51 – 7.30 (m, 3H), 7.24 (t, J = 7.8 Hz, 1H), 6.95 – 6.81 (m, 3H), 4.45 (s, 2H), 4.37 (s, 2H), 4.14 (s, 1H), 3.93 (m, 2H), 3.86 (m, 3H), 3.55 (m, 6H), 3.52 – 3.46 (m, 4H), 3.44 (m, 2H), 3.40 (m, 2H), 3.24 – 2.64 (m, 7H), 2.68 – 2.40 (m, 4H), 2.18 (m, 3H), 2.01 (m, 1H), 2.01 – 1.50 (m, 4H), 1.37 (m, 1H). Example B-9: (2S)-3-(3-(((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)((3-((S)-2- carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1-yl)methyl)amino)ethyl)amino)methyl)phenyl)- 2-((R)-pyrrolidin-3-yl)propanoic acid pentahydrochloride (009). Step 1: In to a 40-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-3-[3- (aminomethyl)phenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (574.97 mg, 1.422 mmol, 3.0 equiv.) ,dibromoethane (89 mg, 0.474 mmol, 1.00 equiv.), DIEA (124 mg, 0.959 mmol, 2.03 equiv.), n-BuOH (10 mL, 190.242 mmol, 401.56 equiv.). The reaction mixture was stirred at 100°C for 16h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 60% in 6 min, 60% ACN to 60% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]ethyl}amino)methyl]phenyl}-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (130 mg, 32.86%yield, 98.5%purity) ,as a yellow oil. Step 2: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)- 3-{3-[({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl}amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (60 mg, 0.072 mmol, 1 equiv.),tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-formylcuban-1- yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30.86 mg, 0.072 mmol, 1 equiv.), DCE (1.2 mL) . The reaction mixture was stirred at 25 °C for 15min. Then added STAB (45.68 mg, 0.216 mmol, 3 equiv.) at 0°C .The reaction mixture was stirred at 25 °C for 2h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({2-[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20 mg, 22.29%yield, 95.1%purity) ,as a yellow oil. Step 3: Into a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)- 3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban- 1-yl}methyl)({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20 mg, 0.016 mmol, 1 equiv.),THF (0.25 mL, 1.00 equiv.) ,HCl (0.15 mL). The reaction mixture was stirred at 25 °C for 3h. Then added HCl (0.15 mL) .The reaction mixture was stirred at 25 °C for 16h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in (2S)-3-(3- {[({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)({2-[({3-[(2S)-2-carboxy-2-[(3R)- pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]ethyl})amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3- yl]propanoic acid pentahydrochloride (009) (9.5 mg, 64.06%yield, 97.1%purity) . LCMS: (ES, m / z): [M+H]+=780.4; Calculated: 779.5. NMR:1H NMR (400 MHz, Methanol-d4) δ 7.65 (s, 1H), 7.50 (s, 2H), 7.48 – 7.28 (m, 5H), 4.40 (s, 2H), 4.23 (m, 3H), 4.02 (m, 2H) 3.87 (m, 3H), 3.49 (m, 13H), 2.99 (m, 10H), 2.58 (m, 4H), 2.19 (m, 3H), 2.01 (m, 1H), 1.82 (m, 5H). Example B-10: Synthesis of 3,3'-(((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-methyl-2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (010). Step 1: To a stirred mixture of tert-butyl (3R)-3-{3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-2- methyl-1-oxopropan-2-yl}pyrrolidine-1-carboxylate (100 mg, 0.207 mmol, 1 equiv.) , tert-butyl (3R)-3-{3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl}pyrrolidine-1- carboxylate (87 mg, 0.208 mmol, 1.00 equiv.), DIEA (54 mg, 0.418 mmol, 2.02 equiv.) and ACN (2.0 mL) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The residue was purified by Prep-TLC (PE:EA=5:3) to afford tert-butyl (3R)-3-[1- (tert-butoxy)-3-(3-{[({3-[3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-methyl-3- oxopropyl]phenyl}methyl)amino]methyl} phenyl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (120 mg, 70.59%yield) as a transparent oil. LCMS: (ES, m / z): [M+H]+= 821.6; Calculated: 819.5. Step 2: The synthesis of 21b can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 8-mL vial, was placed with a mixture of tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3- [3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-methyl-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (30 mg, 0.037 mmol, 1 equiv.), tert-butyl (3R)-3-[(2R)-1-(tert-butoxy)-3- [(1S,2S,5R,6S)-3-formylcuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate 21b (15 mg, 0.035 mmol, 0.95 equiv.), STAB (20 mg, 0.094 mmol, 2.58 equiv.) and, DCE (2.0 mL) . The reaction mixture was stirred at 25oC for 2 h. Then was purified by Prep-HPLC with the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile Phase A: Water (0.05%NH3.H2O); Mobile Phase B: ACN; Gradient: 30% B to 75% B in 12 min; Flow rate: 60 mL / min;Wavelength: 254 nm. The collected fractions were dried by lyophilization. This resulted intert- butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3-[3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl]-2-methyl-3-oxopropyl]phenyl} methyl)({3-[(2R)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]methyl}phenyl)-2-methyl-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 44.32% yield, 95% purity) as white solid. LCMS: (ES, m / z): [M+H]+=1233.8; Calculated: 1232.8. Step 3: To a stirred mixture of tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3-[3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbon yl)pyrrolidin-3-yl]-2-methyl-3-oxopropyl]phenyl}methyl)({3-[(2R)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)py rolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]methyl}phenyl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1-carbo xylate (10 mg, 0.008 mmol, 1 equiv.), HCl (3.0 mL), THF (3.0 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture were concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted 3-(3-{[({3-[(2R)-2- carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]cuban-1-yl}methyl)[(3-{2-carboxy-2-methyl-2-[(3R)- pyrrolidin-3-yl]ethyl}phenyl)methyl]amino]methyl}phenyl)-2-methyl-2-[(3R)-pyrrolidin-3- yl]propanoic acid tetrahydrochloride (010) (11.2 mg, 75.85%yield, 98.4%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=765.5; Calculated:764.5. NMR:1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.31 (s, 6H), 7.56 (s, 2H), 7.48 (s, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.25 (s, 2H), 4.15 (s, 5H), 3.76 (d, J = 29.6 Hz, 6H), 3.00 (t, J = 12.2 Hz, 2H), 2.76 (d, J = 15.9 Hz, 1H), 2.34 (s, 3H), 2.07 (s, 2H), 1.94 (s, 1H), 1.81 (s, 1H), 1.77 – 1.64 (m, 2H), 1.24 (s, 4H), 1.00 (d, J = 5.3 Hz, 7H), 0.83 (s, 3H), 0.00 (s, 8H). Example B-11: (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(5-methoxy-3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (011). Step 1: To a solution of tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)-5-methoxyphenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.201 mmol, 1 equiv.) and tert-butyl (3R)-3-[(2S)-3-[3-(aminomethyl)-5-methoxyphenyl]-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine- 1-carboxylate (174.37 mg, 0.402 mmol, 2 equiv.) in MeCN (2 mL) was added DIEA (51.86 mg, 0.402 mmol, 2 equiv.) at 0oC. The mixture was stirred for 2 h. The residue was purified by Prep- TLC (PE / THF 2 / 1) to afford tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)- 2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5- methoxyphenyl}methyl)amino]methyl}-5-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (120 mg, 70.20%yield, 90%purity) as a white oil. LCMS: (ES, m / z): [M+H]+=852.5; Calculated: 851.5 Step 2: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. A mixture of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-methoxyphenyl}methyl)amino]methyl}-5- methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30 mg, 0.035 mmol, 1 equiv.) and tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (22.68 mg, 0.053 mmol, 1.5 equiv.), DCE (2 mL) was stirred for 10 min at 25 °C under air atmosphere, STAB (11.19 mg, 0.053 mmol, 1.5 equiv.) was added and the mixture was stirred for 1 h. The crude mixture was directly purified by Prep-HPLC with the following conditions: Column: Ultimate: XB C-185um; Mobile Phase A: Water (0.05% TFA); Mobile Phase B: ACN; Gradient: 16% B to 50% B in 12 min; Flow rate: 90 mL / min; Wavelength: 220 nm. The collected fractions were dried by lyophilization. This resulted in tert-butyl (3R)-3-[(2S)-1-(tert- butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]-5-methoxyphenyl}methyl)({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]methyl}-5-methoxyphenyl)- 1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 44.88%yield) as a white solid. LCMS: (ES, m / z): [M+H]+=1265.9; Calculated: 1264.8 Step 3: A mixture of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-5-methoxyphenyl}methyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]methyl}-5-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 0.016 mmol, 1 equiv.) and HCl (0.5 mL), H2O (0.5 mL), THF (1 mL) was stirred for 16 h at 25oC under air atmosphere. The mixture was directly dried by lyophilization. This resulted in (2S)-3-(3- {[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]-5- methoxyphenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (011) (10.9 mg, 73.16%yield) as a light-yellow solid. LCMS: (ES, m / z): [M+H]+=797.5; Calculated: 796.4 NMR:1H NMR (300 MHz, DMSO-d6) δ 8.37 – 5.88 (m, 6H), 4.05 (m, 5H), 3.75 (m, 6H), 3.63 (m, 4H), 3.40 (m, 6H), 3.30 – 3.03 (m, 6H), 2.96( m, 2H), 2.89 – 2.58 (m, 6H), 2.48 – 2.17 (m, 4H), 2.03 (m, 3H), 1.92 – 1.51 (m, 5H), 1.44 (m, 3H), 1.24 (s, 1H). Example B-12: 3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-methyl-2-((R)-pyrrolidin-3- yl)propanoic acid) tetrahydrochloride (012). Step 1: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 40-mL round-bottom flask, was placed tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3- [3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-methyl-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20 mg, 0.024 mmol, 1 equiv.), tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3- [(1S,2S,5R,6S)-3-formylcuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (15.71 mg, 0.036 mmol, 1.5 equiv.), STAB (15.51 mg, 0.072 mmol, 3.0 equiv.), DCE (1.0 mL). The resulting reaction mixture was stirred for 16 h at 25 °C. The mixture was concentrated under reduced pressure. The resulting solution was diluted with 5 mL of MeOH. The pH value of the solution was adjusted to 8-9 with NH4OH. The mixture was concentrated under reduced pressure. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 85% in 15 min); Detector, UV 220&254 nm. The collected fractions were dried by lyophilization.The result in tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3-[3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-methyl-3- oxopropyl]phenyl}methyl)({3-[(2S) -3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]- 3-oxopropyl]cuban-1-yl}methyl)amino]methyl}phen yl)-2-methyl-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (20 mg) as a white solid. LCMS: (ES, m / z): [M+H]+=1234.1; Calculated: 1232.8. Step 2: To a stirred mixture of ttert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({3-[3-(tert-butoxy)-2-[(3R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-methyl-3-oxopropyl]phenyl}methyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butox ycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]methyl}phenyl)-2-methyl-1-oxopropan-2-yl]pyroli dine-1-carboxylate (20 mg, 0.016 mmol, 1 equiv.), HCl (3.0 mL),THF (3.0 mL) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The mixture were concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted 3-(3-{[({3-[(2S)-2- carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]cuban-1-yl}methyl)[(3-{2-carboxy-2-methyl-2-[(3R)- pyrrolidin-3-yl]ethyl}phenyl)methyl]amino]methyl}phe nyl)-2-methyl-2-[(3R)-pyrrolidin-3- yl]propanoic acid tetrahydrochloride (012) (11.7 mg, 79.24%yield, 96.0%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=765.6; Calculated:764.5. NMR:1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.39 (ddd, J = 43.0, 27.9, 7.4 Hz, 8H), 3.79 (d, J = 13.4 Hz, 3H), 3.70 (s, 4H), 3.45 – 2.90 (m, 16H), 2.83 – 2.64 (m, 4H), 2.54 (s, 9H), 2.38 – 2.23 (m, 4H), 2.05 (s, 1H), 1.95 (s, 2H), 1.76 (s, 1H).

[0034] Example B-13: 3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-fluoro-2-((S)-pyrrolidin-3- Step 1: A mixture of tert-butyl (3S)-3-{3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-2-fluoro-1- oxopropan-2-yl}pyrrolidine-1-carboxylate (100 mg, 0.206 mmol, 1 equiv.) and tert-butyl (3S)-3- {3-[3-(aminomethyl)phenyl]-1-(tert-butoxy)-2-fluoro-1-oxopropan-2-yl}pyrrolidine-1-carboxylate (173.73 mg, 0.412 mmol, 2 equiv.) in MeCN (2.5 mL) was stirred. To the above mixture was added DIEA (53.14 mg, 0.412 mmol, 2 equiv.) dropwise at 0 ℃. The resulting mixture was stirred at r.t. for additional 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / THF 2 / 1) to afford tert-butyl (3S)-3-[1-(tert-butoxy)-3- (3-{[({3-[3-(tert-butoxy)-2-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-fluoro-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2-fluoro-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (130 mg, 76.37%yield, 85%purity) as a buff oil. LCMS: (ES, m / z): [M+H]+=828.5; Calculated: 827.5 Step 2: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. A mixture of tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-{[({3-[3-(tert-butoxy)-2-[(3S)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-2-fluoro-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2- fluoro-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (40 mg, 0.048 mmol, 1 equiv.), and tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20.75 mg, 0.048 mmol, 1 equiv.) in DCE (1 mL) was stirred for 10 min at 25oC under air atmosphere, STAB (30.71 mg, 0.144 mmol, 3 equiv.) was added and the mixture was stirred for 1 h. The crude mixture was directly purified by Prep-HPLC with the following conditions: Column: Ultimate: XB C-185um; Mobile Phase A: Water (0.05% TFA); Mobile Phase B: ACN; Gradient: 16% B to 50% B in 12 min; Flow rate: 90 mL / min; Wavelength: 220 nm. The collected fractions were dried by lyophilization. This resulted in tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-{[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)({3-[3-(tert-butoxy)-2-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-2-fluoro-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2-fluoro-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (95%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=1241.9; Calculated: 1240.7 Step 3: A mixture of tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[3-(tert-butoxy)-2-[(3S)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl]-2-fluoro-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-2- fluoro-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (40 mg, 0.032 mmol, 1 equiv.) and HCl (0.5 mL), H2O (0.5 mL), THF (1 mL) was stirred for 16 h at 25 °C under air atmosphere. The resulting mixture was concentrated under reduced pressure directly dried by lyophilization. This resulted in 3-(3-{[({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]cuban-1-yl}methyl)[(3-{2- carboxy-2-fluoro-2-[(3S)-pyrrolidin-3-yl]ethyl}phenyl)methyl]amino]methyl}phenyl)-2-fluoro-2- [(3S)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride (013) (23.8 mg, 80.41%yield, 98.2%purity) as a white solid. LCMS: (ES, m / z): [M+H]+ =773.5; Calculated: 772.4 NMR:1H NMR (300 MHz, DMSO-d6) δ 7.57 (d, J = 7.5 Hz, 2H), 7.41 (dd, J = 15.6, 8.0 Hz, 4H), 7.29 (d, J = 7.6 Hz, 2H), 4.12 (s, 4H), 3.83 (m, 2H), 3.57 (m, 2H), 3.18 (m, 21H), 2.45 – 2.16 (m, 3H), 2.14 – 1.46 (m, 8H), 1.47-1.35(m, 1H). Example B-14: ( yl)ethyl)benzyl)(((2R,3R,4S,5S)-3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)amino)ethyl)((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)amino)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid hexahydrochloride (014). Step 1: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. Into a 8-mL vial, was placed with a mixture of form tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)- 3-{3-[({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl}amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (60 mg, 0.072 mmol, 1 equiv.) ,tert-butyl (3S)-3-[1-(tert-butoxy)-3-(3-formylcuban-1- yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30.86 mg, 0.072 mmol, 1 equiv.) ,DCE (1.2 mL) . The reaction mixture was stirred at 25 °C for 15min. Then added STAB (45.68 mg, 0.216 mmol, 3 equiv.) at 0 °C .The reaction mixture was stirred at 25 °C for 2 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% TFA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under reduced pressure. This resulted in (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2- [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({2-[({3-[3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[(2S)-3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (25 mg, 22.01%yield, 90.1%purity) ,as a yellow oil. Step 2: To a stirred mixture of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({2-[({3-[3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl})amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (25 mg, 0.015 mmol, 1 equiv.), THF (2 mL), HCl (2 mL 6mol / L). The reaction mixture was stirred at 25 °C for 3h. Then added HCl (2 ml 10mol / L). The reaction mixture was stirred at 25 °C for 16h. The residue was lyophilized. This resulted in (2S)-3-(3-{[({3-[(2S)-2- carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)({2-[({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl}methyl)[(3-{2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl}cuban-1- yl)methyl]amino]ethyl})amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid hexahydrochloride (014) (13.2 mg, 69.87%yield, 91.7%purity) as a white solid. LCMS:(ES, m / z): [M+H]+=1037.7; Calculated: 1036.6. NMR:1H NMR (300 MHz, Methanol-d4) δ 7.60 (s, 2H), 7.50 – 7.24 (m, 6H), 4.30 (s, 4H), 4.13 (s, 2H), 3.92 (m, 4H), 3.82-3.81 (m, 6H), 3.73 – 3.51 (m, 8H), 3.46-3.21 (m, 10H), 3.18-3.14 (m, 4H), 3.12–2.84 (m, 8H), 2.59-2.54 (m, 6H), 2.19-2.16 (s, 4H), 1.99-1.96 (m, 2H), 1.88-1.78 (m, 6H). Example B-15: (2S,2'S)-3,3'-((((2-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)amino)ethyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3- t Step 1: To a stirred solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (350 mg, 0.442 mmol, 1.00 equiv.) in anhydrous ACN (3.5 mL) was added 2-bromoacetonitrile (63.60 mg, 0.530 mmol, 1.20 equiv.) followed DIEA (114.22 mg, 0.884 mmol, 2 equiv.) at 25 ℃. The reaction mixture was stirred at 25 ℃ for a period of 4 h. After completion of reaction, the reaction mixture was quenched by addition of water 30 mL. The aqueous layer was extracted with ethyl acetate (3*30 mL). The combined organic phase was washed with brine (30mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford tert-butyl (3R)-3- [(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]- 3-oxopropyl]phenyl}methyl)(cyanomethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (300 mg, 95%yield, 99.7%purity) as a white transparent oily liquid. Step 2: To a stirred solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)(cyanomethyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (300 mg, 0.361 mmol, 1 equiv.) in anhydrous methanol (3 mL) was added nickel chloride (46.78 mg, 0.361 mmol, 1 equiv.) and NaBH4(27.31 mg, 0.722 mmol, 2 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 mins and then heated to 40 °C. After completion of reaction, the reaction mixture was quenched by addition of ammonium chloride solution 30 mL. The aqueous layer was extracted with ethyl acetate (3*30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford tert-butyl (3R)-3-[(2S)-3-(3-{[(2-aminoethyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (205 mg crude product) as a white gelatinous liquid. Step 3: The synthesis of 21a can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. To a stirred solution of tert-butyl (3R)-3-[(2S)-3-(3-{[(2-aminoethyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (105 mg, 0.126 mmol, 1 equiv.) ,tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (64.81 mg, 0.151 mmol, 1.20 equiv.) in anhydrous DCE (1 mL) . The reaction mixture was stirred at 25°C after 30 min of reaction and STAB (79.94 mg, 0.378 mmol, 3 equiv.) was added. After completion of reaction, the reaction mixture was quenched by addition of water 30 mL. The aqueous layer was extracted with dichloromethane (3*30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by Prep-HPLC to afford tert-butyl (3R)-3-[(2S)-1- (tert-butoxy)-3-{3-[({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]cuban-1-yl}methyl)amino]ethyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-oxopropan-2- yl]pyrrolidine-1-carboxylate ( 53 mg ,34%yield, 95%purity) as a white liquid and by-product boranylphosphane; tert-butyl (3R)-3-[(2S)-3-{3-[({2-[bis({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]ethyl}({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate ( 25 mg ,11%yield, 95%purity) as a white liquid. Step 4: Into a 8mL vial were added tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[({3-[(2S)-3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]ethyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (20 mg, 0.016 mmol, 1 equiv.)，HCl (2 mL, 6mol / L) and THF (2 mL) The reaction mixture was stirred at 25°C for 3 h. Then added HCl (2 mL, 10 mol / L) .The reaction mixture was stirred at 25 °C for 16h. The resulting solid was dried by lyophilization to afford (2S)-3-{3-[({2-[bis({3-[(2S)-2- carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]ethyl}amino)methyl]cuban-1-yl}-2- [(3R)-pyrrolidin-3-yl]propanoic acid pentahydrochloride (015) (13.3 mg, 96%yield,90%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=780.6; Calculated: 779.46. NMR:1H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 2H), 7.52 (d, J = 7.1 Hz, 2H), 7.40 (dt, J = 13.6, 7.5 Hz, 4H), 4.48 (d, J = 40.1 Hz, 5H), 4.14 – 3.72 (m, 7H), 3.65 (d, J = 6.3 Hz, 2H), 3.59 (ddq, J = 12.4, 6.0, 3.2 Hz, 2H), 3.54 – 3.34 (m, 3H), 3.23 – 3.11 (m, 4H), 3.06 – 2.96 (m, 6H), 2.95 – 2.84 (m, 2H), 2.72 – 2.46 (m, 5H), 2.28 – 1.92 (m, 5H), 1.91 – 1.69 (m, 4H), 1.67 – 1.49 (m, 1H). Example B-16: (2S,2'S)-3,3'-((((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)((3- ((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)amino)ethyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3- Step 1: Into a 8 mL vial were added tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[({3-[(2S)-3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]ethyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (35 mg, 0.028 mmol, 1 equiv.), tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (13.13 mg, 0.028 mmol, 1.00 equiv.), MeCN (0.3 mL) and DIEA (7 mg, 0.054 mmol, 2.00 equiv.) . The reaction mixture was stirred at 25 °C for 2h. After completion of reaction, the reaction mixture was quenched by addition of water 30 mL. The aqueous layer was extracted with dichloromethane (3*30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by Prep-HPLC to afford tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]ethyl}({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate(17 mg ,40%yield, 95%purity) as a white liquid. Step 2: Into a 8 mL vial were added tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({2-[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[(2S)-3- (tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]ethyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-oxopropan-2- yl]pyrrolidine-1-carboxylate (17 mg, 0.010 mmol, 1 equiv.), HCl (2 mL,6mol / L) and THF (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. Then added HCl (2 mL, 10 mol / L) .The reaction mixture was stirred at 25 °C for 16h. It was dried by lyophilization to afford (2S)-3-{3-[({2- [bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]ethyl}({3-[(2S)-2- carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino)methyl]cuban-1-yl}-2-[(3R)-pyrrolidin- 3-yl]propanoic acid hexahydrochloride (016) (10.2 mg , 96%yield, 97%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=1011.8; Calculated: 1010.59. NMR:1H NMR (400 MHz, Methanol-d4) δ 7.59 (d, J = 7.7 Hz, 3H), 7.51 – 7.23 (m, 9H), 4.31 (d, J = 41.2 Hz, 6H), 3.98 (d, J = 76.2 Hz, 3H), 3.85 – 3.64 (m, 4H), 3.62 – 3.48 (m, 4H), 3.47 – 3.34 (m, 4H), 3.33 – 3.23 (m, 9H), 3.22 – 2.82 (m, 13H), 2.59 (dt, J = 23.5, 9.4 Hz, 5H), 2.28 – 1.93 (m, 5H), 1.85 (ddt, J = 18.0, 12.9, 6.4 Hz, 4H). Example B-17: (2S,2'S)-3,3'-((((2-((((2R,5S)-3-((S)-2-carboxy-2-((R)-pyrrolidin-3- yl)ethyl)cuban-1-yl)methyl)((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)cuban-1- yl)methyl)amino)ethyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) hexahydrochloride (017). Step 1: The synthesis of 21b can be found in Example B-1. Diastereomers were separated by chiral SFC chromatography, see, e.g., Example A-15. To a stirred solution of tert-butyl (3R)-3-[(2S)-3-(3-{[(2-aminoethyl)({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (105 mg, 0.126 mmol, 1 equiv.) ,tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- formylcuban-1-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (64.81 mg, 0.151 mmol, 1.20 equiv.) in anhydrous DCE (1 mL) . The reaction mixture was stirred at 25°C and STAB (79.94 mg, 0.378 mmol, 3 equiv.) was added after 30 min of reaction. After completion of reaction, the reaction mixture was quenched by addition of water 30 mL. The aqueous layer was extracted with dichloromethane (3*30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. The crude product was purified by Prep-HPLC to afford tert-butyl (3R)-3-[(2S)-3-{3-[({2- [bis({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1- yl}methyl)amino]ethyl}({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate ( 25 mg ,11%yield, 95%purity) as a yellow oil. Step 2: Into a 8 mL vial were added tert-butyl (3R)-3-[(2S)-3-{3-[({2-[bis({3-[(2S)-3-(tert-butoxy)- 2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)amino]ethyl}({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3- oxopropyl]phenyl}methyl)amino)methyl]phenyl}-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (25 mg, 0.015 mmol, 1 equiv.) , HCl (2 mL, 6 mol / L) and THF (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. Then added HCl (2 mL, 10 mol / L) .The reaction mixture was stirred at 25 °C for 16 h. The resulting solid was dried by lyophilization to afford (2S)-3-{3-[({2-[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]ethyl}({3- [(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]cuban-1-yl}methyl)amino)methyl]cuban-1-yl}-2- [(3R)-pyrrolidin-3-yl]propanoic acid hexahydrochloride (017) (10.6 mg, 70%yield, 96%purity) as a white solid. LCMS: (ES, m / z): [M+H]+=1037.5; Calculated: 1036.6. NMR:1H NMR (400 MHz, Methanol-d4) δ 7.68 (s, 2H), 7.57 (d, J = 7.0 Hz, 2H), 7.48 – 7.33 (m, 4H), 4.46 (s, 4H), 4.08 (s, 2H), 3.84 (t, J = 18.3 Hz, 12H), 3.66 – 3.48 (m, 8H), 3.47 – 3.36 (m, 5H), 3.30 (dq, J = 5.6, 3.9, 2.8 Hz, 4H), 3.17 (q, J = 9.5, 9.0 Hz, 2H), 3.11 – 2.84 (m, 8H), 2.69 – 2.47 (m, 6H), 2.13 (s, 4H), 2.01 (dd, J = 23.0, 10.2 Hz, 2H), 1.91 – 1.74 (m, 6H), 1.59 (dq, J = 6.0, 3.0 Hz, 2H), 1.29 (d, J = 5.4 Hz, 1H). Example B-18: 3-(8-{[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (118a / b).

[0035] Step 1: To a stirred solution of 8-(methoxycarbonyl)cubane-1-carboxylic acid (5 g, 24.249 mmol, 1 equiv.) in THF (100 mL) was added Borane dimethyl sulfide complex (10 M) (3 mL, 30 mmol, 1.2 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for about 2 hours under nitrogen atmosphere. The reaction was quenched by the slow addition of water (200 mL) and the mixture was then concentrated to remove the THF. The residue was extracted with DCM (3 x 300 mL). The combined organics were dried over Na2SO4and concentrated to give crude material which was purified by flash column chromatography (PE-THF=1:1) to afford the methyl 8-(hydroxymethyl)cubane-1-carboxylate. LCMS: (ES, m / z): [M+H+41]+= 234.1 Step 2: To a stirred solution of methyl 8-(hydroxymethyl)cubane-1-carboxylate (4.4 g, 22.891 mmol, 1 equiv.) Imidazole (4.4 g, 64.631 mmol, 2.82 equiv.) and 2-(diphenylphosphanyl)pyridine (15.7 g, 59.632 mmol, 2.6 equiv.) in THF (88 mL) were added I2(15.1 g, 59.494 mmol, 2.6 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for about 2 hours under nitrogen atmosphere. The reaction was quenched with sat. aq. NaHSO3 (4 mL) at -10 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (10:1) to afford methyl 8-(iodomethyl)cubane-1-carboxylate. LCMS: (ES, m / z): [M+H]+= 303.1 Step 3: To a solution of tert-butyl (3R)-3-[2-(tert-butoxy)-2-oxoethyl]pyrrolidine-1-carboxylate (3.54 g, 12.404 mmol, 1.5 equiv.), HMPA (2.22 g, 12.413 mmol, 1.5 equiv.) in THF (63 mL) was added KHMDS (1.0 M in THF) (12.4 mL, 62.160 mmol, 1.5 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 hour under nitrogen atmosphere. To the above mixture was added methyl 8-(iodomethyl)cubane-1-carboxylate (2.5 g, 8.275 mmol, 1 equiv.) in THF (10 mL) dropwise over 10 minutes at -78 °C. The resulting mixture was stirred at -78 °C for additional 2 hours. The reaction mixture was then quenched with sat. aq. NH4Cl (50 mL) at -78 °C. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, IPA and MeCN (1:1) in Water (0.1% TFA), 10% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl (3R)-3-[1-(tert-butoxy)-3-[8- (methoxycarbonyl)cuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30a / b). LCMS: (ES, m / z): [M+H]+= 460.4 Step 4: Compound 30a / b (1.4 g, 3.046 mmol, 1 equiv.) was purified by Prep-HPLC with the following conditions Column: CHIRALPAK IH-3100*4.6mm, 3.0 um; Mobile Phase A: CO2, Mobile Phase B: IPA: HEX=1:1; Flow rate: 80 mL / min; Gradient (B%): isocratic 30% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: IPA; Injection Volume: 1 mL. RT1(minute): 0.820 to afford first peak and RT2(minute): 0.971 to afford second peak. Chirally enriched material was arbitrarily assigned as compound 30a (first eluting isomer) and compound 30b (second eluting isomer). The first eluting isomer was characterized and used for the next step. The following steps can also be performed using chirally enriched material compound 30b. Step 5: To a solution of 30a (650 mg, 1.414 mmol, 1.00 equiv.) in Diethyl ether (13 mL) was added lithium borohydride (2.0 M in THF) (2.12 mL, 0.097 mmol, 3 equiv.) at 0 °C. The mixture was allowed to warm to RT and stirred for 2 hours. The reaction was quenched by the addition of sat. NH4Cl (aq.) (100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford tert-butyl (3R)-3-[-1-(tert-butoxy)-3-[8- (hydroxymethyl)cuban-1-yl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (31a). LCMS: (ES, m / z): [M+H]+= 432.3 Step 6: To a solution of DIEA (1068 mg, 8.263 mmol, 6.5 equiv.) in DCM (9.1 mL) and DMSO (3.1 mL) was added pyridine; sulfonylideneoxidane (609 mg, 3.826 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 hour. To the above mixture was added 31a (550 mg, 1.274 mmol, 1 equiv.) in DCM (5 mL) dropwise over 10 minutes at 0 °C. The resulting mixture was stirred at 0 °C for additional 2 hours. The reaction mixture was quenched by diluted HCl (1 M, 20 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF / PE (1:5) to afford tert-butyl (3R)- 3-(1-(tert-butoxy)-3-(8-formylcuban-1-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (32a). LCMS:(ES, m / z): [M+H]+= 430.4 Step 7: A solution 32a (45 mg, 0.105 mmol, 1 equiv.), tert-butyl (3R)-3-(1-(tert-butoxy)-3-(3-{[({3- [(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.126 mmol, 1.2 equiv.) in DCE (0.5 mL) was stirred at room temperature for about 60 minutes under nitrogen atmosphere. To the above mixture was added STAB (67 mg, 0.316 mmol, 3 equiv.) in portions over 10 minutes at room temperature. The resulting mixture was stirred at room temperature for additional 2 hours. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 100 % gradient in 30 mins; detector, UV 254 nm. This resulted in tert-butyl (3R)-3-[1-(tert-butoxy)-3-(3-{[({8-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]cuban-1-yl}methyl)({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]methyl}phenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (33a). LCMS: (ES, m / z): [M+H]+= 1206.0 Step 8: A solution of 33a (40 mg, 0.033 mmol, 1 equiv.) and HCl (2 mL, 6 mol / L) in THF (2 mL) was stirred at room temperature for about 6 hours under air atmosphere. The resulting mixture was concentrated under reduced pressure. The collected fractions were dried by lyophilization. This resulted in 3-(8-{[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic id tetrahydrochloride (018a). LCMS: (ES, m / z): [M+H]+= 737.3 Step 9: The resulting 3-(8-{[bis({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (23 mg, 0.026 mmol, 1 equiv.) was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3-(8-{[bis({3-[(2S)-2-carboxy-2-[(3R)- pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}cuban-1-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (118a). LCMS: (ES, m / z): [M+H]+= 737.3 Calculated:736.4NMR: 1H NMR (400 MHz, CF3COOD) δ 7.53 (t, J = 7.7 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.33(d, J = 6.4 Hz, 4H), 4.39 (dd, J = 13.3, 7.0 Hz, 2H), 4.35 – 4.26 (m, 2H), 3.97 (d, J = 5.1 Hz, 3H), 3.86 (dd, J = 15.9, 4.6 Hz, 4H), 3.81 – 3.60 (m, 5H), 3.54 (s, 5H), 3.46 – 3.36 (m, 2H), 3.28 (d, J = 10.4 Hz, 1H), 3.26 – 3.11 (m, 2H), 3.09 – 2.95 (m, 4H), 2.92 – 2.77 (m, 3H), 2.75 – 2.65 (m, 1H), 2.42 (s, 3H), 2.26 – 2.16 (m, 1H), 2.06 (dq, J = 32.8, 10.8 Hz, 3H), 1.95 – 1.89 (m, 1H), 1.35 (s, 1H).

[0036] Example B-19: (2S)-3-(3-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3- yl)ethyl)benzyl)amino)methyl)cuban-1-yl)-2-((R)-pyrrolidin-3-yl)propanoic acid trihydrochloride (019). Step 1: To a vial containing 26a (0.05 mmol, 1 equiv.), anhydrous 1,4-dioxane (0.2 M) was added followed by the addition of aq.6 M HCl (60 eq.) at RT. The reaction mixture was then stirred at RT for 4 days. The reaction mixture was then concentrated to dryness, redissolved in MeOH, and the resulting mixture was filtered to remove insoluble material. The filtrate was then concentrated to dryness to afford compound 019 as an off-white solid (79%). LC-MS: MS m / z [M+H]+506.3. Example C-1: in vitro Lp(a) Assembly Assay Compounds were tested for their ability to inhibit Lp(a) assembly. Media from HEK-293 cells overexpressing ApoA (17 Kringle repeats) and HepG2 cells which endogenously express ApoB100 was collected after 5 days. Compound was diluted into a 96-well plate followed by the addition of 15 µL of ApoA-HEK 293 cell culture media and 75 µL of HepG2 cell culture media and incubated for 2 hours at 37°C. To stop the reaction, 10 µL of 1.5 M EACA (6- aminocaproic acid) was added and 100 µL was transferred to a 96-well ELISA plate, coated with an ApoA antibody. The plate was incubated at room temperature for 1 hour. A horseradish peroxidase labeled (HRP)-anti-ApoB100 antibody was added to the plate for detection of Lp(a) complexes and the plate was incubated for 1 hour at room temperature. After washing the plate, 100 µL / well of substrate solution was added and the plate was incubated for 20 minutes at RT. Stop solution (50 µL / well) was added and OD450 was read within 5 minutes in an Envision (Perkin Elmer) plate reader. High controls were DMSO alone and low controls contained 1 / 50 HepG2 media. Compounds were run in duplicate 1:3 dilution at 10 different concentrations. Data were fit to a 4-parameter curve fit and IC50 values were reported. The : in vitro Lp(a) Assembly assay IC50 data are provided in the table below. “A” indicates an IC50 ≤ 1 nM, “B” indicates an IC50 > 1 but ≤ 10 nM, “C” indicates an IC50 > 10. Assay Data: Example D-1: Isothermal Titration Calorimetry (ITC) Assay Formation of Lp(a) occurs after apo(a) first binds to lysine residues of apoB100 through the Kringle IV (KIV) 7 and 8 domains, and then a disulfide bond forms between apo(a) and apoB- 100 to create Lp(a). Diaz, N., Perez, C., Escribano, A.M. et al. Discovery of potent small-molecule inhibitors of lipoprotein(a) formation. Nature 629, 945–950 (2024) reported that Lp(a) formation can be disrupted through small-molecule interactions with apo(a) KIV7–8, and disclosed compounds that bind to apo(a) KIV7–8. Comparator compounds, including a symmetrical trimer muvalaplin (LY3473329) as described in Diaz et al., and compounds disclosed herein were evaluated in an apo(a) Isothermal Titration Calorimetry (ITC) binding affinity assay as described below to measure binding affinity to apo(a) KIV7–8.

[0037] Certain compounds disclosed herein, being asymmetrical and comprising at least one cubanyl-containing (e.g., non-aromatic) arm, were found to have significantly stronger binding affinity for apo(a) KIV7–8 compared to compounds disclosed in Diaz et al comprising symmetrical and phenyl-containing (e.g., aromatic) arms. For example, a trimeric compound disclosed herein comprising at least one cubanyl-containing arm measured a ~7-fold stronger apo(a) KIV7–8 binding affinity of KD= 45 nM, compared to the symmetrical and phenyl-containing muvalaplin (apo(a) KIV7–8 binding affinity of KD= 332 nM). Further, a dimeric compound disclosed herein comprising one cubanyl-containing arm exhibited a ~4-fold stronger apo(a) KIV7–8 binding affinity of KD = 38 nM, compared to the symmetrical and phenyl-containing dimer of muvalaplin (apo(a) KIV7–8 binding affinity of KD = 160 nM). Thermodynamics of these compounds were also evaluated in the apo(a) binding affinity assay as described below. Compounds disclosed herein, being asymmetrical and comprising at least one cubanyl-containing (e.g., non-aromatic) arm, demonstrated superior stoichiometry of protein:compound compared to compounds disclosed in Diaz et al comprising symmetrical and phenyl-containing (e.g., aromatic) arms. Isothermal Titration Calorimetry (ITC) Assay Protocol Isothermal titration calorimetry (ITC) assays are well described in literature. Exemplary protocols are described in Diaz et al. as well as Bastos M, Velazquez-Campoy A. Isothermal titration calorimetry (ITC): a standard operating procedure (SOP). Eur Biophys J.2021 May;50(3- 4):363-371. Isothermal titration calorimetry (ITC) experiments were conducted using a MicroCal Auto- iTC200 calorimeter (Malvern Panalytical) with a 200 μL cell and a 40 μL microsyringe. All titrations were performed at 25 °C with stirring at 1,000 rpm in ITC buffer (50 mM phosphate, pH 7.4). The microsyringe was loaded with compound solutions quantified by quantitative nuclear magnetic resonance and titrated into the calorimetric cell containing 20 μM of recombinant apo(a) protein in ITC buffer. After system equilibration at 25 °C and a 120-second delay, titrations consisted of one initial 0.4 μL injection followed by 19 injections of 2 μL each, lasting 4 seconds per injection with 150-second intervals. Heat of dilution from ligand injections was subtracted as control. Data were analyzed using MicroCal PEAQ-ITC Analysis Software with a single-binding-site model to determine binding enthalpy (ΔH) and binding constant (K). Thermodynamic parameters were calculated via ΔG = ΔH – TΔS = –RT ln KD, where ΔG, ΔH, and ΔS represent changes in free energy, enthalpy, and entropy respectively; T is absolute temperature and R is the gas constant (1.987 cal mol⁻¹ K⁻¹). Example E-1: Pharmacokinetic and Safety Models Compounds disclosed herein were evaluated in in vitro and in vivo models, including an Lp(a) assembly assay, plasma protein binding ADME assays, and mouse, rat, and cyno pharmacokinetic studies. Compounds disclosed herein were evaluated in non-clinical safety studies for hERG inhibition, CYP inhibition, CYP induction, genotoxicity, and off-targets. Data from the in vitro and in vivo models and non-clinical safety studies demonstrated that compounds disclosed herein are drug-like.

[0038] PARTICULAR EMBODIMENTS The present disclosure provides the following particular embodiments of the lipids, compositions, and uses disclosed herein: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, Formula (I), wherein: G is a bivalent linker, a trivalent linker that is further coupled to R1, or a tetravalent linker that is further coupled to R1and R9(e.g., G is -O-, -N(R1)-, -S-, -S(O)-, -S(O)2-, -OCH2CH2O-, -NHS(O)2NH-, -N(R8)C(O)N(R8)-, -N(CH2CH2OR1)-, -N(CH2CH2NHR1)-, -OCH2C(CH3)(CH2OR1)CH2O-, -OCH2C(CH3)(CH2OR1)NH-, -OCH2C(NH2)(CH2OR1)CH2O-, -N(CH2CH2NR1R9)-, or -OCH2C(CH2OR1)(CH2OR9)CH2O-); each L is independently alkyl, heteroalkyl, or absent, wherein each alkyl or heteroalkyl are independently optionally substituted with R2; each R2is independently hydrogen, halogen, alkyl, or haloalkyl; Group A is a cycloalkyl (e.g., multicyclic cycloalkyl or bicyclic cycloalkyl), bicyclic heterocycloalkyl, or multicyclic heterocycloalkyl; Group B is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group C is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group D is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; each of Ra, Rb, Rc, and Rfare independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, - OC(=O)Rd, -OC(=O)ORd, -OC(=O)N(Re)2, -SRe, -S(=O)Rd, -S(=O)2Rd, -S(=O)2ORe, - S(=O)2N(Re)2, -N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, - NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, - P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rdis independently alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Reis independently hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two Reare taken together with the atom(s) to which they are attached and any intervening atoms between the two Reto form a heterocycloalkyl; each R3and each R5is independently hydrogen, halogen, alkyl, or haloalkyl; each R4is independently hydrogen or alkyl; each R6is independently hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -S(=O)Rd, - S(=O)2Rd, or -C(=O)Rd; each R7is independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, -OC(=O)Rd, - OC(=O)ORd, -OC(=O)N(Re)2, -SRe, -S(=O)Rd, -S(=O)2Rd, -S(=O)2ORe, -S(=O)2N(Re)2, - N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, -NReS(=O)2Rd, -C(=O)Rd, - C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently hydrogen or alkyl, or the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle; each m is independently 0 or 1; each n is independently 1, 2, or 3; each p is independently 0, 1, 2, 3, or 4; and each q is independently 0, 1, or 2. 2. The compound of embodiment 1, wherein the compound of Formula (I) is a compound of Formula (Ia): or a pharmaceutically acceptable salt thereof. 3 The compound of embodiment 1 or 2, wherein: R1 . 4. The compound of embodiment 1 or 2, wherein: 5. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ib): Formula (Ib), or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ic): or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 6, wherein the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle. 8. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Id): or a pharmaceutically acceptable salt thereof. 9. The compound of embodiment 8, wherein R1 . 10. The compound of embodiment 8, wherein 11. The compound of embodiment 1, wherein the compound of Formula (I) has the structure Formula (Ie), or a pharmaceutically acceptable salt thereof. 12. The compound of embodiment 11, wherein R1 13. The compound of embodiment 11, wherein 14. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (If): or a pharmaceutically acceptable salt thereof. 15. The compound of embodiment 14, wherein R1 . 16. The compound of embodiment 14, wherein 17. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ig): or a pharmaceutically acceptable salt thereof. 18. The compound of embodiment 17, wherein R1 . 19. The compound of embodiment 17, wherein 20. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ih): Formula (Ih), or a pharmaceutically acceptable salt thereof. 21. The compound of embodiment 20, wherein R1 22. The compound of embodiment 20, wherein 23. The compound of any one of embodiments 20-22, wherein . 24. The compound of any one of embodiments 20-22, wherein R9is . 25. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ij): or a pharmaceutically acceptable salt thereof. 26. 27. 28. 29. The compound of any one of embodiments 25-27, wherein R9is . 30. The compound of embodiment 1, wherein the compound of Formula (I) has the structure of Formula (Ik): or a pharmaceutically acceptable salt thereof. 31. The compound of embodiment 30, wherein R1i 3 The compound of embodiment 30, wherein 33. The compound of embodiment 1, wherein the compound has the structure of Formula Formula (Im), or a pharmaceutically acceptable salt thereof. 34. The compound of any one of embodiments 1-33, wherein at least one L is methyl optionally substituted with R2. 35. The compound of any one of embodiments 1-34, wherein at least one L is heteroalkyl. 36. The compound of any one of embodiments 1-35, wherein at least one L is absent. 37. The compound of any one of embodiments 1-33, wherein: each L is independently methyl optionally substituted with R2. 38. The compound of any one of embodiments 1-37, wherein: each R2is independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl; each R3is independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl; and each R7is independently hydrogen, halogen, -CN, -OH, -ORd, -OC(=O)Rd, -OC(=O)ORd, -OC(=O)N(Re)2, -N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, - NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, C1-C4alkyl, C1-C4 haloalkyl, or C1-C4heteroalkyl. 39. The compound of any one of embodiments 1-38, wherein: each R2is independently hydrogen, F, Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3,-CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or - CH2CCl3; each R3is independently hydrogen, F, -CH3, -CH2CH, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3; each R4is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, or -CH2(CH3)3; and each R7is independently hydrogen, F, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. 40. The compound of any one of embodiments 1-39, wherein: each R2is independently hydrogen or -CH3; each R3is independently hydrogen or -CH3; and each R4is independently hydrogen, -CH3, or -CH2CH3. 41. The compound of any one of embodiments 1-40, wherein: each R2is hydrogen; each R3is hydrogen; and each R4is hydrogen. 42. The compound of any one of embodiments 1-33, wherein each L is absent. 43. The compound of embodiment 42, wherein: each R3is independently hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl; and each R7is independently hydrogen, halogen, -CN, -OH, -ORd, -OC(=O)Rd, -OC(=O)ORd, -OC(=O)N(Re)2, -N(Re)2, -NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, - NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, C1-C4alkyl, C1-C4haloalkyl, or C1-C4heteroalkyl. 44. The compound of embodiment 42 or embodiment 43, wherein: each R3is independently hydrogen, F, -CH3, -CH2CH, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3; each R4is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, or -CH2(CH3)3; and each R7is independently hydrogen, F, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. 45. The compound of any one of embodiments 42-44, wherein: each R3is independently hydrogen or -CH3; and each R4is independently hydrogen, -CH3, or -CH2CH3. 46. The compound of any one of embodiments 42-45, wherein: each R3is hydrogen; and each R4is hydrogen. 47. The compound of embodiment 1, wherein the compound has the structure of Formula Formula (II), or a pharmaceutically acceptable salt thereof,

[0039] 48. The compound of embodiment 47, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 49. The compound of embodiment 47, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 50. The compound of embodiment 47, wherein the compound has the structure of Formula (IIa3): or a pharmaceutically acceptable salt thereof. 51. The compound of embodiment 47, wherein the compound has the structure of Formula (IIa4): or a pharmaceutically acceptable salt thereof. 52. The compound of embodiment 47, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 53. The compound of embodiment 47, wherein the compound has the structure of Formula (IIb1): or a pharmaceutically acceptable salt thereof. 54. The compound of embodiment 47, wherein the compound has the structure of Formula (IIb2): or a pharmaceutically acceptable salt thereof. 55. The compound of embodiment 47, wherein the compound has the structure of Formula (IIc1): Formula (IIc1), or a pharmaceutically acceptable salt thereof. 56. The compound of embodiment 47, wherein the compound has the structure of Formula (IIc2): or a pharmaceutically acceptable salt thereof. 57. The compound of embodiment 47, wherein the compound has the structure of Formula Formula (IIc3), or a pharmaceutically acceptable salt thereof. 58. The compound of embodiment 47, wherein the compound has the structure of Formula (IId1):

[0040] Formula (IId1), or a pharmaceutically acceptable salt thereof. 59. The compound of embodiment 47, wherein the compound is a compound of Formula (IIe1): or a pharmaceutically acceptable salt thereof. 60. The compound of embodiment 47, wherein the compound is a compound of Formula (IIf1): or a pharmaceutically acceptable salt thereof. 61. The compound of embodiment 47, wherein the compound is a compound of Formula (IIg1): or a pharmaceutically acceptable salt thereof. 62. The compound of embodiment 47, wherein the compound is a compound of Formula (IIh1): or a pharmaceutically acceptable salt thereof. 63. The compound of embodiment 47, wherein the compound is a compound of Formula or a pharmaceutically acceptable salt thereof. 64. The compound of embodiment 47, wherein the compound is a compound of Formula (IIj1): or a pharmaceutically acceptable salt thereof. 65. The compound of embodiment 47, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 66. The compound of embodiment 47, wherein the compound has the structure of Formula (IIm1): or a pharmaceutically acceptable salt thereof. 67. The compound of embodiment 47, wherein the compound has the structure of Formula (IIm2): or a pharmaceutically acceptable salt thereof. 68. The compound of any one of embodiments 1-67, wherein: Group A is a caged C8-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5- C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5- C12heterocycloalkyl, or caged C1-C12heterocycloalkyl. 69. The compound of embodiment 68, wherein: Group A is a caged C8-C12cycloalkyl or a bridged bicyclic C5-C12cycloalkyl. 70. The compound of any one of embodiments 1-69, wherein: Group A is a cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or bicyclo[3.2.2]octanyl. 71. The compound of any one of embodiments 1-70, wherein: Group A is a cubanyl or bicyclo[1.1.1]pentanyl. 72. The compound of any one of embodiments 1-71, wherein: Group A is a cubanyl. 73. The compound of any one of embodiments 1-72, wherein: Group A is a bicyclo[1.1.1]pentanyl. 74. The compound of any one of embodiments 1-69, wherein: , closo-1,12-carboranyl. 75. The compound of any one of embodiments 1-69, wherein: 76. The compound of any one of embodiments 1-69, wherein: Group 77. The compound of any one of embodiments 1-69, wherein: Group 78. The compound of any one of embodiments 1-77, wherein: Group B, Group C, and Group D are each independently caged C8-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5- C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, caged C1- C12heterocycloalkyl, phenyl, or pyridyl. 79. The compound of any one of embodiments 1-78, wherein: Group B, Group C, and Group D are each independently cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. 80. The compound of any one of embodiments 1-79, wherein: Group B, Group C, and Group D are each independently cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. 81. The compound of any one of embodiments 1-80, wherein: Group B, Group C, and Group D are each independently cubanyl or phenyl, each optionally substituted with 1-4 Rb, Rc, or Rf. 82. The compound of any one of embodiments 1-78, wherein: 83. The compound of any one of embodiments 1-78, wherein: Group B, Group C, and Group D are each independently , 84. The compound of any one of embodiments 1-78, wherein: Group B, Group C, and Group D are each independently , , 85. The compound of any one of embodiments 1-78, wherein: Group B, Group C, and Group D are each independently . 86. The compound of any one of embodiments 1-67, wherein:

[0041] 87. The compound of any one of embodiments 1-67, wherein: 88. The compound of any one of embodiments 1-67, wherein:

[0042] 89. The compound of any one of embodiments 1-67, wherein: 90. The compound of any one of embodiments 1-77, wherein: Group B and Group C are each independently caged C8-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5-C12heterocycloalkyl, caged C1-C12heterocycloalkyl, phenyl, or pyridyl. 91. The compound of any one of embodiments 1-77 and 90, wherein: Group B and Group C are each independently cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. 92. The compound of any one of embodiments 1-77, 90, and 91, wherein: Group B and Group C are each independently cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. 93. The compound of any one of embodiments 1-77 and 90-92, wherein: Group B and Group C are each independently cubanyl or phenyl, each optionally substituted with 1-4 Rbor Rc. 94. The compound of any one of embodiments 1-77 and 90, wherein: Group B and Group C are each independently , , , , , , carboranyl, closo-1,12-carboranyl, 95. The compound of any one of embodiments 1-77 and 90, wherein: Group B and Group C are each independently , 96. The compound of any one of embodiments 1-77 and 90, wherein: Group B and Group C are each independently 97. The compound of any one of embodiments 1-77 and 90, wherein: Group B and Group C are each independently . 98. The compound of any one of embodiments 1-67, wherein: 99. The compound of any one of embodiments 1-67, wherein: 100. The compound of any one of embodiments 1-67, wherein:

[0043] 101. The compound of any one of embodiments 1-67, wherein: 102. The compound of any one of embodiments 1-77, wherein: Group B is caged C8-C12cycloalkyl, bridged bicyclic C5-C12cycloalkyl, spiro bicyclic C5- C12cycloalkyl, spiro bicyclic C5-C12heterocycloalkyl, bridged bicyclic C5- C12heterocycloalkyl, caged C1-C12heterocycloalkyl, phenyl, or pyridyl. 103. The compound of any one of embodiments 1-77 and 102, wherein: Group B is cubanyl, cuneanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, phenyl, or pyridyl. 104. The compound of any one of embodiments 1-77, 102, and 103, wherein: Group B is cubanyl, bicyclo[1.1.1]pentanyl, phenyl, or pyridyl. 105. The compound of any one of embodiments 1-77, 102, 103, and 104, wherein: Group B is cubanyl or phenyl, each optionally substituted with 1-4 Rb. 106. The compound of any one of embodiments 1-77 and 102, wherein: 1,7-carboranyl, closo-1,12-carboranyl, 107. The compound of any one of embodiments 1-77 and 102, wherein: 108. The compound of any one of embodiments 1-77 and 102, wherein: o 109. The compound of any one of embodiments 1-77 and 102, wherein: Group 110. The compound of any one of embodiments 1-67, wherein: 111. The compound of any one of embodiments 1-67, wherein: 112. The compound of any one of embodiments 1-67, wherein: 113. The compound of any one of embodiments 1-67, wherein: 114. The compound of any one of embodiments 1-113, wherein: each R6is independently hydrogen, -CH3, -CH2CH, -CH2CH2CH3, -CH2CH(CH3)2, - CH2CH2CH2CH3, -CH2CH(CH2)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3,- CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -CH2CHCl2, or -CH2CCl3. 115. The compound of any one of embodiments 1-114, wherein: each R6is independently hydrogen, -CH3, -CH2CH, -CH2CH2CH3, or -CH2CH(CH3)2. 116. The compound of any one of embodiments 1-115, wherein: each R6is hydrogen. 117. The compound of any one of embodiments 1-116, wherein: each m is 1; and each n is 1. 118. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa1):

[0044] or a pharmaceutically acceptable salt thereof. 119. The compound of embodiment 1, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 120. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa3): or a pharmaceutically acceptable salt thereof. 121. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa4): or a pharmaceutically acceptable salt thereof. 122. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa5): or a pharmaceutically acceptable salt thereof. 123. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa6): or a pharmaceutically acceptable salt thereof. 124. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa7):

[0045] Formula (IIIa7), or a pharmaceutically acceptable salt thereof. 125. The compound of embodiment 1, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 126. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa9): or a pharmaceutically acceptable salt thereof. 127. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIa10): or a pharmaceutically acceptable salt thereof. 128. The compound of embodiment 1, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 129. The compound of embodiment 1, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 130. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIb3): or a pharmaceutically acceptable salt thereof. 131. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIc1): Formula (IIIc1), or a pharmaceutically acceptable salt thereof. 132. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIc2): Formula (IIIc2), or a pharmaceutically acceptable salt thereof. 133. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIc3): Formula (IIIc3), or a pharmaceutically acceptable salt thereof. 134. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIc4): Formula (IIIc4), or a pharmaceutically acceptable salt thereof. 135. The compound of embodiment 1, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 136. The compound of embodiment 1, wherein the compound has the structure of Formula ( or a pharmaceutically acceptable salt thereof. 137. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIk1):

[0046] Formula (IIIk1), or a pharmaceutically acceptable salt thereof. 138. The compound of embodiment 1, wherein the compound has the structure of Formula ( or a pharmaceutically acceptblae salt thereof. 139. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIk3):

[0047] Formula (IIIk3), or a pharmaceutically acceptblae salt thereof. 140. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIk4): or a pharmaceutically acceptblae salt thereof. 141. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIm1): or a pharmaceutically acceptable salt thereof. 142. The compound of embodiment 1, wherein the compound has the structure of Formula (IIIm2): or a pharmaceutically acceptable salt thereof. 143. The compound of embodiment 1, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 144. The compound of embodiment 1, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 145. The compound of embodiment 1, wherein the compound has the structure of Formula or a pharmaceutically acceptable salt thereof. 146. The compound of any one of embodiments 118-145, wherein:

[0048] 147. The compound of any one of embodiments 118-146, wherein: 148. The compound of any one of embodiments 1-145, wherein: each R5is independently hydrogen, F, or -CH3. 149. The compound of any one of embodiments 1-148, wherein the compound has the following structure: pharmaceutically acceptable salt thereof. 150. The compound of any one of embodiments 1-149, wherein: each Ra, Rb, Rc, and Rfare independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, - CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, - CH2CHCl2, -CH2CCl3, -CD3, -CN, -NH2, -NH(CH3), -N(CH3)2, -CO2H, -CO2(C1-C4alkyl), - C(=O)(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), or -C(=O)N(C1-C4alkyl)2. 151. The compound of any one of embodiments 1-150, wherein: each Ra, Rb, Rc, and Rfare independently hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, - CF3, -CH2Cl, -CHCl2, -CCl3, or -CN. 152. The compound of embodiment 1, wherein the compound has the following structure: each R5is independently H, -CH3, or F. 153. The compound of embodiment 1, wherein the compound has the following structure:

[0049] each R5is independently H, -CH3, or F; and each Rbis independently, H, -CH3, -OCH3, or F. 154. The compound of embodiment 1, wherein the compound has the following structure: , wherein: each R5is H, -CH3, or F; and Rband Rcare each independently H, -CH3, -OCH3, or F. 155. The compound of embodiment 1, wherein the compound has the following structure: each R5is independently H, -CH3, or F. 156. The compound of embodiment 1, wherein the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rbis H, -CH3, -OCH3, or F. 157. The compound of embodiment 1, wherein the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rbis H, -CH3, -OCH3, or F.

[0050] 158. The compound of embodiment 1, wherein the compound has the following structure: , wherein: each R5is independently H, -CH3, or F; and Rband Rcare each independently H, -CH3, -OCH3, or F. 159. The compound of embodiment 1, wherein the compound has the following structure: each R5is independently H, -CH3, or F; and Rcand Rfare each independently H, -CH3, -OCH3, or F.

[0051] 160. The compound of embodiment 1, wherein the compound has the following structure: Rcand Rfare each independently, H, -CH3, -OCH3, or F. 161. The compound of embodiment 1, wherein the compound has the following structure: each R5is independently H, -CH3, or F; and Rcis H, -CH3, -OCH3, or F. 162. The compound of embodiment 1, wherein the compound has the following structure: each R5is independently H, -CH3, or F; and Rband Rcare each independently H, -CH3, -OCH3, or F. 163. The compound of embodiment 1, wherein the compound has the following structure:

[0052] ,

[0053] pharmaceutically acceptable salt thereof. 164. A pharmaceutical composition comprising a compound of any one of embodiments 1- 163, and at least one pharmaceutically acceptable excipient. 165. A method of treating a cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, in a subject comprising administering a compound of any one of embodiments 1-163 to the subject. 166. The method of embodiment 165, wherein the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, is characterized by elevated lipoprotein(a) plasma levels. 167. The method of embodiment 165 or 166, wherein the cardiovascular disease or disorder is coronary artery disease, acute myocardial infarction, asymptomatic carotid atherosclerosis, stroke, atrial fibrillation, hypercholesterolemia, peripheral artery occlusive disease, cerebrovascular disease, renal artery stenosis, or hypertensive heart disease. 168. The method of any one of embodiments 165-167, wherein the metabolic disease or disorder is dyslipidemia, hyperlipidemia, hyperlipoproteinemia(a), hypercholesterolemia, fatty liver, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis. 169. The method of any one of embodiments 165-167, wherein the metabolic disease or disorder is lipid metabolism disorder. 170. The method of embodiment 165, wherein the cardiovascular disease or disorder, metabolic disease or disorder, or combination thereof, comprises metabolic syndrome. 171. A method of decreasing the likelihood of having a heart attack, a stroke, aortic stenosis, or a combination thereof, in a subject comprising administering a compound of any one of embodiments 1-163 to the subject. 172. The method of embodiment 171, wherein the method results in reducing lipoprotein(a) plasma levels in the subject. 173. A method of inhibiting assembly of lipoprotein(a) in a subject, comprising administering a compound of any one of embodiments 1-163 to the subject. 174. A method of reducing lipoprotein(a) plasma levels in a subject, comprising administering a compound of any one of embodiments 1-163 to the subject. INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation numerous equivalents to the compounds and methods of use thereof described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. Those skilled in the art will also recognize that all combinations of embodiments described herein are within the scope of the invention.

Claims

CLAIMS 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein: G is a bivalent linker, a trivalent linker that is further coupled to R1, or a tetravalent linker that is further coupled to R1and R9(e.g., G is -O-, -N(R1)-, -S-, -S(O)-, -S(O)2-, -OCH2CH2O-, -NHS(O)2NH-, -N(R8)C(O)N(R8)-, -N(CH2CH2OR1)-, -N(CH2CH2NHR1)-, -OCH2C(CH3)(CH2OR1)CH2O-, -OCH2C(CH3)(CH2OR1)NH-, -OCH2C(NH2)(CH2OR1)CH2O-, -N(CH2CH2NR1R9)-, or -OCH2C(CH2OR1)(CH2OR9)CH2O-);each L is independently alkyl, heteroalkyl, or absent, wherein each alkyl or heteroalkyl are independently optionally substituted with R2; each R2is independently hydrogen, halogen, alkyl, or haloalkyl; Group A is a cycloalkyl (e.g., multicyclic cycloalkyl or bicyclic cycloalkyl), bicyclic heterocycloalkyl, or multicyclic heterocycloalkyl; Group B is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group C is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; Group D is a multicyclic cycloalkyl, bicyclic cycloalkyl, bicyclic heterocycloalkyl, multicyclic heterocycloalkyl, aryl, or heteroaryl; each of Ra, Rb, Rc, and Rfare independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, -C(=O)Rd, -C(=O)ORe, -C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rdis independently alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Reis independently hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two Reare taken together with the atom(s) to which they are attached and any intervening atoms between the two Reto form a heterocycloalkyl; each R3and each R5is independently hydrogen, halogen, alkyl, or haloalkyl; each R4is independently hydrogen or alkyl; each R6is independently hydrogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -S(=O)Rd, - S(=O)2Rd, or -C(=O)Rd; each R7is independently hydrogen, halogen, -CN, -NO2, -OH, -ORd, -OC(=O)Rd, - OC(=O)ORd, -OC(=O)N(Re)2, -SRe, -S(=O)Rd, -S(=O)2Rd, -S(=O)2ORe, -S(=O)2N(Re)2, -N(Re)2, - NReC(=O)N(Re)2, -NReC(=O)Rd, -NReC(=O)ORe, -NReS(=O)2Rd, -C(=O)Rd, -C(=O)ORe, - C(=O)N(Re)2, -C(=O)NReORe, -B(ORe)2, -P(=O)(ORe)2, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently hydrogen or alkyl, or the two R8are taken together with the atoms to which they are attached and the intervening C(O) to form a heterocycle; each m is independently 0 or 1; each n is independently 1, 2, or 3; each p is independently 0, 1, 2, 3, or 4; and each q is independently 0, 1, or 2.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ia):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein:

4. The compound of claim 1, wherein the compound of Formula (I) has the structure ofFormula (Id):or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein6. The compound of claim 1, wherein the compound of Formula (I) has the structure of Formula (Ih):Formula (Ih), or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein8 The compound of any one of claims 6-7, wherein9. The compound of any one of claims 1-8, wherein:each R2is hydrogen; each R3is hydrogen; and each R4is hydrogen.

10. The compound of any one of claims 1-9, wherein each L is absent.

11. The compound of claim 1, wherein the compound has the structure of Formula (II):Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1, when present, iwherein R9, when present, i12. The compound of any one of claims 1-11, wherein:

13. The compound of any one of claims 1-12, wherein: Group B and Group C are each independently, , ,14. The compound of claim 1, wherein the compound has the structure of Formula (IIIa3):or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein the compound is selected from the group consisting of: ,,16. The compound of claim 1, wherein the compound has the structure of Formula (IIIa5):or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein the compound is:or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is selected from the group consisting of: ,,19. A pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

20. A method of decreasing the likelihood of having a heart attack, a stroke, aortic stenosis, or a combination thereof, in a subject comprising administering to the subject a compound of any one of claims 1-18 or the pharmaceutical composition of claim 19 to the subject.

21. A method of inhibiting assembly of lipoprotein(a) in a subject, comprising administering to the subject a compound of any one of claims 1-18 or the pharmaceutical composition of claim 19 to the subject.

22. A method of reducing lipoprotein(a) plasma levels in a subject, comprising administering to the subject a compound of any one of claims 1-18 or the pharmaceutical composition of claim 19 to the subject.

23. A method of treating a cardiovascular disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-18 or the pharmaceutical composition of claim 19 to the subject.

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