Multi-target compounds, process for the preparation of the compounds, intermediates, pharmaceutical composition, pharmaceutically acceptable salts, combination, medicament, use of a compound and method of treatment

Abstract

The present invention relates to novel compounds of general Formula I with multifaceted pharmacological activities. The compounds of the invention exhibit SGLT1, SGLT2, and DPP4 inhibition. The present invention also provides processes and intermediates to obtain the compounds of the invention, pharmaceutical compositions comprising encompasses the compounds, processes and intermediates for the synthesis of the compounds, pharmaceutical compositions, combinations, medicaments, therapeutical uses and methods for the treatment of diseases, for instance, cardiovascular and renal diseases, including heart failure, chronic kidney disease, diabetes mellitus, diabetic nephropathy and myocardial infarction.

Description

DescriptionMULTI-TARGET COMPOUNDS, PROCESS FOR THE PREPARATION OF THE COMPOUNDS, INTERMEDIATES, PHARMACEUTICAL COMPOSITION, PHARMACEUTICALLY ACCEPTABLE SALTS, COMBINATION, MEDICAMENT, USE OF A COMPOUND AND METHOD OF TREATMENTField of the Invention

[0001] The present invention relates to novel compounds with multifaceted pharmacological activities, specifically targeting the sodiumglucose co-transporter 1 and 2 (SGLT1 and SGLT2, respectively) and the dipeptidyl peptidase IV (DPP4) enzyme. These compounds are useful for the treatment of several diseases, such as cardiovascular, metabolic and renal diseases, including heart failure, chronic kidney disease, diabetes mellitus, diabetic nephropathy and myocardial infarction. The invention encompasses the compounds, processes and intermediates for the synthesis of the compounds, pharmaceutical compositions, combinations, medicaments, therapeutical uses and methods for the treatment of diseases in which the SGLT1 , SGLT2 and DPP4 receptors are involved.Background of the Invention

[0002] Cardiovascular, metabolic and renal diseases, such as heart failure, chronic kidney disease, diabetes and obesity, represent a major burden to society and affect millions of people worldwide. Particularly, diabetes is a chronic metabolic disease characterized by high levels of glucose in the blood, which in the long term can cause serious damage to the heart, kidneys, eyes, among other organs. The most common type of the disease, type 2 diabetes (T2D), mainly affects adults and, in this case, the body becomes resistant to insulin and / or has low production of this hormone. In turn, type 1 diabetes (T1 D) is a chronic condition in which the pancreas produces little or no insulin. According to the World Health Organization (WHO), in 2014, more than 422 million people in the world arediabetic. It is estimated that 1.6 million deaths were directly caused by diabetes in 2016, making it the seventh leading cause of death in the same year.

[0003] Cardiovascular, metabolic and renal diseases are complex conditions often characterized by interrelated pathophysiological mechanisms. Patients with diabetes and obesity are at an increased risk of cardiovascular and renal complications. In addition, heart failure patients that concomitantly exhibit diabetes have worse disease prognosis. The management of such diseases is challenging due to the interplay of hyperglycemia, dyslipidemia, hypertension, and other metabolic derangements. The treatment of these disorders typically involves the use of multiple medications, each targeting a specific aspect of the disease, such as antidiabetics, antihypertensives, lipid-lowering, anti-atherosclerotic, antiobesity and / or antiplatelet drugs. Therefore, there is a need for novel therapies that simultaneously address relevant aspects of the disease, such as providing glycemic control, improvement of insulin resistant and reduction of the risk of cardiovascular and renal damage.

[0004] Dipeptidyl peptidase-4 inhibitors (DPP4i), sodium -glucose cotransporter 2 inhibitors (SGLT2i) and sodium-glucose co-transporter 1 inhibitors (SGLTI i) are new drug classes with antihyperglycemic pharmacology that have been recently introduced into therapy. Although these compounds were originally approved for treating T2D, their use in the clinic was expanded to other indications, such as chronic kidney disease and heart failure for patients with or without T2D, due to their pharmacological benefits in preventing and treating cardiovascular and renal damage.

[0005] DPP4i inhibit the enzyme dipeptidyl peptidase-4 (DPP4), which is an exopeptidase expressed in different organs and which is also found in soluble form in plasma. Its enzymatic activity in the kidneys is one of the highest when compared to other tissues. This enzyme is responsible for the degradation of the glucagon-like peptide 1 (GLP-1 ) receptor and theglucose-dependent insulinotropic peptide (GIP), resulting in higher plasma concentrations of the same. The increase in the concentration of these hormones provides greater secretion of insulin produced by the beta cells of the pancreas and reduces the release of glucagon produced by the alpha cells. Consequently, the production of endogenous glucose is also reduced, generating a lower concentration of glucose in the blood and greater control of glycemic levels. Clinical studies confirm that DPP4i increases plasma GLP-1 levels and improves plasma glucose control with a low risk of hypoglycemia and other side effects. Recent studies also provide cardiovascular protection for this therapeutic class through GLP-1 - dependent and GLP-1 -independent mechanisms. The potential nephroprotection resulting from DPP4 inhibition is described in the literature due to the anti-fibrotic effects in diabetic mouse models and in models of chronic kidney disease in rats, in addition to anti-inflammatory effects also observed in different models of kidney disease. Additionally, the nephroprotective effects of DPP4i may be related to the improvement of endothelial function as described in recent studies in patients with T2D treated with linagliptin.

[0006] The two sodium-dependent glucose co-transporters, SGLT1 and SGLT2, in the proximal tubule of the kidney are responsible for reabsorbing more than 99% of the plasma glucose that is filtered in the glomerulus. Approximately 90% of the contribution of this reabsorption is made from type 2 transporters (SGLT2) and the remaining 10% from type 1 transporters (SGLT1 ). SGLT2i reduce plasma glucose concentration by inhibiting reabsorption of renal glucose promoting the excretion of glucose in the urine which is accompanied by weight loss due to the resulting negative energy balance. Furthermore, SGLT2i are also capable of blocking sodium absorption in the proximal tubules, generating a decrease in blood pressure. SGLT1 is also expressed in the small intestine and exerts an important role in oral glucose absorption, thus contributing to the antihyperglycemic effect of SGLT1 inhibitors (SGLTI i). SGLTI i lead to increased plasma GLP-1secretion by the elevated glucose levels in the lower segment of the small intestine, which leads to GLP-1 secretion by enteroendocrine L cells.

[0007] Due to the high complexity of the pathogenesis of T2D involving multiple metabolic issues, the use of combined therapy with antidiabetic drugs with different mechanisms of action has the advantage of reducing compensatory mechanisms and resulting in improved glucose control. Second the latest consensus report from the American Diabetes Association and the European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends the preferential use of GLP-1 agonists, SGLT2i and some DPP4i after the use of metformin as initial monotherapy in diabetic patients with established chronic kidney or atherosclerotic cardiovascular disease and at risk of hypoglycemia or problems related to body weight. Moreover, combined treatment of diabetic animals (Zucker diabetic fatty rats) with SGLTI i and DPP4i results in superior active GLP-1 levels in plasma and improved glucose tolerance compared with either therapy alone (Oguma, T, et al. J Pharmacol Exp Then 2015;354(3):279- 289). This occurs because SGLTI i promotes GLP-1 secretion and DPP4i prevents its cleavage, thus resulting in increased active GLP-1 levels, which exerts further benefits for treatment of T2D. Therefore, the combination of SGLT1 , SGLT2 and DPP4 inhibition is a promising therapeutic strategic for T2D due to the complementary of these mechanisms of action.

[0008] SGLT1 i and SGLT2i also present pleiotropic effects reducing the number of cardiovascular events, cardiovascular mortality and overall mortality in diabetic patients with established heart disease and / or at risk. Moreover, potential nephroprotective effects are also described in the literature for SGLT2L Clinical evidence indicates that these agents can reduce the risk of developing or worsening albuminuria, a marker of kidney damage, through several mechanisms such as decreasing blood pressure, reducing intraglomerular pressure and hyperfiltration, modifying inflammatory processes and reducing renal injury resulting from of ischemia.

[0009] Considering the pleiotropic effects known for SGLT1 i, SGLT2i and DPP4i, it is proposed that a compound with concomitant activity at these receptors would be capable of controlling plasma glucose levels and presenting desirable renal and cardiac protective effects. Along with the described cardiovascular benefits of the SGLT2i class, the renal protective effects could reduce the risk of developing other comorbidities associated with obesity / T2D, including cardiovascular diseases (e.g., hypertension and acute myocardial infarction) and renal diseases (e.g., diabetic nephropathy).

[0010] In general, drug combinations in single doses offer several advantages for therapy, such as improving patient adherence to therapy, reducing cost, reduction in the amount of medication administered daily, increase effectiveness by mitigating the risks of adverse effects related to treatment and, also, enable a possible reduction in the doses of each drug than would be necessary to achieve the same objectives with monotherapy, thus providing greater tolerability for the user. In addition, the development of fixed-dose combination formulations incorporating two or more existing active ingredient would pose significant challenges from the pharmaceutical technology perspective. Each active ingredient may have different physicochemical properties, pharmacokinetic profiles, and formulation requirements, necessitating careful consideration of compatibility, stability, and dosing accuracy.

[0011] Although molecules active against either SGLT2, SGLT 1 or DPP4 have already been described, no compound with triple activity at SGLT1 , SGLT2 and DPP4 has been disclosed yet. Such compounds would be useful for the treatment of cardiovascular, metabolic and renal diseases by concomitantly modulating different aspects of the diseases.Summary of the Invention

[0012] The present invention describes novel compounds that possess multi-target pharmacological activities, including inhibition of SGLT1 , SGLT2, and DPP4. These compounds offer a unique and synergistic approach to the treatment of cardiovascular, metabolic and renal diseases,allowing for the simultaneous modulation of glucose homeostasis, sodium reabsorption, and incretin hormone activity.

[0013] In a first aspect, the present invention relates to a compound of general formula I or its pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0014] [Chem. 1 ] Compound of Formula Iwherein, dotted lines indicate the presence, when applicable, of an aliphatic cyclic ring; n is selected from zero (single bond between 0 or C, i.e., six-member ring) or 1 (seven-member ring);P is absent or selected from hydrogen, CH2, C-alkyl linear or branched chain (C1 -C20), 0, S, NH or N-alkyl linear or branched chain (C1 -C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1- C20), OH, 0- or NH-alkyl linear or branched chain (C1 -C20) or NH2;B is absent or selected from hydrogen, C-alkyl linear or branched chain (C1- C20), 0, NH, 0- or NH-alkyl linear or branched chain (C1-C20) or NH2;Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1- C20), C-alkyl linear or branched chain (C1 -C20), OH, F, Cl, Br, I, O- or NH- alkyl linear or branched chain (C1-C20) or NH2;M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH-alkyl, alkyl being linear or branched chain (C1 -C20);W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);K is selected from CH2, CH-alkyl linear or branched chain (C1-C20), 0, NH, N-alkyl linear or branched chain (C1 -C20) or S;A is absent or selected from 0, S, NH, CH2, NH- or CH-alkyl chain (C1 -C20);D is absent or selected from hydrogen, carbon or sulfur;LT is selected from hydrogen, methyl or fluorine;II is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or -OC(O)NH- alkyl, alkyl being linear or branched chain (C1 -C20);Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0-alkyl, - CH20C(0)-alkyl -CH20C(0)N-alkyl; moreover Z or P can, together, form a cycloalkyl ring;X is a linker space selected from these moieties as follow (when applicable)

[0015] [Chem. 1 ] radical moieties iY is absent or it is a heterocyclic aliphatic moiety selected from these groups as follow:

[0016] [Chem. 1 ] radical moieties ii

[0017] The present invention is also directed to processes and intermediates, which are useful to obtain the compounds of the general formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0018] The compounds of the present invention can be prepared by a process comprising the following general steps: a) reacting a compound of formula II under protecting group reaction that form a product comprising the formula III:Formula II Formula III b) treating the compound of formula III under conditions that form a product comprising the formula IV:Formula IV c) react a compound of formula IV with a compound of formula V under conditions that form a product comprising the formula VI:Formula V Formula VI d) optionally, react the compound of formula VI under mild-basic hydrolysis conditions to form a compound of Formula I:Formula I wherein, refers to a dotted line indicating the presence, when applicable, of an aliphatic cyclic ring; n is selected from zero (single bond between O or C, i.e. , six-member ring) or 1 (seven-member ring);P is absent or selected from CH2, C-alkyl linear or branched chain (C1- C20), O, S, NH or N-alkyl linear or branched chain (C1-C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1 - C20), O, N-alkyl linear or branched chain (C1-C20) or NH;B is absent or selected from C-alkyl linear or branched chain (C1-C20), 0, NH, O- or NH-alkyl linear or branched chain (C1-C20) or NH2;Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1 - C20), C-alkyl linear or branched chain (C1-C20), OH, F, Cl, Br, I, 0- or NH- alkyl linear or branched chain (C1-C20) or NH2;W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);V is selected from CH2-CI or CH2-Br;K is selected from CH2, CH-alkyl linear or branched chain (C1 -C20), 0, NH, N-alkyl linear or branched chain (C1-C20) or S;A is absent or selected from O, S, NH, CH2, NH- or CH-alkyl chain (C1- C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silylderivativesLT is selected from hydrogen, methyl or fluorine;U is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or -OC(O)NH- alkyl, alkyl being linear or branched chain (C1 -C20);Z is absent or selected from methyl, CH20H, S-Me, -CH2OC(O)O-alkyl, - CH2OC(O)-alkyl -CH2OC(O)N-alkyl; moreover Z or P can, together, form a cycloalkyl ring;D is absent or selected from hydrogen, carbon or sulfur;T is selected from hydrogen, methyl, ethyl, or a C-alkyl linear or branched chain (C1-C20);E is an “amino-linker space” selected from the following moieties:X is a linker space selected from these moieties as follow (when applicable)Y is absent or it is a heterocyclic aliphatic moiety selected from these groups as follow

[0019] Also provided is a process to obtain the compound of formula XV according to the invention: a) reacting a compound of formula VII with protecting groups under conditions that form a product of formula VIIIFormula VII Formula VIII b) treat the compound of formula VIII under carbon-carbon couplingconditions to form a reactional product of formula IXFormula IX c) react the compound of formula IX with dealkylating reagents under conditions to form a reactional product of formula XFormula X d) reacting the compound of formula X with a compound of formula XI under conditions that form a compound of formula XIIJ— OHFormula XI Formula XII e) react a compound of formula XII with a compound of formula XIII under conditions that form a reactional product of formula XIVCk JFormula XIII Formula XIV f) optionally react a compound of formula XIV under mild-basic hydrolysis reactions to form a compound of formula XVFormula XV wherein, n is selected from zero (single bond between 0 and C, i.e. , six-member ring) and 1 (seven-member ring);A is selected from 0, S, NH, CH2, CH-alkenyl chain (C1 -C20);P is absent or selected from CH2, C-alkyl linear or branched chain (C1 -C20), O, S, NH or N-alkyl linear or branched chain (C1 -C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silyl derivatives.R1 is selected from methyl or ethyl;R2 is selected from C-alkyl linear or branched chain (C1-C20),OH, 0- or N-alkyl linear or branched chain (C1-C20) and NH2;Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0-alkyl; moreover, Z and P can, together, form a cycloalkyl ring;JH is an “amino-linker space” selected from these moieties as follow:J is a “linker space” selected from these moieties as followY is a “heterocyclic aliphatic moiety” selected from these groups as follow:

[0020] In a third aspect, the invention is also directed to a pharmaceutical composition comprising at least one compound of formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, and at least one pharmaceutically acceptable excipient.

[0021] As a fourth objective, it is provided a combination for simultaneous, separate or sequential use, comprising at least one compound of formula I or any pharmaceutically acceptable salts, crystals,stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, and at least one other drug useful for the treatment of a disease comprising cardiovascular, renal and metabolic diseases.

[0022] It is a fifth objective to provide a medicament comprising a compound of formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0023] The present invention is also directed to use of compounds of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof to manufacture a medicament, for the treatment of diseases.

[0024] A seventh aspect of the invention relates to a method for treating diseases, such as cardiovascular and renal diseases, e.g. heart failure, chronic kidney disease, diabetes mellitus, diabetic nephropathy and myocardial infarction, comprising the administration to a patient of a therapeutically effective amount of at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.Detailed description of the inventionAdvantages of the Invention

[0025] Comprehensive Disease Management: the compounds of the present invention provide a multi-target pharmacological profile, which is useful for the treatment of cardiovascular disorders by simultaneously addressing multiple underlying mechanisms, including glucose dysregulation and sodium reabsorption.

[0026] Enhanced Efficacy: The combined activity at SGLT1 , SGLT2, and DPP4 offers the potential for greater therapeutic efficacy compared to single-agent therapies.

[0027] Increased GLP-1 levels: The inhibition of SGLT1 in the intestine leads to the secretion of GLP-1 , which, when combined with DPP4inhibitors, may enhance GLP-1 half-life in plasma and its associated cardiovascular and renal benefits.

[0028] Simplified Treatment: Patients can benefit from a more streamlined treatment regimen, reducing the need for multiple medications and improving treatment adherence.

[0029] Thus, the invention of multi-target compounds with SGLT1 , SGLT2, and DPP4 activity represents a promising and innovative approach to the treatment of cardiovascular disorders. By simultaneously modulating multiple disease pathways, these compounds offer the potential for enhanced therapeutic efficacy and improved quality of life for the treatment of diseases, in particular cardiovascular and renal diseases, such as heart failure, chronic kidney disease, diabetes mellitus, diabetic nephropathy and myocardial infarction.Definitions

[0030] Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

[0031] It is noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Further, definitions of standard chemistry terms may be found in reference works, including Carey and Sundberg “Advanced Organic Chemistry 4™ Ed.” Vols. A (2000) and B (2001 ), Plenum Press, New York. Also, unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed.

[0032] “Alicyclic” means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quaternized or oxidized and the sulfuratoms can be optionally oxidized. Examples of alicyclic moieties include but are not limited to moieties with (C3-8) rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

[0033] “Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.

[0034] “Alkenyl” means a straight or branched, carbon chain that contains at least one carbon-carbon double bond (-CR=CR'- or -CR=CR'R", wherein R, R' and R" are each independently hydrogen or further substituents). Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, etc. In particular embodiments, “alkenyl,” either alone or represented along with another radical, can be a (C2-20)alkenyl, a (C2-15)alkenyl, (C2-10)alkenyl, (C2- 5)alkenyl or (C2-3)alkenyl. Alternatively, “alkenyl,” either alone or represented along with another radical, can be a (C2)alkenyl, a (C3)alkenyl or a (C4)alkenyl.

[0035] “Alkoxy” means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.

[0036] “Alkyl” represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with one or more of the carbon atoms being replaced with oxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl”), sulfur (See “thioalkyl”), and / or nitrogen (See “azaalkyl”). (Cx)alkyl and (Cx-y)alkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, (C1-6)alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tertbutyl, vinyl, allyl, 1 -propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl etc) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-10)aryl(C1_3)alkyl includes, benzyl, phenethyl, 1- phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl, etc). In particular embodiments, “alkyl,” either alone or represented along with another radical, can be a (C1 -20)alkyl, a (C1 -15)alkyl, a (C1 -10)alkyl, a (C1- 5)alkyl or a (C1 -3)alkyl. Alternatively, “alkyl,” either alone or represented along with another radical, can be a (C1 )alkyl, a (C2)alkyl or a (C3)alkyl.

[0037] “Amido” means the radical -C(=0)-NR-, -C(=0)-NRR', -NR-C(=0)- and / or -NR-C(=O)R', wherein each R and R' are independently hydrogen or a further substituent.

[0038] “Amino” means a nitrogen moiety having two further substituents where, for example, a hydrogen or carbon atom is attached to the nitrogen. For example, representative amino groups include -NH2, -NHCH3, - N(CH3)2, -NH((C1-10)alkyl), -N((C1 -10)alkyl)2, -NH(aryl), -NH(heteroaryl), - N(aryl)2, -N(heteroaryl)2, etc. Optionally, the two substituents together with the nitrogen may also form a ring. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.

[0039] “Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2 (according to Huckel's law). An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (See “heteroaryl”).

[0040] “Aryl” means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. (Cx)aryl and (Cx-y)aryl are typically used where Xand Y indicate the number of carbon atoms in the ring. In particular embodiments, “aryl,” either alone or represented along with another radical, can be a (C3-14)aryl, a (C3-10)aryl, a (C3-7)aryl, a (C8-10)aryl or a (C5- 7)aryl. Alternatively, “aryl,” either alone or represented along with another radical, can be a (C5)aryl, a (C6)aryl, a (C7)aryl, a (C8)aryL, a (C9)aryl or a (C10)aryl.

[0041] “Bicycloalkyl” means a saturated or partially unsaturated fused, spiro or bridged bicyclic ring assembly. In particular embodiments, “bicycloalkyl,” either alone or represented along with another radical, can be a (C4-15)bicycloalkyl, a (C4-10)bicycloalkyl,a (C6-10)bicycloalkyl or a (C8- 10)bicycloalkyl. Alternatively, “bicycloalkyl,” either alone or represented along with another radical, can be a (C8)bicycloalkyl, a (C9)bicycloalkyl or a (C10)bicycloalkyl.

[0042] “Bicycloaryl” means a fused, spiro or bridged bicyclic ring assembly wherein at least one of the rings comprising the assembly is aromatic. (Cx)bicycloaryl and (Cx-y)bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring. In particular embodiments, “bicycloaryl,” either alone or represented along with another radical, can be a (C4-15)bicycloaryl, a (C4-10)bicycloaryl, a (C6-10)bicycloaryl or a (C8-10)bicycloaryl.Alternatively, “bicycloalkyl,” either alone or represented along with another radical, can be a (C8)bicycloaryl, a (C9)bicycloaryl or a (C10)bicycloaryl.

[0043] “Bridging ring” and “bridged ring” as used herein refer to a ring that is bonded to another ring to form a compound having a bicyclic or polycyclic structure where two ring atoms that are common to both rings are not directly bound to each other. Nonexclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, etc. One or both rings of the bicyclic system may also comprise heteroatoms.

[0044] “Carbamoyl” means the radical -OC(O)NRR', wherein R and R' are each independently hydrogen or further substituents.

[0045] “Carbocycle” means a ring consisting of carbon atoms.

[0046] “Carbonyl” means the radical -C(=0)- and / or -C(=0)R, wherein R is hydrogen or a further substituent. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.

[0047] “Carboxy” means the radical -C(=0)-0- and / or -C(=0)-OR, wherein R is hydrogen or a further substituent. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, etc.

[0048] “Cyano” means the radical -CN.

[0049] “Cycloalkyl” means a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or polycyclic ring assembly. (Cx)cycloalkyl and (Cx-y)cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, (C3-10)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5- cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, etc. In particular embodiments, “cycloalkyl,” either alone or represented along with another radical, can be a (C3-14)cycloalkyl, a (C3-10)cycloalkyl, a (C3-7)cycloalkyl, a (C8-10)Cycloalkyl or a (C5-7)cycloalkyl. Alternatively, “cycloalkyl,” either alone or represented along with another radical, can be a (C5)cycloalkyl, a (C6)cycloalkyl, a (C7)cycloalkyl, a (C8)cycloalkyl., a (C9)cycloalkyl or a (C10)cycloalkyl.

[0050] “Fused ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where the ring atoms that are common to both rings are directly bound to each other. Nonexclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, etc.Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, etc.

[0051] “Halo” means fluoro, chloro, bromo or iodo.

[0052] “Heteroalkyl” means alkyl, as defined in this Application, provided that one or more of the atoms within the alkyl chain is a heteroatom. In particular embodiments, “heteroalkyl,” either alone or represented along with another radical, can be a hetero(C1-20)alkyl, a hetero(C1 -15)alkyl, a hetero(C1-10)alkyl, a hetero(C1 -5)alkyl, a hetero(C1-3)alkyl or a hetero(C1- 2)alky I. Alternatively, “heteroalkyl,” either alone or represented along with another radical, can be a hetero(C1 )alkyl, a hetero(C2)alkyl or a hetero(C3)alkyl.

[0053] “Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic group wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. Monocyclic heteroaryl groups include, but are not limited to, cyclic aromatic groups having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quatemerized and the sulfur atoms can be optionally oxidized. Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1 ,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1 ,3,4-thiadiazole, triazole and tetrazole. “Heteroaryl” also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring. These bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridinc, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1 ,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole,im idazo[l , 5-a]pyrid ine, pyrazolo[1 ,5-a]pyridine, imidazo[1 ,2-a]pyrimidine, imidazo[1 ,2-c]pyrimidine, imidazo[1 ,5-a]pyrim idine, imidazo[1 ,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2- c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrim idine, pyrrolo[2,3-b]pyrazine, pyrazolo[1 ,5-a]pyridine, pyrrolo[1 ,2-b]pyridazine, pyrrolo[1 , 2c]pyrim id ine, pyrrolo[1 ,2-a]pyrim idine, pyrrolo[1 ,2-a]pyrazine, triazo[1 ,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazene, phenoxazine, 1 ,2- dihydropyrrolo[3,2, 1 -hi]indole, indolizine, pyrido[1 ,2-a]indole and 2(1 H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused. The heteroaryl groups of this invention can be substituted or unsubstituted. In particular embodiments, “heteroaryl,” either alone or represented along with another radical, can be a hetero(C1 -13)aryl, a hetero(C2-13)aryl, a hetero(C2-6)aryl, a hetero(C3-9)aryl or a hetero(C5- 9)aryl. Alternatively, “heteroaryl,” either alone or represented along with another radical, can be a hetero(C3)aryl, a hetero(C4)aryl, a hetero(C5)aryl, a hetero(C6)aryl, a hetero(C7)aryl, a hetero(C8)aryl or a hetero(C9)aryl.

[0054] “Heteroatom” refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur.

[0055] “Heteroatom moiety” includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include -NR-, -N+(0-)=, -0-, -S- or -S(O)2-, wherein R is hydrogen or a further substituent.

[0056] “Heterobicycloalkyl” means bicycloalkyl, as defined in this application, provided that one or more of the atoms within the ring is a heteroatom. For example hetero(C9-12)bicycloalkyl as used in this application includes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl, 2- aza-bicyclo[3.1 ,0]hex-2-yl, 3-aza-bicyclo[3.1 ,0]hex-3-yl, etc. In particular embodiments, “heterobicycloalkyl,” either alone or represented along withanother radical, can be a hetero(C1-14)bicycloalkyl, a hetero(C4- 14)bicycloalkyl, a hetero(C4-9)bicycloalkyl or a hetero(C5-9)bicycloalkyl. Alternatively, “heterobicycloalkyl,” either alone or represented along with another radical, can be a hetero(C5)bicycloalkyl, hetero(C6,)bicycloalkyl, hetero(C7)bicycloalkyl, hetero(C8)bicycloalkyl or a hetero(C9)bicycloalkyl.

[0057] “Heterobicycloaryl” means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom. For example, hetero(C4-12)bicycloaryl as used in this application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin- 6-yl, tetrahydroisoquinolinyl, etc. In particular embodiments, “heterobicycloaryl,” either alone or represented along with another radical, can be a hetero(C1 -14)bicycloaryl, a hetero(C4-14)bicycloaryl, a hetero(C4- 9)bicycloarylor a hetero(C5-9)bicycloaryl. Alternatively, “heterobicycloaryl,” either alone or represented along with another radical, can be a hetero(C5)bicycloaryl, hetero(C6)bicycloaryl, hetero(C7)bicycloaryl, hetero(C8)bicycloaryl or a hetero(C9)bicycloaryl.

[0058] “Heterocycloalkyl” means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, 0, or S. Non-exclusive examples of heterocycloalkyl include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1 ,4-diazaperhydroepinyl, 1,3-dioxanyl, 1 ,4-dioxanyl etc. In particular embodiments, “heterocycloalkyl,” either alone or represented along with another radical, can be a hetero(C1 -13)cycloalkyl, a hetero(C1 - 9)cycloalkyl, a hetero(C1-6)cycloalkyl, a hetero(C5-9)cycloalkyl or a hetero(C2-6)cycloalkyl. Alternatively, “heterocycloalkyl,” either alone or represented along with another radical, can be a hetero(C2)cycloalkyl, a hetero(C3)cycloalkyl, a hetero(C4)cycloalkyl, a hetero(C5)cycloalkyl, a hetero(C6)cycloalkyl, hetero(C7)cycloalkyl, hetero(C8)cycloalkyl or a hetero(C9)cycloalkyl.

[0059] “Hydroxy” means the radical -OH.

[0060] “IC50” means the molar concentration of an inhibitor that produces50% inhibition of the target enzyme.

[0061] “Imino” means the radical -CR(=NR') and / or -C(=NR')-, wherein R and R' are each independently hydrogen or a further substituent.

[0062] “Isomers” means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a “racemic mixture.” A compound that has more than one chiral center has 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a “diastereomeric mixture.” When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see “Advanced Organic Chemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).

[0063] “Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e. , an atom or group displaceable under reaction (e.g., alkylating) conditions. Examples of leaving groups include, but are not limited to, halo (e.g., F, Cl, Br and I), alkyl (e.g.,methyl and ethyl) and sulfonyloxy (e.g., mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy), thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy, benzyloxy, isopropyloxy, acyloxy, etc.

[0064] “Moiety providing X atom separation” and “linker providing X atom separation” between two other moieties mean that the chain of atoms directly linking the two other moieties is X atoms in length. When X is given as a range (e.g., X1-X2), then the chain of atoms is at least X1 and not more than X2 atoms in length. It is understood that the chain of atoms can be formed from a combination of atoms including, for example, carbon, nitrogen, sulfur and oxygen atoms. Further, each atom can optionally be bound to one or more substituents, as valences allow. In addition, the chain of atoms can form part of a ring. Accordingly, in one embodiment, a moiety providing X atom separation between two other moieties (R and R') can be represented by R-(L)x-R' where each L is independently selected from the group consisting of CR"R”’, NR"", 0, S, CO, CS, C=NR , SO, SO2, etc, where any two or more of R", R'", R"" and R’”” can be taken together to form a substituted or unsubstituted ring.

[0065] “Oxaalkyl” means an alkyl, as defined above, except where one or more of the carbon atoms forming the alkyl chain are replaced with oxygen atoms (-0- or -OR, wherein R is hydrogen or a further substituent). For example, an oxa(C1-10)alkyl refers to a chain comprising between 1 and 10 carbons and one or more oxygen atoms.

[0066] “Oxoalkyl” means an alkyl, as defined above, except where one or more of the carbon atoms forming the alkyl chain are replaced with carbonyl groups (-C(=0)- or -C(=0)-R, wherein R is hydrogen or a further substituent). The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid halide. For example, an oxo(C1-10)alkyl refers to a chain comprising between 1 and 10 carbon atoms and one or more carbonyl groups.

[0067] “Oxy” means the radical -O- or -OR, wherein R is hydrogen or a further substituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxy groups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

[0068] “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

[0069] “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic / organic acids such as with inorganic or organic salts selected from hydrochloride, hydrobromide, hydroiodide, hemisulfate, sulfate, lactate, carbonate, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, decanoate, 2,2-dichloroacetate, digluconate, dodecylsulfate, ethane-1 ,2-disulfonate, ethanesulfonate, formate, phosphate, fumarate, galactarate, gentisate, glucoheptanoate, gluconate, glucuronate, glutamate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane-sulfonate, isobutyrate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, 3-phenylpropionate, phosphate, L-pyroglutamate, pivalate, propionate, salicylate, sebacate, hydrogen sebacate, stearate, succinate, tannate, tartrate, hydrogen tartrate, tosylate, or undecanoate salt.

[0070] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine etc.

[0071] “Prodrug” means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention. The prodrug itself may or may not also have activity with respect to a given target protein. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene- bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, etc. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

[0072] “Protected derivatives” means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0073] “Ring” and “ring assembly” means a carbocyclic or a heterocyclic system and includes aromatic and non-aromatic systems. The system can be monocyclic, bicyclic or polycyclic. In addition, for bicyclic and polycyclic systems, the individual rings comprising the polycyclic ring can be fused, spiro or bridging rings.

[0074] “Subject” and “patient” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc) and non-mammals (e.g., birds, etc).

[0075] “Substituent convertible to hydrogen in vivo” means any group that is convertible to a hydrogen atom by enzymological or chemical means including, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, o- nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl, diphenylphosphinyl, etc. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, etc. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, t- butoxycarbonyl [(CH3)3C-OCO-], benzyloxycarbonyl, p- m ethoxybenzyloxycarbonyl, vinyloxycarbonyl, |3-(p- toluenesulfonyl)ethoxycarbonyl, etc. Examples of suitable amino acid residues include amino acid residues per se and amino acid residues that are protected with a protecting group. Suitable amino acid residues include, but are not limited to, residues of Gly (glycine), Ala (alanine;CH3CH(NH2)CO-), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), lie (isoleucine), Leu (leucine; (Ch3)2CHCH2CH(NH2)CO-), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Vai (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4- hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and |3-Ala. Examples of suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethyloxycarbonyl groups (such as benzyloxycarbonyl and p- nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH3)3C-OCO-], etc. Suitable peptide residues include peptide residues comprising two to five, and optionally two to three, of the aforesaid amino acid residues. Examples of such peptide residues include, but are not limited to, residues of such peptides as Ala-Ala [CH3CH(NH2)CO- NHCH(CH3)C0-], Gly-Phe, Nva- Nva, Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met- Met, Leu-Met and Ala- Leu. The residues of these amino acids or peptides can be present in stereochemical configurations of the D-form, the L-form or mixtures thereof. In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having an asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Vai, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetric carbonatom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Examples of suitable amino acid protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethyloxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t- butoxycarbonyl groups [(CH3)3C-0C0-], etc. Other examples of substituents “convertible to hydrogen in vivo” include reductively eliminable hydrogenolyzable groups. Examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl groups (such as o-toluenesulfonyl); methyl groups substituted with phenyl or benzyloxy (such as benzyl, trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); and halogenoethoxycarbonyl groups (such as p,p,p-trichloroethoxycarbonyl and - iodoethoxycarbonyl).

[0076] “Substituted or unsubstituted” means that a given moiety may consist of only hydrogen substituents through available valences (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valences (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by -CH3. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, (C1- 10)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted. In one particular embodiment, examples of substituents include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1 -10)alkyl, halo(C1 -1 O)alkyl, hydroxy(C1 -10)alkyl, carbonyl(C1- 10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1 -10)alkyl, sulfinyl(C 1 -1 O)alkyl, (C1 -10)azaalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-5)alkyl, hetero(C3- 12)cycloalkyl(C1 -10)al ky I , aryl(C1 -10)alky I, hetero(C1 -10)aryl(C1 -5)alky I , (C9-12)bicycloaryl(C1 -5)alkyl, hetero(C8-12)bicycloaryl(C1 -5)alkyl, (C3- 12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3- 12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl. In addition, the substituent is itself optionally substituted by a further substituent. In one particular embodiment, examples of the further substituent include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1 - 10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1 -10)alkyl, halo(C1- 10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1- 10)alkyl, sulfonyl(C1 -10)alkyl, sulfinyl(C1 -10)alkyl, (C1-10)azaalkyl, imino(C1 -10)alky I, (C3-12)cycloalkyl(Ci_5)alkyl, hetero(C3-12)cycloalkyl(C1 - 10)alkyl, aryl(C1 -10)alkyl, hetero(C1-10)aryl(C1-5)alkyl, (C9- 12)bicycloaryl(C1 -5)alkyl, hetero(C8-12)bicycloaryl(C1 -5)alkyl, (C3- 12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3- 12)bicycloalkyl, (C4_12)aryl, hetero(C1 -10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl. “Sulfinyl” means the radical -SO- and / or -SO-R, wherein R is hydrogen or a further substituent. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.

[0077] “Sulfonyl” means the radical -SO2- and / or -SO2-R, wherein R is hydrogen or a further substituent. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.

[0078] “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

[0079] “Thio” denotes replacement of an oxygen by a sulfur and includes, but is not limited to, -SR, -S- and =S containing groups.

[0080] “Thioalkyl” means an alkyl, as defined above, except where one or more of the carbon atoms forming the alkyl chain are replaced with sulfur atoms (-S- or -S-R, wherein R is hydrogen or a further substituent). For example, a thio(C1 -10)alkyl refers to a chain comprising between I and 10 carbons and one or more sulfur atoms.

[0081] “Thiocarbonyl” means the radical -C(=S)- and / or -C(=S)-R, wherein R is hydrogen or a further substituent. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.

[0082] “Treatment” or “treating” means any administration of a compound of the present invention and includes:

[0083] preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,

[0084] inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and / or symptomatology), or

[0085] ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and / or symptomatology).

[0086] It is noted regarding all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a C1 alkyl indicates that there is one carbon atom but does not indicate what arethe substituents on the carbon atom. Hence, a (C1 )alkyl comprises methyl (i.e. , -CH3) as well as -CRR'R" where R, R', and R" may each independently be hydrogen or a further substituent where the atom attached to the carbon is a heteroatom or cyano. Hence, CF3, CH2OH and CH2CN, for example, are all (C1 )alkyls. Similarly, terms such as alkylamino etc comprise dialkylamino etc.

[0087] A compound having a dashed bond is intended to include the formulae optionally having zero, one or double bonds, as exemplified in the Formula I shown below:

[0088] [Chem. 1 ] Compound of Formula I

[0089] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0090] Therefore, it is a first aspect, the present invention relates to a compound of general formula I or its pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0091] [Chem. 1 ] Compound of Formula Iwherein, dotted line indicates the presence, when applicable, of an aliphatic cyclic ring; n is selected from zero (single bond between 0 or C, i.e., six-member ring) or 1 (seven-member ring);P is absent or selected from hydrogen, CH2, C-alkyl linear or branched chain (C1 -C20), 0, S, NH or N-alkyl linear or branched chain (C1 -C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1- C20), OH, O- or NH-alkyl linear or branched chain (C1-C20) or NH2;B is absent or selected from hydrogen, C-alkyl linear or branched chain (C1-C20), 0, NH, O- or NH-alkyl linear or branched chain (C1-C20) or NH2; Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1-C20), C-alkyl linear or branched chain (C1-C20), OH, F, Cl, Br, I, 0- or NH-alkyl linear or branched chain (C1 -C20) or NH2;M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);K is selected from CH2, CH-alkyl linear or branched chain (C1-C20), 0, NH, N-alkyl linear or branched chain (C1-C20) or S;A is absent or selected from 0, S, NH, CH2, NH- or CH-alkyl chain (C1- C20);D is absent or selected from hydrogen, carbon or sulfur;LT is selected from hydrogen, methyl or fluorine;U is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0-alkyl,-CH20C(0)-alkyl -CH20C(0)N-alkyl; moreover Z or P can, together, form a cycloalkyl ring;X is a linker space selected from these moieties as follow (when applicable)

[0092] [Chem. 1 ] radical moieties iY is absent or it is a heterocyclic aliphatic moiety selected from these groups as follow:

[0093] [Chem. 1 ] radical moieties ii(ii).

[0094] The present invention is also directed to processes and intermediates, which are useful to obtain the compounds of the general formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0095] The compounds of the present invention can be prepared by a process comprising the following general steps: a) reacting a compound of formula II under protecting group reaction that form a product comprising the formula III:Formula II Formula III b) treating the compound of formula III under conditions that form a product comprising the formula IV:Formula IV c) react a compound of formula IV with a compound of formula V under conditions that form a product comprising the formula VI:Formula V Formula VI d) optionally, react the compound of formula VI under mild-basic hydrolysis conditions to form a compound of Formula I:Formula I wherein, dotted line indicates the presence, when applicable, of an aliphatic cyclic ring; n is selected from zero (single bond between O or C, i.e. , six-member ring) or 1 (seven-member ring);P is absent or selected from CH2, C-alkyl linear or branched chain (C1- C20), O, S, NH or N-alkyl linear or branched chain (C1-C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1- C20), O, N-alkyl linear or branched chain (C1-C20) or NH;B is absent or selected from C-alkyl linear or branched chain (C1-C20), 0, NH, O- or NH-alkyl linear or branched chain (C1-C20) or NH2;Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1 - C20), C-alkyl linear or branched chain (C1-C20), OH, F, Cl, Br, I, 0- or NH- alkyl linear or branched chain (C1-C20) or NH2;W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH-alkyl, alkyl being linear or branched chain (C1-C20);V is selected from CH2-CI or CH2-Br;K is selected from CH2, CH-alkyl linear or branched chain (C1 -C20), 0, NH, N-alkyl linear or branched chain (C1-C20) or S;A is absent or selected from 0, S, NH, CH2, NH- or CH-alkyl chain (C1- C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silyl derivatives LT is selected from hydrogen, methyl or fluorine;II is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or -OC(O)NH- alkyl, alkyl being linear or branched chain (C1 -C20);Z is absent or selected from methyl, CH20H, S-Me, -CH2OC(O)O-alkyl, - CH2OC(O)-alkyl -CH2OC(O)N-alkyl; moreover Z or P can, together, form a cycloalkyl ring;D is absent or selected from hydrogen, carbon or sulfur;T is selected from hydrogen, methyl, ethyl, or a C-alkyl linear or branched chain (C1 -C20);E is an “amino-linker space” selected from the following moieties:X is a linker space selected from these moieties as follow (when applicable)Y is absent or it is a heterocyclic aliphatic moiety selected from these groups as follow

[0096] Also provided is a process to obtain the compound of formula XV according to the invention: g) reacting a compound of formula VII with protecting groups under conditions that form a product of formula VIIIFormula VII Formula VIII h) treat the compound of formula VIII under carbon-carbon coupling conditions to form a reactional product of formula IXFormula IX i) react the compound of formula IX with dealkylating reagents under conditions to form a reactional product of formula XFormula X j) reacting the compound of formula X with a compound of formula XI under conditions that form a compound of formula XIIFormula XI Formula XII k) react a compound of formula XII with a compound of formula XIII under conditions that form a reactional product of formula XIVFormula XIII Formula XIVI) optionally react a compound of formula XIV under mild-basic hydrolysis reactions to form a compound of formula XVFormula XV wherein, n is selected from zero (single bond between 0 and C, i.e., six-member ring) and 1 (seven-member ring);A is selected from 0, S, NH, CH2, CH-alkenyl chain (C1-C20);P is absent or selected from CH2, C-alkyl linear or branched chain (C1- C20), O, S, NH or N-alkyl linear or branched chain (C1-C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silyl derivatives. R1 is selected from methyl or ethyl;R2 is selected from C-alkyl linear or branched chain (C1 -C20), OH, 0- or N- alkyl linear or branched chain (C1-C20) and NH2;Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0-alkyl; moreover Z and P can, together, form a cycloalkyl ring;JH is an “amino-linker space” selected from these moieties as followJ is a “linker space” selected from these moieties as followY is a “heterocyclic aliphatic moiety” selected from these groups as follow:

[0097] In a third aspect, the invention is also directed to a pharmaceutical composition comprising at least one compound of formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, and at least one pharmaceutically acceptable excipient. Compounds of the invention may be administered for example, in the crystalline or the amorphous forms, or mixtures thereof.

[0098] In the pharmaceutical composition of the current invention, it is considered a pharmaceutically acceptable excipient or vehicle any composition other than the compound of general Formula I, which has been intentionally added thereto to produce a pharmaceutical dosage formsuitable to a route of administration. Non-limiting examples of pharmaceutical compositions and acceptable excipients suitable for pharmaceutical composition are described in Handbook of Pharmaceutical Manufacturing Formulations - Vol. 1 to 6 - 2004 - Sarfaraz K. Niazi - CRC Press and Remington's Pharmaceutical Sciences, Mack Publishing. A compound of general Formula I may constitute anywhere from 0.001 % to 99% by weight, with a preference for 0.01 % to 90% by weight, depending on the formulation's nature and whether additional dilution is necessary before application.

[0099] Preferably, the composition may be tablets, pills, powders, sachets, suspensions, emulsions, solutions, aerosols (in solid or liquid medium), creams, hard or soft capsules, suppositories, injections, dry powder, solutions and suspensions for inhalation and nasal administration. Non-limiting examples of routes of administration of the composition comprising a compound of general formula I are by oral, parenteral, rectal, transmucosal, transdermal, topical, inhalation or nasal. Preferably, the compositions are formulated for oral, by inhalation, topical, nasal, rectal, or injectable administration.

[0100] Optionally, the pharmaceutical composition comprises from 0.1 to 10,000 mg of a compound of general formula I, preferably 1 to 1 ,000 mg of a compound of general formula I, more preferably 1 to 500 mg of a compound of general formula I.

[0101] As a fourth objective, it is provided a combination for simultaneous, separate or sequential use, comprising at least one compound of formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, and at least one other drug useful for the treatment of a disease comprising cardiovascular, renal and metabolic diseases.

[0102] It is a fifth objective to provide a medicament comprising a compound of formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0103] The present invention is also directed to use of compounds of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof to manufacture a medicament, for the treatment of diseases.

[0104] A seventh aspect of the invention relates to a method for treating diseases, such as cardiovascular and renal diseases, e.g. heart failure, chronic kidney disease, diabetes mellitus, diabetic nephropathy and myocardial infarction, comprising the administration to a patient of a therapeutically effective amount of at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof.

[0105] The present invention is also directed to pharmaceutically acceptable salts of a compound of general formula 1 wherein the salt is selected from the group comprising organic or inorganic salts, preferably selected from hydrochloride, hydrobromide, hydroiodide, hemisulfate, sulfate, lactate, carbonate, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, decanoate, 2,2-dichloroacetate, digluconate, dodecylsulfate, ethane-1 ,2- disulfonate, ethanesulfonate, formate, phosphate, fumarate, galactarate, gentisate, glucoheptanoate, gluconate, glucuronate, glutamate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2- hydroxyethane-sulfonate, isobutyrate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, 3-phenylpropionate, phosphate, L-pyroglutamate, pivalate, propionate, salicylate, sebacate, hydrogen sebacate, stearate, succinate, tannate, tartrate, hydrogen tartrate, tosylate, or undecanoate salt.

[0106] The present invention is also directed to use of compounds of the general formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereoffor treating human diseases, in particular cardiovascular and renal diseases, such as diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy. A compound of general formula I is intended for treating pathological conditions or diseases modulated by the SGLT1 , SGLT2, DPP4 inhibition, or the concomitant inhibition of two or more of these therapeutic targets. Non-limiting examples of the use of the compounds of the invention for the treatment of human diseases include cardiovascular and renal diseases, such as diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy.

[0107] The therapeutic dose to be used with respect to the compounds of the present invention should be planned and calculated according to route of administration chosen, age, weight and condition of the patient and disorder severity. The compounds of the present invention may be administered in therapeutically effective doses ranging from about 0.1 mg to about 10,000 mg per day, preferably 1 mg to about 1 ,000 mg per day, more preferably 1 mg to 500 mg per day. Effective doses may be extrapolated from doseresponse curves obtained from in vitro or animal models. The compounds of the current invention may be administered from 1 to 5 times a day.Preferably, the compounds of the invention will be administered once, twice or three times a day. Typically, the physician will administer the compound to a suitable dose in order to achieve the expected therapeutic effect.

[0108] The present invention also comprises the use of compounds of the general Formula I or any pharmaceutically acceptable salts, crystals,stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof to manufacture a pharmaceutical composition or a medicament, in particular, to manufacture a pharmaceutical composition or a medicament for treating human diseases. A pharmaceutical composition or a medicament containing a compound of general formula I is useful for treating pathological conditions or diseases associated with SGLT 1 , SGLT2, DPP4, or a combination of two or more of them. Non-limiting examples of the use of the pharmaceutical composition or a medicament of the invention for the treatment of human diseases include cardiovascular and renal diseases, such as diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy.

[0109] The present invention is also comprises a method for treating human diseases, in particular cardiovascular and renal diseases, by comprising the administration of a therapeutically effective amount of at least one compound of general Formula I to a patient in need. The present invention is also directed to method for treating cardiovascular and renal diseases, such as diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy, by comprising the administration to a patient of a therapeutically effective amount of at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof. The therapeutic dose to be used with respect to the compounds of the present invention should be planned and calculated according to route of administration chosen, age,weight and condition of the patient and disorder severity. The method of treatment may comprise administering to the patient a compound of the present invention at therapeutically effective doses ranging from about 0.1 mg to about 10,000 mg per day, preferably 1 mg to about 1 ,000 mg per day, more preferably 1 mg to about 500 mg per day. Effective doses may be extrapolated from dose-response curves obtained from in vitro or animal models. The method of treatment may comprise administering compounds of the current invention from 1 to 5 times a day, preferably once, twice or three times a day. Typically, the physician will administer the compound to a suitable dose in order to achieve the expected therapeutic effect.

[0110] The present invention is also directed to a combination for simultaneous, separate or sequential use, either in the same or in separate pharmaceutical compositions, which comprises:

[0111] at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof; and

[0112] one or more agents selected from the list comprising drugs useful for treating cardiovascular, renal, metabolic diseases, diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy.

[0113] In another embodiment, the present invention is also directed to a combination for simultaneous, separate or sequential use, which comprises:

[0114] at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof; and

[0115] one or more agents selected from antidiabetics, antihypertensives, lipid-lowering, anti-atherosclerotic, anti-obesity and / or antiplatelet drugs.

[0116] In another embodiment, the present invention is also directed to a combination comprising i) at least one compound of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof, and ii) one or more agent selected from metformin, glipizide, glyburide, glimepiride, repaglinide, nateglinide, pioglitazone, rosiglitazone, exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, acarbose, miglitol, insulin, lisinopril, enalapril, ramipril, losartan, valsartan, amlodipine, nifedipine, verapamil, diltiazem, atenolol, metoprolol, bisoprolol, carvedilol, propranolol, spironolactone, furosemide, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, ezetimibe, niacin, fenofibrate, gemfibrozil, omega-3 fatty acids, alirocumab, evolocumab, colesevelam, cholestyramine, colestipol, aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole, eptifibatide, tirofiban, abciximab, cilostazol, vorapaxar, orlistat, phentermine, liraglutide, lorcaserin, naltrexone, bupropion, topiramate, semaglutide and sibutramine.EXAMPLESSynthesis of molecules according the present invention Synthesis of Molecule 1General procedure for preparation of compound 21 2

[0117] TMSCI (73.2 g, 673 mmol, 85.5 mL, 6.00 eq) was added a solution of compound 1 (20.0 g, 112 mmol, 1 .00 eq) and NMM (90.8 g, 898 mmol, 98.7 mL, 8.00 eq) in THF (140 mL) at 0~10°C, then the mixture was stirred at 30°C for 16 h. TLC (DCM / MeOH = 3 / 1 , Rf = 1 .00) indicated compound 1 was consumed completely. MTBE (300 mL) was added to the reaction, thenthe mixture was cooled to 0°C, H2O (400 mL), was added dropwise at a rate such that the temperature didn't exceed 10°C, after mixing, the organic layer was separated and washed with water (200 mL), NaH2PO4 (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure (below 30°C) to give a residue. Compound 2 (54 g, crude) was obtained as a light-yellow oil. [M+H] 467.2General procedure for preparation of compound 53 4 5

[0118] n-BuLi (2.50 M, 29.5 mL, 1.20 eq) was added dropwise to a solution of compound 3 (20.0 g, 61 .4 mmol, 1 .00 eq) in THF (40.0 mL) and toluene (160 mL) at -70 ~ -60°C, the reaction turned yellow, and the mixture was stirred at -70 ~ -60°C for 0.5 h. A solution of compound 2 (37.3 g, 79.8 mmol, 1 .30 eq) in toluene (160 mL) was added dropwise to above mixture at -70 ~ -60°C, after stirred at -70°C for 2 h. TLC (Petroleum ether / Ethyl acetate = 20 / 1) indicated -10% of compound 1 was remained, and one major new spot with larger polarity was detected. A solution of MsOH (13.6 g, 141 mmol, 10.1 mL, 2.30 eq) in MeOH (100 mL) was added, then stirred at 25°C for 16 h, the reaction turned pink. TLC (Petroleum ether / Ethyl acetate = 10 / 1 , Rf of product = 0.00) indicated reaction was consumed completely and one major new spot with larger polarity was detected. The reaction was adjusted pH~9 with DIPEA, the mixture turned yellow and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM / MeOH = 80 / 1 ~ 0 / 1 ). LCMS (RT of product = 1 .229 min). Compound 5 (32 g, crude) was obtained as a yellow oil. [M+H] 439.2.General procedure for preparation of compound 75 7

[0119] CSA (1.10 g, 4.76 mmol, 0.25 eq) and compound 6 (5.79 g, 38.1 mmol, 5.73 ml_, 2.00 eq) were added to a solution of compound 5 (16.7 g, 19.0 mmol, 1.00 eq) in dry ACN (100 mL) at 25 °C, then stirred at 25 °C for 24 h under N2, the reaction was light-yellow solution. TLC (DCM / MeOH = 10 / 1 , Rf of 7 = 0.80, Rf of 5 = 0.15) indicated ~10% of compound 5 remained, one major new spot with lower polarity was detected. TEA (0.50 eq, 1.00 g) was added to the reaction and stirred, the reaction was yellow solution, added EtOAc (50 mL) and water (150 mL) and separated, the aqueous layer was extracted with EtOAc (50 mL, 40 mL), the organic layers were washed with brine (50 mL) and dried over Na2SO4, then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 , 2 / 1 ; DCM / MeOH = 20 / 1 , 0 / 1 ). LCMS (RT of 7 = 1.338 min). Compound 7 (7.10 g, 13.5 mmol, 70.8% yield) was obtained as a white solid. [M+H] 527.2.General procedure for preparation of compound 87 8

[0120] A solution of TBSCI (2.40 g, 15.9 mmol, 1 .95 mL, 1 .20 eq) in dry DCM (1.75 mL) and dry DMF (7 mL) was added to a solution of compound 7 (7.00 g, 13.3 mmol, 1.00 eq) and imidazole (3.62 g, 53.1 mmol, 4.00 eq) in dry DMF (30 mL) at 25 °C, then stirred at 50 °C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 7 = 0.10, Rf of 8 = 1.00 (PMA)) indicated complete conversion. The reaction was cooled to 25 °C, added water (250 mL), extracted with EtOAc (100 mL, 50 mL, 50 mL), the organic layers were washed with brine (80 mL) and dried over Na2SO4,concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 , 40 / 1 (product), 2 / 1 ). Compound 8 (6.00 g, 9.36 mmol, 70.4% yield) was obtained as a white solid. [M+H] 641 .3.General procedure for preparation of compound 98 9

[0121] AC2O (1.91 g, 18.7 mmol, 1.75 mL, 2.00 eq) was added to a solution of compound 8 (6.00 g, 9.36 mmol, 1 .00 eq) and DMAP (343 mg, 2.81 mmol, 0.30 eq) in Py (30 mL) at 0~15 °C, then warmed to 25 °C and stirred for 20 h under N2. TLC (Petroleum ether / Ethyl acetate = 10 / 1 , Rf of 8 = 0.40, Rf of 9 = 0.45 (PMA)) indicated complete conversion. Added water (250 mL) at 0~15 °C, extracted with EtOAc (60 mL, 40 mL, 30 mL), the organic layers were washed with brine (60 mL) and dried over Na2SC>4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 , 40 / 1 (product), 2 / 1 ). Compound 9 (5.40 g, 7.90 mmol, 84.5% yield) was obtained as a white solid. [M+H] 683.3.General procedure for preparation of compound 109 10

[0122] HF-Py (30.5 g, 215 mmol, 27.7 mL, 70.0% purity, 30.0 eq) was added dropwise to a solution of compound 9 (4.90 g, 7.17 mmol, 1 .00 eq) and dried Py (28.4 g, 359 mmol, 28.9 mL, 50.0 eq) in dried DCM (49 mL) at 0~15 °C, then warmed to 25 °C and stirred for 20 h under N2. TLC (Petroleum ether / Ethyl acetate = 10 / 1 , Rf of 9 = 0.43, Rf of 10 = 0.00 (PMA)) indicated complete conversion. The reaction was poured into ice water (200mL), and extracted with DCM (80 mL, 50 mL, 30 ml_), the organic layers were washed with brine (50 mL) and dried over Na2SCU, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 10 / 1~0 / 1 ). Compound 10 (4.20 g, crude) was obtained as a white solid. [M+H] 569.2.General procedure for preparation of compound 1210 12

[0123] Compound 11 (1 .74 g, 9.75 mmol, 1 .50 eq) was added to a solution of compound 10 (3.70 g, 6.50 mmol, 1.00 eq) and DMAP (1.19 g, 9.75 mmol, 1 .50 eq) in dry ACN (37 mL) at 25 °C, then the reaction was stirred at 70 °C (outside temperature) (inter temperature: 60 °C) for 19 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 10 = 0.31 , Rf of 12 = 0.24 (PMA)) and LCMS (RT of 12 = 1.419 min) indicated complete conversion. The reaction was poured into water (80 mL), extracted with EtOAc (50 mL, 40 mL, 30 mL), the organic layers were washed with brine (50 mL), dried over Na2SCU, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 ~ 0 / 1 ).Compound 12 (4.10 g, crude) was obtained as a white solid. [M+H] 679.2.General procedure for preparation of compound 1312 13

[0124] AIBN (919 mg, 5.60 mmol, 1 .00 eq) was added to a solution of compound 12 (3.80 g, 5.60 mmol, 1.00 eq) in toluene (38 mL), the added (n- Bu)sSnH (3.26 g, 11 .2 mmol, 2.96 mL, 2.00 eq) and stirred at 130 °C for 1 h under N2. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of 12 = 0.43, Rf of 13 = 0.80 (PMA)) indicated the reaction was consumed completely. The reaction was cooled to 25°C, added water (150 mL), extracted with EtOAc (40 mL, 30 mL, 20 mL), the organic layers were washed with brine (40 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2 / K2COs powder = 9 / 1 , Petroleum ether / Ethyl acetate = 1 / 0, 30 / 1 (product), 20 / 1 , 0 / 1 ).

[0125] Compound 13 (1.90 g, 3.44 mmol, 61.4% yield) was obtained as a white solid. [M+H] 553.2.General procedure for preparation of compound 1413 14

[0126] A solution of compound 13 (1.90 g, 3.44 mmol, 1.00 eq) in MeOH (12 mL) and THF (12 mL) was stirred at 25 °C, followed by addition of CSA (399 mg, 1.72 mmol, 0.50 eq) and H2O (619 mg, 34.4 mmol, 619 uL, 10.0 eq), then stirred at 25 °C for 20 h. TLC (Petroleum ether / Ethyl acetate = 5 / 1 , Rf of 13 = 0.50, Rf of 14 = 0.00 (PMA)) indicated complete conversion.Added EtOAc (50 mL) and water (100 mL) and separated, the aqueous layer was extracted with EtOAc (30 mL, 30 mL), the organic layers were washed with brine (40 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. LCMS (RT of 14 = 1.175 min) indicated desired MS. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 , 3 / 1 , 2 / 1 (product), 1 / 1 , 0 / 1 ). Compound 14 (1.20 g, 2.58 mmol, 75.1 % yield) was obtained as a white solid. [M+H] 465.2.General procedure for preparation of compound 1514 15

[0127] H2O (50.4 mg, 2.80 mmol, 50.4 uL, 1 .00 eq) was added to a solution of compound 14 (1 .30 g, 2.80 mmol, 1 .00 eq) in ACN (9.1 mL), then added EtsSiH (1 .04 g, 8.95 mmol, 1.43 mL, 3.20 eq) and BFs-Et20 (952 mg, 6.71 mmol, 828 uL, 2.40 eq) at 0~15 °C under N2, then stirred at 25 °C for 16 h under N2. LCMS (RT of 15 = 1.244 min) indicated complete conversion. The reaction was quenched with saturated NaHCOs (50 mL) in ice bath, extracted with EtOAc (30 mL, 20 mL, 20 mL), the layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 15 (1.40 g, crude) was obtained as a light-yellow oil. [M+H] 435.1.General procedure for preparation of compound 1615 16

[0128] AC2O (1.64 g, 16.1 mmol, 1.51 mL, 5.00 eq) was added to a solution of compound 15 (1 .40 g, 3.22 mmol, 1 .00 eq) and DMAP (118 mg, 966 umol, 0.30 eq) in Py (14 mL) at 0~15 °C, then warmed to 25 °C and stirred for 16 h. TLC (Petroleum ether / Ethyl acetate = 1 / 2, Rf of 15 = 0.40, Rf of 16 = 0.90 (PMA)) indicated complete conversion. Added water (80 mL) at 0~15 °C, extracted with EtOAc (50 mL, 40 mL), the organic layers were washed with brine (40 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 , 8 / 1 (product), 0 / 1 ). Compound 16 (1.20 g, 2.31 mmol, 71.8% yield) was obtained as a light-yellow oil. [M+H] 519.2.General procedure for preparation of Molecule 116 Molecule 1

[0129] Compound 16 (100 mg, 193 umol, 1 .00 eq) was dissolved in MeOH (1 mL), then NaOMe (6.94 mg, 38.5 umol, 30.0% purity, 0.20 eq) was added and stirred at 25 °C for 1.5 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of Molecule 1 = 0.00, Rf of 16 = 0.50) and LCMS (RT of Molecule 1 = 1.1 6 min) indicated the reaction was consumed completely and desired MS. AcOH was added to the reaction and adjust pH ~ 6, then concentrated under reduced pressure to give a residue at 45 °C. HPLC (RT of product = 1.961 min). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-55%,10 min). HPLC (RT of product = 1.971 min). Molecule 1 (35.0 mg, 84.6 umol, 43.9% yield, 95.0% purity) was obtained as a white solid. [M+H] = 410.2 / 375.1Synthesis of Molecule 2General procedure for preparation of compound 175 17

[0130] AC2O (39.4 g, 386 mmol, 36.2 mL, 5.30 eq) was added a solution of DIPEA (52.8 g, 408 mmol, 71 .1 mL, 5.60 eq), DMAP (891 mg, 7.29 mmol, 0.10 eq) and compound 5 (32.0 g, 72.9 mmol, 1 .00 eq) in toluene (160 mL) at 0~10°C, the reaction turned black and stirred at 25°C for 16 h. TLC (DCM / MeOH = 10 / 1 , Rf of product = 1 .00) indicated compound 5 was consumed completely. The reaction was added H2O (600 mL) at 5~10°C, extracted with EtOAc (250 mL, 200 mL, 100 mL), the organic layers were washed with brine (400 mL x 2) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SO2, Petroleum ether / Ethyl acetate = 10 / 1 ~ 0 / 1). HPLC(RT of product = 4.083 min). Compound 17 (14.2 g, 23.4 mmol, 32.1 % yield) was obtained as a yellow solid. [M+H] 607.2.General procedure for preparation of compound 1817 18

[0131] H2O (214 mg, 11.9 mmol, 214 uL, 1.00 eq) added a solution of compound 17 (7.20 g, 11.9 mmol, 1.00 eq) in ACN (50 mL), then added EtsSiH (4.41 g, 37.9 mmol, 6.06 mL, 3.20 eq) and BF3.Et2O (4.04 g, 28.5 mmol, 3.51 mL, 2.40 eq) at 0~10°C under N2, stirred at 30°C for 5.5 h. Added EtsSiH (2.21 g) and BF3.Et2O (2.02 g) at 0-10°C under N2, stirred at 30°C for 16 h. HPLC (RT of product = 3.944 min) indicated compound 17 was consumed completely. The reaction was quenched with saturated NaHCOs (150 mL), extracted with EtOAc (50 mL x 3), the layers were washed with brine (80 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10 / 1 (80 mL, 10 V) at 25°C for 2 h.Compound 18 (5.80 g, 10.1 mmol, 84.7% yield) was obtained as a white solid. [M+H] 577.2.General procedure for preparation of compound 1918 19

[0132] A solution of BBr3 (34.4 g, 137 mmol, 13.2 mL, 8.00 eq) in dried DCM (137 mL) was add dropwise to a solution of compound 18 (9.90 g, 17.2 mmol, 1 .00 eq) in dried DCM (99.0 mL) at -70°C, then stirred at -70°C for 1 .5 h and -30°C for 3 h. Added a solution of BBr3 (17.2 g) in (50 mL) at -70°C, then stirred at -30°C for 2 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.20) indicated -10% of compound 18 remained, and one majornew spot with larger polarity was detected. The reaction was poured into ice and neutralized with sat.NaHC03 (400 mL) and solid NaHCO3 in ice-bath, separated and the aqueous layer was extracted with DCM (200 mL, 100 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether / Ethyl acetate = 5 / 1 (90 mL, 10 V) at 25 oC for 0.5 h. HPLC (RT of product = 3.390 min) and LCMS (RT of product = 1.388 min) indicated desired compound.Compound 19 (8.80 g, 16.0 mmol, 93.4% yield) was obtained as a white solid. [M+H] 549.1.General procedure for preparation of compound 2119 21

[0133] PPhs (239 mg, 911 umol, 2.50 eq) was added to a solution of compound 19 (200 mg, 364 umol, 1.00 eq) and compound 20 (185 mg, 911 umol, 2.50 eq) in THF (1 .40 mL) under N2, DIAD (184 mg, 911 umol, 177 uL, 2.50 eq) was added to above solution, the mixture was stirred at 25°C for 20 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of product = 0.65) indicated ~10% compound 19 remained, HPLC (RT of compound 21 = 4.452 min) indicated ~4% compound 19 remained. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 5 / 1 , 3 / 1 , 0 / 1 ). LCMS (RT of compound 21 = 2.999 min) indicated desired MS. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1 ). Compound 21 (240 mg, crude) was obtained as a white solid. [M+H] 734.3.General procedure for preparation of compound 2221 22

[0134] TFA (370 mg, 3.24 mmol, 240 uL, 9.92 eq) was added a solution of compound 21 (240 mg, 327 umol, 1 .00 eq) in DCM (2.40 mL), then stirred at 25°C for 1 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.00) indicated compound 21 was consumed completely. LCMS (RT of compound 22 = 1 .423 min) and HPLC (RT of compound 22 = 2.929 min) indicated the desired compound. The reaction was concentrated under reduced pressure to give a residue. ACN was added to remove TFA under reduced pressure. The crude product compound 22 (270 mg crude, TFA) was obtained as a pink oil and used into the next step without further purification. [M+H] 634.2.General procedure for preparation of compound 2422 24

[0135] A solution of compound 23 (50.8 mg, 294 umol, 1.10 eq) in DMF (1 .00 mL) was added dropwise to a solution of compound 22 (200 mg, 267 umol, 1 .00 eq, TFA), K2CO3 (111 mg, 802 umol, 3.00 eq) powder and Nal (16.0 mg, 107 umol, 0.40 eq) in DMF (1.00 mL) under N2, then stirred at 25°C for 20 h. TLC (DCM / MeOH = 20 / 1 , Rf of product = 0.20) indicated compound 22 was consumed completely. LCMS (RT of product = 1.431 min) and HPLC (RT of product = 3.307 min) indicated desired compound. H2O (10 mL) was added to the mixture, extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product compound 24 (230 mg, crude) was obtained as yellow oil and used into the next step without further purification. [M+H] 770.3.General procedure for preparation of Molecule 224 Molecule 2

[0136] Compound 24 (230 mg, 298 umol, 1 .00 eq) was dissolved in NH3 / MeOH (7.00 M, 2.30 mL, 53.9 eq), then stirred at 25°C for 5 h. LCMS (RT of product = 1.212 min) indicated compound 24 was consumed completely. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 3) to remove NHs under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (0.04%NH3H20+10mM NH4HCO3)- ACN]; B%: 28%-48%, 10.5 min). Molecule 2 (30.0 mg, 49.3 umol, 16.5% yield, 98.9% purity) was obtained as a white solid. [M+H] 602.3.Synthesis of Molecule 3General procedure for preparation of 2619 26

[0137] PPhs (203 mg, 774 umol, 2.50 eq) and compound 19 (170 mg, 310 umol, 1.00 eq) and compound 25 (168 mg, 774 umol, 2.50 eq) were switched with toluene (3.00 mL x 5) under reduced pressure, then dissolved in redistilled THF (1.20 mL) under N2, DIAD (157 mg, 774 umol, 151 uL, 2.50 eq) was added to above solution at 0~5°C, the reaction was turning yellow, then stirred at 25°C for 20 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf Of product = 0.60) indicated compound 19 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 7 / 1 , 5 / 1 , 3.5 / 1 , 0 / 1 ). The residue was purified by prep- TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). Compound 26 (168 mg, 224 umol, 72.5% yield) was obtained as a white solid. [M+H] 748.3.General procedure for preparation of compound 2726 27

[0138] TFA (231 mg, 2.03 mmol, 0.15 mL, 10.2 eq) was added a solution of compound 26 (148 mg, 198 umol, 1.00 eq) in DCM (1.50 mL), then stirred at 30°C for 2 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.00) indicated compound 26 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. ACN (3.00 mL x 5) was added to remove TFA under reduced pressure. The crude product compound 27 (150 mg, crude, TFA) was used into the next step without further purification and obtained as a pink oil. [M+H] 648.2.General procedure for preparation of compound 2827 28

[0139] A solution of compound 23 (33.9 mg, 197 umol, 1 .00 eq) in DMF (0.50 mL) was added a solution of compound 27 (150 mg, 197 umol, 1 .00 eq, TFA) and K2CO3 (81.6 mg, 590 umol, 3.00 eq) powder, Nal (2.95 mg, 19.7 umol, 0.10 eq) in DMF (1 .00 mL) at 0~5°C, warming to 25°C and stirred at 25°C for 24 h. LCMS (RT of product = 2.667 min) indicated ~14% of compound 15 remained. H2O (15 mL) was added to the mixture, extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SCU, filtered, and concentrated under reduced pressure to give a residue. The crude product compound 28 (120 mg, crude) was used into the next step without further purification and obtained as a yellow oil. [M+H] 784.3.General procedure for preparation of Molecule 328 Molecule 3

[0140] Compound 28 (120 mg, 153 umol, 1 .00 eq) was dissolved in NHs / MeOH (7.00 M, 3.00 mL, 137 eq), then sealed and stirred at 25°C for 6 h. LCMS (RT of product = 2.008 min) indicated compound 28 was consumed completely and desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 3) to remove NHs under reduced pressure at 25°C. HPLC (RT of product = 2.294 min) and LCMS (RT of product = 1.227 min). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 20%-40%,12min). Molecule 3 (18.0 mg, 29.2 umol, 19.1% yield, 100% purity) was obtained as a white solid. [M+H] 616.3.Synthesis of Molecule 4General procedure for preparation of compound 3019 30

[0141] PPhs (239 mg, 911 umol, 2.50 eq) and compound 19 (200 mg, 364 umol, 1 .00 eq) and compound 29 (147 mg, 911 umol, 141 uL, 2.50 eq) were switched with toluene (4.00 mL x 5) under reduced pressure, then dissolved in redistilled THF (1 mL) under N2, DIAD (184 mg, 911 umol, 177 uL, 2.50 eq) was added to above solution at 0~5°C, the reaction was turning yellow, then stirred at 25°C for 20 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.60) indicated -10% compound 19 remained. HPLC (RT of product = 3.968 min) indicated -10% compound 19 remained. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 6 / 1 , 5 / 1 , 3.5 / 1 , 0 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). Compound 30 (200 mg, 289 umol, 79.3% yield) was obtained as a white solid. [M+H] 692.2.General procedure for preparation of compound 3130 31

[0142] TFA (308 mg, 2.70 mmol, 0.20 mL, 9.35 eq) was added to a solution of compound 30 (200 mg, 289 umol, 1 .00 eq) in DCM (2.00 mL), then stirred at 25°C for 1 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.00) indicated compound 30 was consumed completely. HPLC (RT of product = 2.790 min). The reaction was concentrated under reduced pressure to give a residue. The crude product compound 31 (250 mg, crude, TFA) was obtained as pink oil and used into the next step without further purification. [M+H] 592.2.General procedure for preparation of compound 1931 32

[0143] Compound 23 (67.2 mg, 389 umol, 1 .10 eq) in DMF (1 .00 mL) was added dropwise to a solution of compound 31 (250 mg, 354 umol, 1 .00 eq, TFA), K2CO3 (147 mg, 1 .06 mmol, 3.00 eq) powder and Nal (21 .2 mg, 141 .6 umol, 0.40 eq) in DMF (1 .50 mL) under N2, then stirred at 25°C for 16 h.TLC (DCM / MeOH = 20 / 1 , Rf of product = 0.34) indicated ~10% compound 31 remained, two major new spot with lower polarities were detected. HPLC indicated the desired compound. H2O (10 mL) was added to the mixture, extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 , 80 / 1 , 50 / 1 , 20 / 1 , 0 / 1 ).Compound 32 (80.0 mg, 110 umol, 31 .0% yield) was obtained as a yellow oil. [M+H] 728.3.General procedure for preparation of Molecule 432 Molecule 4

[0144] Compound 32 (80.0 mg, 110 umol, 1 .00 eq) was dissolved in NHs / MeOH (7.00 M, 800 uL, 50.9 eq), then sealed and stirred at 25°C for 6 h. HPLC (RT of product =1.880 min) and LCMS (RT of product =1.135 min) indicated compound 32 was consumed completely. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 5) to remove NH3 under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water(0.04%NH3-H20+10mM NH4HCO3)-ACN];B%: 17%-47%, 10.5min). Molecule 4 (12.0 mg, 20.5 umol, 18.7% yield, 95.8% purity) was obtained as a white solid. [M+H] 560.2.Synthesis of Molecule 5General procedure for preparation of compound 3419 34

[0145] PPhs (203 mg, 774 umol, 2.50 eq) and compound 19 (170 mg, 310 umol, 1.00 eq) and compound 33 (147 mg, 774 umol, 2.50 eq) were switched with toluene (3.00 mL x 5) under reduced pressure, then dissolved in redistilled THF (1.20 mL) under N2, DIAD (157 mg, 774 umol, 151 uL, 2.50 eq) was added to above solution at 0~5°C, the reaction was turning yellow, then stirred at 25°C for 20 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.53) indicated ~10% of compound 19 remained. The reaction was concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiC>2 , Petroleum ether / Ethyl acetate = 7 / 1 , 5 / 1 , 3.5 / 1 , 0 / 1 ). The residue was purified by prep- TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). Compound 34 (190 mg, crude) was obtained as a white solid. [M+H] 720.3General procedure for preparation of compound 3534 35

[0146] TFA (262 mg, 2.30 mmol, 0.17 mL, 9.73 eq) was added to a solution of compound 34 (170 mg, 236 umol, 1 .00 eq) in DCM (1 .70 mL), then stirred at 30°C for 2 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.00) indicated compound 34 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. ACN (3 mL x 5) was added to removed TFA under reduced pressure. The crude product compound 35 (170 mg, crude, TFA) was used into the next step without further purification and obtained as a pink oil. [M+H] 620.2.General procedure for preparation of compound 36

[0147] A solution of compound 23 (37.6 mg, 218 umol, 1.00 eq) in DMF (0.60 mL) was added to a solution of compound 35 (160 mg, 218 umol, 1.00 eq, TFA), K2CO3 (90.4 mg, 654 umol, 3.00 eq) powder and Nal (3.27 mg, 21 .8 umol, 0.1 eq) in DMF (1 .00 mL) at 0~5°C, then warming to 25°C for 9 h. LCMS (RT of product = 2.549 min) indicated desired MS. H2O (15 mL) was added to the mixture, extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. The crudeproduct compound 36 (190 mg, crude) was used into the next step without further purification and obtained as a yellow oil. [M+H] 756.3.General procedure for preparation of Molecule 536 Molecule 5

[0148] Compound 36 (150 mg, 198 umol, 1 .00 eq) was dissolved in NHs / MeOH (7.00 M, 3.00 mL, 106 eq) was added, then stirred at 25°C for 3 h. LCMS (RT of product = 1.172 min) showed desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 3) to remove NH3 under reduced pressure at 25°C. LCMS (RT of product = 1.829 min) and HPLC (RT of product = 2.059 min). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-35%, 12min). LCMS (RT of product = 1.168 min) and HPLC (RT of product = 2.051 min). Molecule 5 (13.6 mg, 22.4 umol, 11 .3% yield, 96.8% purity) was obtained as a white solid. [M+H] = 588.2.Synthesis of Molecule 6General procedure for preparation of compound 3837 38

[0149] TosCI (834 mg, 4.37 mmol, 2.20 eq) was added to a solution of compound 37 (0.40 g, 1.99 mmol, 1.00 eq) in Py (2.80 mL) at 5~10°C, then stirred at 25°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.70) indicated compound 37 was consumed completely. The reaction was added to H2O (30 mL) at 25°C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed with brine (20 mL) and dried over NazSCk, filtered and concentrated under reduced pressure to give a residue. ACN (15 mL x 3) was added to removed Py under reducedpressure at 45°C. Compound 38 (360 mg, 1.01 mmol, 50.9% yield) was obtained as a light-yellow oil. [M+H] 356.1.General procedure for preparation of compound 3919 39

[0150] CS2CO3 (300 mg, 922 umol, 2.30 eq) was added to a solution of compound 19 (220 mg, 401 umol, 1.00 eq) and compound 38 (285 mg, 802 umol, 2 eq) in DMF (1.50 mL), the mixture was stirred at 86°C for 16 h.LCMS (RT of product = 2.539 min) indicated ~30% of compound 19 was remained and desired MS. The reaction was added to H2O (30 mL) at 25°C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 39 (400 mg, crude) was obtained as a yellow oil. [M+H] 648.2.General procedure for preparation of compound 4039 40

[0151] A solution of compound 39 (400 mg, 617 umol, 1 .00 eq) in NHs / MeOH (7.00 M, 8.00 mL, 90.7 eq) was stirred at 25°C for 4 h. TLC (DCM / MeOH = 10 / 1 , Rfof product = 0.24) and LCMS (RT of product = 1.318 min) indicated compound 39 was consumed completely. The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NH3 under reduced pressure at 30°C. The residue was purified by column chromatography (SiO2, DCM / MeOH = 50 / 1 , 40 / 1 , 30 / 1 ). LCMS (RT of product = 1.319 min) indicated desired MS. Compound 40 (170 mg, 301 umol, 48.8% yield) was obtained as a white solid. [M+H] 564.2.General procedure for preparation of compound 4140 41

[0152] TFA (308 mg, 2.70 mmol, 0.20 mL, 9.52 eq) was added a solution of compound 40 (160 mg, 284 umol, 1 .00 eq) in DCM (2.00 mL), then stirred at 25°C for 1 .5 h. TLC (DCM / MeOH = 10 / 1 , Rfof product = 0.10) indicated compound 40 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. ACN (5 mL x 3) was added to remove TFA under reduced pressure. LCMS (RT of product = 1 .130 min). Compound 41 (240 mg, crude, TFA) was obtained as a pink oil. [M+H] 464.2.General procedure for preparation of Molecule 641 Molecule 6

[0153] Compound 23 (25.4 mg, 147 umol, 0.50 eq) was added to a solution of compound 41 (170 mg, 294 umol, 1.00 eq, TFA), Nal (4.41 mg, 29.4 umol, 0.10 eq) and K2CO3 (122 mg, 882 umol, 3.00 eq) in DMF (1.00 mL), then stirred at 25°C for 2.5 h. LCMS (RT of product = 1.187 min) and HPLC (RT of product = 2.107 min) indicated desired MS. The reaction was filtered, and filtrate was used to purification. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-40%, 20 min). HPLC (ET20981-128-P1 J1 , RT of product = 2.088 min). Molecule 6 (14.1 mg, 22.9 umol, 7.78% yield, 97.4% purity) was obtained as a white solid. [M+H] = 600.2.Synthesis of Molecule 7General procedure for preparation of compound 4342 43

[0154] TosCI (417 mg, 2.19 mmol, 2.20 eq) was added a solution of compound 42 (200 mg, 994 umol, 1.00 eq) in Py (1.40 mL) at 5~10°C, then the reaction was stirred at 15°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 42 = 0.10, Rf of product = 0.50 (Ninhydrin)) indicated compound 42 was consumed completely. The reaction was added to H2O (20 mL) at 15°C, and extracted with EtOAc (15 mL, 10 mL, 8 mL), the organic layers were washed with HCI (0.5 N, 15 mL) and brine (15 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 43 (320 mg, 900 umol, 90.6% yield) was obtained as a light-yellow solid. [M+H] 356.1.General procedure for preparation of compound 7-119 44

[0155] Compound 43 (405 mg, 1.14 mmol, 2.50 eq) was added to a solution of compound 19 (250 mg, 455 umol, 1.00 eq) and CS2CO3 (341 mg, 1.05 mmol, 2.30 eq) in DMF (2.50 mL), then stirred at 85°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of product = 0.24, Rf of product = 0.43 (PMA)) indicated compound 19 was consumed completely. The two reactions were added to H2O (40 mL) at 15°C, and extracted with EtOAc (25 mL, 20 mL, 15 mL), the organic layers were washed with brine (20 mL) and dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2 , Petroleum ether / Ethyl acetate = 4 / 1 , 3 / 1 ). Compound 44 (310 mg, 423 umol, 92.9% yield) was obtained as a white solid. [M+H] 732.3.General procedure for preparation of compound 4544 45

[0156] TFA (462 mg, 4.05 mmol, 0.30 mL, 9.57 eq) was added a solution of compound 44 (310 mg, 423 umol, 1 .00 eq) in DCM (3.00 mL) at 15°C, then stirred at 15°C for 3 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of product = 0.00, Rf of reactant 1 = 0.24) indicated compound 44 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 6 / 1 ). Compound 45 (290 mg, 389 umol, 91 .8% yield, TFA) was obtained as a white solid. [M+H] 632.2.General procedure for preparation of compound 7-345 46

[0157] Compound 23 (64.8 mg, 375 umol, 1 .00 eq) was added a solution of compound 45 (280 mg, 375 umol, 1.00 eq, TFA), K2CO3 (156 mg, 1.13 mmol, 3.00 eq) powder and Nal (22.5 mg, 150 umol, 0.40 eq) in DMF (3.00 mL) at 15°C, then stirred at 15°C for 16 h. TLC (DCM / MeOH = 10 / 1 , Rf of reactant 1 = 0.10, Rf of product = 0.50 (PMA)) indicated ~20% compound 45 remained, LCMS (RT of reactant 1 = 2.474 min, RT of product = 2.527 min) indicated desired MS. H2O (30 mL) was added to the mixture, extracted with EtOAc (20 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 46 (280 mg, crude) was obtained as a light-yellow oil. [M+H] 768.3.General procedure for preparation of Molecule 746 Molecule 7

[0158] A solution of compound 46 (280 mg, 364 umol, 1 .00 eq) in NH3 / MeOH (7 M, 6.00 mL, 115 eq) was stirred at 15°C for 5 h. LCMS (RT of product = 1.165 min) indicated the reaction was consumed completely. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20% - 40%, 20 min). Molecule 7 (25.0 mg, 41.2 umol, 11 .3% yield, 98.9% purity) was obtained as a white solid. [M+H] = 600.2Synthesis of Molecule 8

[0159] Molecule 8 was prepared according to the procedure used for the synthesis of Molecule 7, thus the description of the reaction conditions will be summarized for this example.General procedure for preparation of compound 4847 48

[0160] TosCI (417 mg, 2.19 mmol, 2.20 eq) was added to a solution of compound 47 (200 mg, 994 umol, 1.00 eq) in Py (1.40 mL) at 5-10°C. Then the reaction was stirred at 15°C for 16 h. Compound 48 (330 mg, crude) was obtained as a light-yellow solid. [M+H] 356.1.General procedure for preparation of compound 4919 49

[0161] Compound 48 (405 mg, 1.14 mmol, 2.50 eq), CS2CO3 (341 mg, 1 .05 mmol, 2.30 eq) and compound 19 (250 mg, 455 umol, 1 .00 eq), DMF (1 ,7o mL), compound 49 (280 mg, crude) was obtained as a white solid. [M+H] 732.3.General procedure for preparation of compound 5049 50

[0162] TFA (462 mg, 4.05 mmol, 0.30 mL, 10.6 eq), compound 49 (280 mg, 382 umol, 1.00 eq), DCM (3.00 mL), compound 50 (190 mg, 255umol, 66.5% yield, TFA) was obtained as a white solid. [M+H] 632.2.General procedure for preparation of compound 5150 51

[0163] Compound 23 (41 .6 mg, 241 umol, 1 .00 eq), compound 50 (180 mg, 241 umol, 1.00 eq, TFA) and K2CO3 (100 mg, 724 umol, 3.00 eq) powder, Nal (14.5 mg, 96.5 umol, 0.40 eq), DMF (2.00 mL), compound 51 (180 mg, crude) was obtained as a light-yellow oil. [M+H] 768.3.General procedure for preparation of Molecule 851 Molecule 8

[0164] Compound 51 (180 mg, 234 umol, 1 .00 eq), NH3 / MeOH (7.00 M, 4.00 mL, 119 eq). Molecule 8 (20.0 mg, 32.9 umol, 14.1 % yield, 99.0% purity) was obtained as a white solid. [M+H] = 600.2Synthesis of Molecule 9General procedure for preparation of compound 5319 53

[0165] Compound 19 (250 mg, 455 umol, 1.00 eq), compound 52 (229 mg, 1.1 mmol, 2.50 eq) and PPhs (298 mg, 1.14 mmol, 2.50 eq) were switched with fresh THF (5.00 mL x 4) under reduced pressure, then dissolved in THF (1 .75 mL) and cooled to 0~10°C, DIAD (1 .90 M, 599 uL, 2.50 eq) (1 .9 mol / L in toluene) was added, then stirred at 15°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.35, Rf of compound 19 = 0.24 (UV 254 nm and PMA)) indicated compound 19 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 5 / 1 , 4 / 1 , 3 / 1 , 0 / 1 ). Compound 53 (300 mg, 409 umol, 89.9% yield) was obtained as a white solid. [M+H] 732.3.General procedure for preparation of compound 5453 54

[0166] TFA (616 mg, 5.40 mmol, 0.40 mL, 13.2 eq) was added a solution of compound 53 (300 mg, 409 umol, 1 .00 eq) in DCM (3.00 mL) at 15°C, then stirred at 15°C for 1 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.00, Rf of compound 53 = 0.70 (PMA)) indicated compound 53 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate= 2 / 1 , DCM / MeOH = 10 / 1). Compound 54 (290 mg, 388 umol, 94.8% yield, TFA) was obtained as a light-yellow solid. [M+H] 632.2.General procedure for preparation of compound 5554 55

[0167] Compound 23 (62.5 mg, 361.9 umol, 1.00 eq) was added a solution of compound 54 (270 mg, 361.9 umol, 1.00 eq, TFA), K2CO3 (150 mg, 1 .09 mmol, 3.00 eq) powder and Nal (21.7 mg, 145 umol, 0.40 eq) in DMF (2.70 mL) at 15°C, then stirred at 15°C for 16 h. TLC (DCM / MeOH = 10 / 1 , Rf of reactant 1 = 0.10, Rf of product = 0.50 (PMA)) indicated -10% of compound 54 remained, LCMS (RT of product = 1.376 min) indicated desired MS. H2O (30 mL) was added to the mixture, extracted with EtOAc (20 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 55 (270 mg, crude) was obtained as a white solid. [M+H] 768.3.General procedure for preparation of Molecule 955 Molecule 9

[0168] A solution of compound 55 (270 mg, 351 umol, 1 .00 eq) in NH3 / MeOH (7.00 M, 4.00 mL, 79.7 eq) was stirred at 15°C for 4.5 h. LCMS (RT of product = 1.860 min) indicated desired MS. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 28%-48%,10.5 min). Molecule 9 (18.6 mg, 30.8 umol, 8.75% yield, 99.2% purity) was obtained as a white solid. [M+H] = 600.2.Synthesis of Molecule 10

[0169] Molecule 10 was prepared according to the procedure used for the synthesis of Molecule 9.General procedure for preparation of compound 5719 57

[0170] Compound 19 (200 mg, 364 umol, 1 .00 eq), compound 56 (183 mg, 911 umol, 2.50 eq) and PPhs (239mg, 911 umol, 2.50 eq), THF (1 .40 mL), DIAD (1 .90 M, 479 uL, 2.50 eq) (1 .9 mol / L in toluene), compound 57 (260 mg, crude) was obtained as a white solid. [M+H] 732.3.General procedure for preparation of compound 5857 58

[0171] TFA (616 mg, 5.40 mmol, 0.40 mL, 15.2 eq), compound 57 (260 mg, 355 umol, 1.00 eq), DCM (3.00 mL), compound 58 (250 mg, 335umol, 94.3% yield, TFA) was obtained as a light-yellow solid. [M+H] 632.2.General procedure for preparation of compound 5958 59

[0172] Compound 23 (53.2 mg, 308 umol, 1.00 eq), compound 58 (230 mg, 308 umol, 1.00 eq, TFA), K2CO3 (128 mg, 925 umol, 3.00 eq) powder and Nal (18.5 mg, 123 umol, 0.40 eq), DMF (2.3 mL), compound 59 (220 mg, crude) was obtained as a white solid. [M+H] 768.3.General procedure for preparation of Molecule 1059 Molecule 10

[0173] Compound 59 (220 mg, 286 umol, 1 .00 eq), NHs / MeOH (7.00 M, 3.00 mL, 73.3 eq), Molecule 10 (17.5 mg, 28.8 umol, 10.1 % yield, 98.8% purity) was obtained as a white solid. [M+H] = 600.2Synthesis of Molecule 11General procedure for preparation of compound 6160 61

[0174] TosCI (1.95 g, 10.2 mmol, 2.20 eq) was added a solution of compound 60 (1 .00 g, 4.64 mmol, 1.00 eq) in Py (7.00 mL) at 5~10°C, then stirred at 25°C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.80) indicated compound 60 was consumed completely.The reaction was added to H2O (40 mL) at 25°C, and extracted with EtOAc (25 mL, 20 mL, 15 mL), the organic layers were washed brine (30 mL x 3) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. ACN (20 mL x 5) was added to removed Py under reduced pressure at 45°C. Compound 61 (1.70 g, 4.60 mmol, 99.0% yield) was obtained as a light-yellow oil. [M+H] 370.2.General procedure for preparation of compound 6219 62

[0175] K2CO3 (579 mg, 4.19 mmol, 2.30 eq) powder was added to a solution of compound 19 (1 .00 g, 1.82 mmol, 1 .00 eq) and compound 61 (1 .35 g, 3.64 mmol, 2.00 eq) in DMF (7.00 mL), then stirred at 86°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.30) indicated -80% of compound 19 was remained, and one major new spot with lower polarity was detected. The reaction was added to H2O (50 mL) at 25°C, andextracted with EtOAc (20 mL, 15 mL, 15 ml_), the organic layers were washed brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 7 / 1 , 4 / 1 , 3 / 1 , 1 / 1 , 0 / 1 ). The residue was purified by prep-TLC (SiC>2, Petroleum ether / Ethyl acetate = 3 / 2). LCMS (RT of product = 1.529 min) indicated desired MS. Compound 62 (90.0 mg, 120umol, 6.62% yield) was obtained as a lightyellow oil. [M+H] 746.3.General procedure for preparation of compound 6362 63

[0176] TFA (154 mg, 1.35 mmol, 0.10 mL, 11.2 eq) was added a solution of compound 62 (90.0 mg, 120 umol, 1.00 eq) in DCM (1.00 mL), then the reaction was stirred at 25°C for 4 h. LC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.00) and LCMS (RT of product = 1.159 min) indicated compound 62 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. ACN (5 mL x 3) was added to removed TFA under reduced pressure. Compound 63 (92.0 mg, 84.7 umol, 70.3% yield, 70.0% purity, TFA) was obtained as a pink oil. [M+H] 646.2.General procedure for preparation of compound 8E63 64

[0177] Compound 23 (14.3 mg, 82.9 umol, 0.70 eq) was added a solution of compound 63 (90 mg, 118 umol, 1 .00 eq, TFA), K2CO3 (65.4 mg, 473 umol, 4.00 eq) and Nal (1.77 mg, 11.8 umol, 0.10 eq) in DMF (1.00 mL), then the mixture was stirred at 25°C for 4 h. LCMS (RT of product = 1 .436 min) indicated compound 63 was consumed completely. H2O (15 mL) wasadded to the mixture, extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 64 (80.0 mg, crude) was obtained as a yellow oil. [M+H] 782.3.General procedure for preparation of Molecule 1164 Molecule 11

[0178] A solution of compound 64 (80.0 mg, 102 umol, 1 .00 eq) in NH3 / MeOH (7.00 M, 2.00 mL, 137 eq) was stirred at 10°C for 2.5 h. LCMS (RT of product = 1.215 min) and HPLC (RT of product = 2.198 min) indicated compound 64 was consumed completely. The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NH3under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 25%-45%, 20 min). HPLC (RT of product = 2.197 min). Molecule 11 (9.70 mg, 15.7 umol, 15.3% yield, 99.3% purity) was obtained as a white solid. [M+H] 614.3.Synthesis of Molecule 12General procedure for preparation of compound 6665 66

[0179] Compound 65 (2.00 g, 17.4 mmol, 1 .00 eq) was suspend in DCM(14.0 mL) and cooled to 5~10°C, BOC2O (4.55 g, 20.8 mmol, 4.79 mL, 1.20 eq) was added to the mixture portion-wised over 15 min, the reaction mixture was stirred under N2 for 15 min, TEA (3.51 g, 34.7 mmol, 4.83 mL, 2.00 eq) was added to the mixture at 10°C, then the mixture was stirred at 25°C for 16 h. TLC (DCM / MeOH = 10 / 1 , product’s Rf= 0.60(ninhydrin)) showed desired product formed. The mixture was poured to 20 mL saturatedNH4CI (aq.) extracted with DCM (20 mL x 2), all organic layers were combined, then washed with 20 mL brine, dried with Na2SO4, filtered and concentrated to give a residue. Purified with silica gel column (DCM / MeOH = 100 / 1 ~20 / 1 ). Compound 66 (1.00 g, 4.64 mmol, 26.7% yield) was obtained as a white solid. [M+H] 216.2.General procedure for preparation of compound 6766 67

[0180] TosCI (974 mg, 5.11 mmol, 2.20 eq) was added a solution of compound 66 (500 mg) in Py (3.50 mL) at 25°C, then stirred at 25°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.80) indicated compound 66 was consumed completely. The reaction was added to H2O (30 mL) at 25°C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (30 mL x 2) and dried over Na2SO4, filtered and the organic layers and yellow precipitate were concentrated under reduced pressure to give a residue. ACN (10 mL x 3) was added to removed Py under reduced pressure at 45°C. Compound 67 (900 mg, crude) was obtained as a light-yellow solid. [M+H] 370.2.General procedure for preparation of compound 6819 68

[0181] K2CO3 (278 mg, 2.01 mmol, 2.30 eq) powder was added a solution of compound 19 (480 mg, 874 umol, 1.00 eq) and compound 67 (646 mg, 1.75 mmol, 2.00 eq) in DMF (3.30 mL), then the mixture was stirred at 80°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.30) indicated ~80% compound 19 was remained, one new spot was detected. LCMS (RT of product = 1.515 min) indicated desired MS. The two reactions were added to H2O (35 mL) at 25°C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (30 mLx 2) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 3 / 2). Compound 68 (90.0 mg, 121 umol, 6.90% yield) was obtained as a white solid. [M+H] 746.3.General procedure for preparation of compound 6968 69

[0182] TFA (308 mg, 2.70 mmol, 0.20 mL, 22.4 eq) was added a solution of compound 68 (90.0mg, 121 umol, 1 .00 eq) in DCM (1 .00 mL) at 25°C, then stirred at 25°C for 3 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.00) indicated compound 68 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. ACN (3 mL x 5) was added to removed TFA under reduced pressure. Compound 69 (100 mg, crude, TFA) was obtained as a pink oil. [M+H] 646.2.General procedure for preparation of compound 7069 70

[0183] Compound 23 (20.9 mg, 121 umol, 1 .00 eq) was added to a solution of compound 69 (92.0 mg, 121 umol, 1.00 eq, TFA), K2CO3 (100 mg, 726 umol, 6.00 eq) powder and Nal (7.26 mg, 48.4 umol, 0.40 eq) in DMF (0.90 mL) under N2, then stirred at 25°C for 6 h. TLC (DCM / MeOH = 10 / 1 , Rf of product = 0.43) indicated compound 69 was consumed completely. LCMS (RT of product = 2.603 min) indicated desired MS. H2O (20 mL) was added to the mixture, extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give aresidue. Compound 70 (104 mg, crude) was obtained as a yellow oil. [M+H] 782.3.General procedure for preparation of Molecule 1270 Molecule 12

[0184] A mixture of compound 70 (100 mg, 128 umol, 1.00 eq) in NH3 / MeOH (7.00 M, 3.00 mL, 164 eq) was stirred at 10°C for 4.5 h. LCMS (RT of product = 1.944 min) and HPLC (RT of product = 2.166 min) indicated desired compound. The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NHs under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Xtimate C18 150*25 mm*5 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 28%-48%, 10.5 min). HPLC (RT of product = 2.147 min). Molecule 12 (17.0 mg, 27.7 umol, 21.6% yield, 100% purity) was obtained as a white solid. [M+H] = 614.3.Synthesis of Molecule 13General procedure for preparation of compound 7271 72

[0185] Ethyl carbonochloridate (767 mg, 7.07 mmol, 673 uL, 1.65 eq) was added a solution of compound 71 (1 .00 g, 4.29 mmol, 1 .00 eq) and TEA (715 mg, 7.07 mmol, 984 uL, 1 .65 eq) in THF (7.00 mL) at -20°C~ -15°C under N2 to result a white precipitate, then stirred at -15°C for 0.5 h.NH3.H2O (12.0 g, 85.7 mmol, 13.21 mL, 25.0% purity, 20.0 eq) was added dropwise at -20°C ~ -13°C over a period of 15 min, the temperature of the reaction mixture was slowly raised to 25°C and stirred at 25°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 0 / 1 , Rf of product = 0.60) indicatedcompound 71 was consumed completely. LCMS (RT of product = 1.136 min) showed desired MS. The reaction was extracted with DCM (15 mL, 15 mL, 10 mL, 10 mL), the combined organic layers were washed with H2O (20 mL x 3) and brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 0 / 1).Compound 72 (730 mg, 3.14 mmol, 73.3% yield) was obtained as a lightyellow oil. [M+H] 233.1.General procedure for preparation of compound 7372 73

[0186] TFAA (990 mg, 4.71 mmol, 656 uL, 1 .50 eq) was added dropwise into a solution of compound 72 (730 mg, 3.14 mmol, 1 .00 eq) and TEA (954 mg, 9.43 mmol, 1 .31 mL, 3.00 eq) in dry THF (3.50 mL) at -5°C ~ 5°C, the mixture was stirred at the same temperature for 1 .5 h. TLC (Petroleum ether / Ethyl acetate = 0 / 1 , Rf of product = 0.90) indicated compound 72 was consumed completely. The reaction was added H2O (20 mL) at 0°C, extracted with DCM (15 mL, 10 mL), the combined layers were washed H2O (15 mL x 3) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product compound 73 (690 mg, crude) was obtained as a brown solid and used into the next step without further purification. [M+H] 215.1.General procedure for preparation of compound 7473 74

[0187] TSOH-H2O (919 mg, 4.83 mmol, 1.50 eq) was added a stirred solution of compound 73 (690 mg, 3.22 mmol, 1 .00 eq) in ACN (4.80 mL) at 25°C and the mixture was stirred at 25°C for 24 h under N2. TLC (Petroleumether / Ethyl acetate = 0 / 1 , Rf of product = 0.00) indicated compound 73 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The crude product compound 74 (1 .50 g, crude) was obtained as a brown solid and used into the next step without further purification. [M+H] 115.1.General procedure for preparation of compound 7674 76

[0188] A mixture of compound 74 (1 .30 g, 4.54 mmol, 1 .00 eq) and TEA (919 mg, 9.08 mmol, 1 .26 mL, 2.00 eq) in DCM (4.50 mL) was added dropwise to a stirred and cooled (0°C) solution of compound 75 (513 mg, 4.54 mmol, 361 uL, 1.00 eq) in DCM (4.50 mL) at 0 ~ 5°C, then stirred at 0°C for 2 h. TLC (DCM / MeOH = 10 / 1 , Rfof product = 0.10) indicated compound 74 was consumed completely. The reaction was added water (30 mL), extracted with DCM (20 mL x 5), the combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 76 (360 mg, 1.89 mmol, 41.6% yield) was obtained as a brown solid. [M+H] 191.1.General procedure for preparation of compound 7722 77

[0189] A mixture of compound 22 (180 mg, 284 umol, 1 .00 eq), Nal (4.25 mg, 28.4 umol, 0.10 eq), K2CO3 (196 mg, 1 .42 mmol, 5.00 eq) and compound 76 (54.1 mg, 284 umol, 1.00 eq) in DMF (1.80 mL) was stirred at 25°C for 4 h under N2. Added compound 76 (12.0 mg), then mixture was stirred at 25°C for 16 h. TLC (DCM / MeOH = 10 / 1 , Rfof product = 0.70(PMA)) indicated ~20% of compound 22 remained, and one major new spot with lower polarity was detected. LCMS (RT of product = 1 .450 min) indicated desired MS. HPLC (RT of product = 3.409 min). H2O (20 mL) was added to the mixture, extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of product = 1.446 min). Compound 77 (240 mg, crude) was obtained as a brown oil. [M+H] 788.3.General procedure for preparation of Molecule 1377 Molecule 13

[0190] A mixture of compound 77 (240 mg, 304 umol, 1 .00 eq) inNHs / MeOH (7.00 M, 3.00 mL, 68.9 eq) was stirred at 25°C for 4 h. LCMS (RT of product = 1.234 min) indicated desired MS. HPLC (RT of product = 2.275 min). The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCOs)-ACN]; B%: 25%-40%, 20 min). HPLC (RT of product = 2.286 min). Molecule 13 (12.3 mg, 19.2 umol, 6.31 % yield, 96.9% purity) was obtained as a white solid, RT = 1.778 min [M+H] = 620.2.Synthesis of Molecule 14

[0191] Molecule 14 was prepared according to the procedure used for the synthesis of Molecule 3 and Molecule 13.General procedure for preparation of compound 2726 27

[0192] TFA (308 mg, 2.70 mmol, 0.20 mL, 20.2 eq), compound 26 (100 mg, 134 umol, 1.00 eq), DCM (2.00 mL), compound 27 (100 mg, crude, TFA) was obtained as a pink oil, [M+H] 648.3.General procedure for preparation of compound 7827 78

[0193] Compound 76 (22.5 mg, 118. umol, 1.00 eq), compound 27 (90.0 mg, 118 umol, 1 .00 eq, TFA), K2CO3 (81 .6 mg, 590 umol, 5.00 eq) and Nal (1 .77 mg, 11 .8 umol, 0.1 Oeq), DMF (0.60 mL). Compound 78 (90.0 mg, crude) was obtained as a yellow oil, [M+H] 788.3.General procedure for preparation of Molecule 1478 Molecule 14

[0194] Compound 78 (90.0 mg, 112 umol, 1 .00 eq), NH3 / MeOH (7.00 M, 2.00 mL, 125 eq). The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45%, 20 min). Molecule 14 (9.60 mg, 15.1 umol, 13.5% yield, 100% purity) was obtained as a white solid. RT = 2.688 min, [M+H] = 634.2.Synthesis of Molecule 15

[0195] Molecule 15 was prepared according to the procedure used for the synthesis of Molecule 4.General procedure for preparation of compound 8019 80

[0196] PPhs (239 mg, 911 umol, 2.50 eq), compound 19 (200 mg, 364 umol, 1 .00 eq), compound 79 (160 mg, 911 umol, 156 uL, 2.50 eq), THF (1 .50 mL), DIAD (184 mg, 911 umol, 2.50 eq). Compound 80 (190 mg, 269 umol, 73.8% yield) was obtained as a white solid. HPLC: RT of product = 4.060 min, [M+H] 706.3.General procedure for preparation of compound 8180 81

[0197] TFA (293mg, 2.57 mmol, 190 uL, 9.54 eq), compound 80 (190 mg, 269 umol, 1.00 eq), DCM (1.90 mL), the crude product compound 81 (220 mg, crude, TFA) was obtained as a pink oil and used into the next step without further purification. [M+H] 606.2.General procedure for preparation of compound 8281 82

[0198] Compound 23 (32.4 mg, 187 umol, 0.90 eq), compound 81 (150 mg, 208 umol, 1.00 eq, TFA), K2CO3 (86.4 mg, 625 umol, 3.00 eq) powder and Nal (3.12 mg, 20.8 umol, 0.10 eq), DMF (1.50 mL), the crude product compound 82 (150 mg, crude) was used into the next step without further purification and obtained as a yellow oil. LCMS: RT of product = 2.488 min, [M+H] 742.3.General procedure for preparation of Molecule 1582 Molecule 15

[0199] Compound 82 (150 mg, 202 umol, 1.00 eq), NHs / MeOH (7.00 M, 3.00 mL, 104 eq), the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-30%, 12 min). Molecule 15 (4.70 mg, 7.74 umol, 3.83% yield, 94.5% purity) was obtained as a white solid, RT = 2.106 min, [M+H] = 574.2.Synthesis of Molecule 16General procedure for preparation of Molecule 16Molecule 3 Molecule 16

[0200] 4 batches in parallel. Compound 83 (2.11 mg, 19.5 umol, 1 .85 uL,1 .20 eq) was added to a solution of Molecule 3 (10.0 mg, 16.2 umol, 1 .00 eq) and 2,6-lutidine (3.48 mg, 32.5 umol, 3.78 uL, 2.00 eq) in Acetone (0.5 mL) at 5~10°C under N2, then the mixture warmed to 25°C and stirred for 20 h under N2. LCMS (RT of product = 1.289 min) indicated ~11 % Molecule 3 was remained, but desired MS was detected, without work up and directly used to purify. The reaction was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45%, 20 min). Molecule 16 (18.9 mg, 27.1 umol, 41.7% yield, 98.7% purity) was obtained as a white solid. RT = 1 .968 min, [M-H] = 688.3.Synthesis of Molecule 17General procedure for preparation of compound 85

[0201] Compound 84 (18.8 mg, 98.4 umol, 1.00 eq) was added to a mixture of compound 27 (75.0 mg, 98.4 umol, 1.00 eq, TFA), Nal (1.48 mg, 9.84 umol, 0.10 eq) and K2CO3 (68.0 mg, 492 umol, 5.00 eq) powder in DMF (1 .00 mL), then stirred at 25°C for 20 h. TLC (DCM / MeOH = 10 / 1, Rfof product = 0.70 (PMA)) indicated ~20% compound 27 was remained and one major new spot with lower polarity was detected, H2O (20 mL) was added to the mixture at 0~10°C, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.Compound 85 (90.0 mg, crude) was obtained as a yellow oil. LCMS: RT of product = 1.445 min, [M+H] 802.3.General procedure for preparation of Molecule 1785 Molecule 17

[0202] A solution of compound 85 (90.0 mg, 112 umol, 1 .00 eq) in NHs / MeOH (7.00 M, 2.00 mL, 125 eq) was added to sealed container and stirred at 0-10°C for 3.5 h, then stirred at 25°C for 5 h. LCMS (RT of product = 2.007 min) indicated desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45%, 20 min). Molecule 17 (12.1 mg, 18.9 umol, 16.8% yield, 99.0% purity) was obtained as a white solid, RT = 1 .770 min, [M+H] = 634.3.Synthesis of Molecule 18General procedure for preparation of compound 87

[0203] TFAA (9.28 g, 44.2 mmol, 6.15 mL, 4.00 eq) was added dropwise to a solution of compound 86 (2.50 g, 11.1 mmol, 1.00 eq) in Py (17.0 mL) at -10 ~ -5°C, the mixture warmed to 25°C and stirred at 25°C for 16 h, the reaction turned brown. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.90) indicated compound 86 was consumed completely. The reaction was added to H2O (50 mL) at 25°C, and extracted with EtOAc (30 mL, 25 mL, 20 mL), the organic layers were washed 0.5 N HCI (30 mL) and brine (30 mL x 2) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 87 (2.20 g, 10.6 mmol, 95.6% yield) was obtained as a brown solid, [M+H] 209.1 .General procedure for preparation of compound 8887 88

[0204] TSOH-H2O (5.02 g, 26.4 mmol, 2.50 eq) was added a solution of compound 87 (2.20 g, 10.6 mmol, 1.00 eq) in ACN (14.0 mL) at 25°C, then stirred at 25°C for 16 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.00) indicated compound 87 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The crude was triturated with EtOAc (50 mL, 7V) at -30°C for 1 .5 h, the solid was filtered, washed cold EtOAc and dried in vacuo. Compound 88 (2.60 g, 9.27 mmol, 87.8% yield) was obtained as a white solid, [M+H] 109.1.General procedure for preparation of compound 8988 89

[0205] Compound 75 (3.14 g, 27.8 mmol, 2.21 mL, 3.00 eq) was added dropwise to a solution of compound 88 (2.60 g, 9.27 mmol, 1 .00 eq) andTEA (9.38 g, 92.7 mmol, 12.9 mL, 10.0 eq) in DCM (18.0 mL) at -5~5°C, warmed 25°C and stirred at 25°C for 4 h. TLC (DCM / MeOH = 10 / 1 , Rf of product = 0.38) indicated compound 88 was consumed completely. The reaction was diluted with DCM (20 mL), and washed H2O (20 mL x 2), brine (25 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM / MeOH = 50 / 1 ). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 4 / 1 ). Compound 89 (1.30 g, 7.04 mmol, 75.9% yield) was obtained as a yellow oil. LCMS: RT = 0.884 min, [M+H] 185.0.General procedure for preparation of compound 9027 90

[0206] Compound 89 (18.2 mg, 98.4 umol, 1.00 eq) was added to a mixture of compound 27 (75.0 mg, 98.4 umol, 1.00 eq, TFA), Nal (1.48 mg, 9.84 umol, 0.10 eq) and K2CO3 (68.0 mg, 492 umol, 5.00 eq) powder in DMF (1 .00 mL) at 25°C, then stirred at 25°C for 20 h. TLC (DCM / MeOH = 10 / 1 , Rf of product = 0.70 (PMA)) indicated ~20% compound 27 remained and one major new spot with lower polarity was detected. LCMS (RT of product = 1.463 min) indicated desired MS. H2O (20 mL) was added to the mixture at 0~10°C, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 90 (90.0 mg, crude) was obtained as a yellow oil. RT = 1.463 min, [M+H] 796.3.General procedure for preparation of Molecule 1890 Molecule 18

[0207] A solution of compound 90 (90.0 mg, 113 umol, 1 .00 eq) in NHs / MeOH (7.00 M, 2.00 mL, 124 eq) was added to sealed container and stirred at 0~10°C for 3.5 h, then stirred at 25°C for 5 h. LCMS (RT of product = 2.054 min) indicated desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (5 mL x 3) to remove NHs under reduced pressure at room temperature. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-45%, 20 min). Molecule 18 (13.9 mg, 22.0 umol, 19.5% yield, 99.5% purity) was obtained as a white solid. RT = 1 .864 min, [M+H] = 628.3.Synthesis of Molecule 19General procedure for preparation of compound 9219 92

[0208] K2CO3 (405.34 mg, 2.93 mmol, 2.3 eq) was added a solution of compound 19 (700 mg, 1.28 mmol, 1eq) and 34a-2 (942.25 mg, 2.55 mmol, 2 eq) in DMF (4.9 mL), then the mixture was stirred at 80°C for 18 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.25) indicated -80% compound 19 was remained, one new spot was detected. To the reaction was added to H2O (35 mL) at 25°C and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (30 mL x 2) and dried over Na2SO4, filtered and the organic layers and yellow precipitate were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). Compound 92 (160 mg, 214.41 umol, 16.81% yield) was obtained as a white solid, [M+H] 746.3.General procedure for preparation of compound 9392 93

[0209] To a solution of compound 92 (160.00 mg, 214.41 umol, 1 eq) in DCM (0.2 mL) was added TFA (307.99 ug, 2.70 umol, 0.2 uL). The mixture was stirred at 25°C for 2 h. TLC (Petroleum ether / Ethyl acetate =2 / 1 , Rf of product = 0.00) indicated reactant 92 was consumed completely. The reaction mixture was concentrated under reduced pressure. The residue was switched with DCM (5mL x 4). Without further purification. The crude product 93 (160 mg, 210.49 umol, 98.17% yield, TFA) was used into the next step without further purification, and the crude product is a pink oil, [M+H] 646.2.General procedure for preparation of compound 9493 94

[0210] Compound 23 (30.66 mg, 177.60 umol, 0.9 eq) was added to a solution of 93 (150 mg, 197.33 umol, 1 eq, TFA), K2CO3 (136.36 mg, 986.65 umol, 5 eq) and Nal (2.96 mg, 19.73 umol, 0.1 eq) in DMF (1.5 mL), the mixture was stirred at 25°C for 6 h. LCMS (RT of product=1.421 min) indicated desired MS. To the reaction was added to H2O (8 mL) at 25°C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (15 mL x 2) and dried over Na2SO4, filtered and the organic layers were concentrated under reduced pressure to give a residue, without further purification. Compound 94 (140 mg, 178.97 umol, 90.69% yield) was obtained as a light-yellow oil, RT =1.421 min, [M+H] =782.3.General procedure for preparation of Molecule 1994 Molecule 19

[0211] A solution of compound 94 (140 mg, 178.97 umol, 1 eq) in NH3 / MeOH (7 M, 2.8 mL, 109.52 eq) was stirred at 0°C for 5 h. LCMS (RT of product = 1.199 min) indicated the reactant was consumed completely and desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 3) to remove NH3 under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10mM NH4HCO3)-ACN];B%: 25%-45%,20min). Molecule 19 (12.6 mg, 20.52 umol, 11.46% yield) was obtained as a white solid, RT = 1.199 min, [M+H] = 614.3.Synthesis of Molecule 20General procedure for preparation of compound 96

[0212] TosCI (1.95 g, 10.22 mmol, 2.2 eq) was added to a solution of 34A-1 (1 g, 4.64 mmol, 1 eq) in Py (7 mL) at 0-10°C, the mixture turned yellow, then stirred at 25°C for 23 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.80) indicated Reactant 1 was consumed completely. The reaction was added H2O (30 mL) at 25°C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed 0.5 M HCI (15 mL) and brine (15 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, without further purification. Compound 34A-2(1.7 g, 4.60 mmol, 99.06% yield) was obtained as a light yellow solid, [M+H] 370.2.General procedure for preparation of compound 9719 97

[0213] K2CO3 (11 .58 mg, 83.79 umol, 2.3 eq) was added to a solution of compound 19 (700 mg, 1.28 mmol, 1 eq) and compound 96 (945.85 mg, 2.56 mmol, 2 eq) in DMF (4.9 mL) , then the mixture was stirred at 80°C for 18 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.25) indicated ~80% reactant 19 remained, one new spot was detected. LCMS (RT of product = 1.541 min) indicated desired MS. The reaction was added to H2O (35 mL) at 25°C and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed with brine (30 mL x 2) and dried over Na2SO4, filtered and the organic layers and yellow precipitate were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). Compound 97 (75 mg, 100.50 umol, 7.85% yield) was obtained as a white solid.1H NMR indicated desired product, [M+H] 746.3.General procedure for preparation of compound 9897 98

[0214] To a solution of compound 97 (75 mg, 100.50 umol, 1 eq) in DCM (2 mL) was added TFA (256.66 mg, 2.25 mmol, 166.66 uL, 22.40 eq). The mixture was stirred at 25°C for 4 h. TLC (Petroleum ether / Ethyl acetate =2 / 1 , Rf of product = 0.00) indicated reactant 97 was consumed completely. The reaction mixture was concentrated under reduced pressure. The residue was switched with DCM *(5mL x 4). Without further purification. The crude product 98 (76 mg, 99.98 umol, 99.48% yield, TFA) was used into the nextstep without further purification, and the crude product was an orange oil, [M+H] 646.2.General procedure for preparation of compound 9998 99

[0215] Compound 23 (15.53 mg, 89.98 umol, 0.9 eq) was added to a solution of compound 98 (76 mg, 99.98 umol, 1 eq, TFA), K2CO3 (69.09 mg, 499.90 umol, 5 eq) and Nal (1 .50 mg, 10.00 umol, 0.1 eq) in DMF (0.8 mL), the mixture was stirred at 25°C for 6 h. LCMS (RT of product=1 .427 min) indicated desired MS. The reaction was added to H2O (8 mL) at 25°C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed with brine (15 mL x 2) and dried over Na2SO4, filtered and the organic layers were concentrated under reduced pressure to give a residue without further purification. Compound 99 (107 mg, crude) crude was obtained as a light-yellow oil, RT of product=1.427 min, [M+H] = 782.4.General procedure for preparation of Molecule 2099 Molecule 20

[0216] A solution of compound 99 (107 mg, 136.78 umol, 1 eq) in NH3 / MeOH (7 M, 2.14 mL, 109.52 eq) was stirred at 0°C for 6 h. LCMS (RT of product =1 .205 min) indicated reactant 99 was consumed completely and desired MS. The reaction was concentrated under reduced pressure at 25°C, added MeOH (3 mL x 3) to remove NH3 under reduced pressure at 25°C. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10mMNH4HCO3)-ACN];B%: 25%-45%,20min) Molecule 20 (12 mg, 19.54 umol,14.29% yield) was obtained as a white solid. RT of product =1.205 min, [M+H] =614.3.Synthesis of Molecule 21General procedure for preparation of compound 10019 100

[0217] Compound 19 (160 mg, 291 umol, 1 .00 eq) and compound 42 (147 mg, 729 umol, 2.50 eq) and PPhs (191 mg, 729 umol, 2.50 eq) were switched with fresh THF (5.00 mL x 4) under reduced pressure at 40 °C, then dissolved in THF (1.10 mL) and cooled to -5~5 °C, DIAD (1.90 M, 383 uL, 2.50 eq) (1 .90 mol / L in toluene) was added, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of compound 19 = 0.40, Rf of product 100 = 0.48) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 4 / 1 , 3 / 1 , 0 / 1 ). Compound 100 (230 mg, crude) was obtained as a white solid, [M+H] 732.3.General procedure for preparation of compound 101100 101

[0218] TFA (354 mg, 3.11 mmol, 0.23 mL, 9.89 eq) was added a solution of compound 100 (230 mg, 314 umol, 1.00 eq) in DCM (2.30 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of reactant 100= 0.30, Rf of product 101 = 0.00 (PMA)) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO?, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1 ). Compound 101(220 mg, 295 umol, 93.8% yield, TFA salt) was obtained as a light-yellow solid, [M+H] 632.2.General procedure for preparation of compound 102101 102

[0219] Compound 84 (53.6 mg, 281 umol, 1 .00 eq) was added a mixture of compound 101 (210 mg, 281 umol, 1 .00eq, TFA salt) and K2CO3 (116 mg, 844 umol, 3.00 eq) powder and Nal (16.9 mg, 112 umol, 0.40 eq) in DMF (2.10mL), then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rf of compound 101 = 0.10, Rf of compound 102 = 0.30 (PMA)) indicated ~20% of compound 101 remained, and one major new spot with lower polarity was detected. H2O (25 mL) was added to the mixture in ice bath, extracted with EtOAc (15 mL, 10 mL, 8 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of product = 2.510 min) indicated desired MS. Compound 102 (200 mg, crude) was obtained as a yellow oil, [M+H] 786.3.General procedure for preparation of Molecule 21102 Molecule 21

[0220] A solution of compound 102 (200 mg, 254 umol, 1.00 eq) in NHs / MeOH (7.00 M, 4.00 mL, 110 eq) was stirred at 15 °C for 8 h in sealed bottle. LCMS (RT of product = 1.171 min) indicated desired MS. HPLC (RT of product = 1.940 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. HPLC (RT of product = 1.948 min). The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-50%, 10.5 min). Molecule 21 (25.0 mg, 40.4 umol, 15.9% yield, 100% purity) was obtained as a white solid, RT = 2.214 min, [M+H] = 618.2.Synthesis of Molecule 22General procedure for preparation of compound 10319 103

[0221] Compound 19 (160 mg, 291 umol, 1 .00 eq) and compound 47 (147 mg, 729 umol, 2.50 eq) and PPhs (191 mg, 729 umol, 2.50 eq) were switched with fresh THF (5.00 mL x 4) under reduced pressure at 40 °C, then dissolved in THF (1.10 mL) and cooled to -5~5 °C, DIAD (1.90 M, 383 uL, 2.50 eq) (1 .90 mol / L in toluene) was added, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rtof reactant 19 = 0.40, Rf of product 103 = 0.48) indicated ~20% of compound 19 remained, and one major new spot with lower polarity was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 4 / 1 , 3 / 1 , 0 / 1 ). Compound 103 (200 mg, crude) was obtained as a white solid, [M+H] 732.3.General procedure for preparation of compound 104103 104

[0222] TFA (308 mg, 2.70 mmol, 0.20 mL, 9.89 eq) was added a solution of compound 103 (200 mg, 273 umol, 1.00 eq) in DCM (2.00 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of reactant 103= 0.30, Rf of product 104= 0.00 (PMA)) indicated complete conversion. The reaction was concentrated under reduced pressure to givea residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1 ). Compound 104 (160 mg, 214 umol, 78.5% yield, TFA) was obtained as a light-yellow solid, [M+H] 632.2.General procedure for preparation of compound 105104 105

[0223] Compound 84 (38.3 mg, 201 umol, 1 .00 eq) was added a mixture of compound 104 (150 mg, 201 umol, 1 .00 eq, TFA) and K2CO3 (83.3 mg, 603 umol, 3.00 eq) powder and Nal (12.1 mg, 80.4 umol, 0.40 eq) in DMF (1.50 mL) at 15 °C, then stirred at 15 °C for 16 h. TLC (DCM / MeOH = 10 / 1 , Rf of compound 104 = 0.10, Rf of compound 105 = 0.30 (PMA)) indicated ~20% of compound 104 remained, and one major new spot with lower polarity was detected. H2O (20 mL) was added to the mixture, extracted with EtOAc (15 mL, 10 mL, 8 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT = 2.509 min) indicated desired MS. Compound 105 (160 mg, crude) was obtained as a yellow oil, [M+H] 786.3.General procedure for preparation of Molecule 22105 Molecule 22

[0224] A solution of compound 105 (160 mg, 203 umol, 1.00 eq) in NHs / MeOH (7.00 M, 3.20 mL, 110 eq) at 15 °C for 8 h in sealed bottle.LCMS (RT of product = 1.172 min) indicated desired MS. HPLC (RT of product = 1.951 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reducedpressure at room temperature. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-50%, 10.5 min). HPLC (RT of product = 1.952 min). Molecule 22 (20.0 mg, 32.1 umol, 15.7% yield, 99.1 % purity) was obtained as a white solid, RT = 2.218 min, [M+H] = 618.2.Synthesis of Molecule 23General procedure for preparation of compound 10619 106

[0225] Compound 19 (170 mg, 309 umol, 1.00 eq) and compound 52 (156 mg, 774 umol, 2.50 eq) and PPh3(203 mg, 774 umol, 2.50 eq) were switched with fresh THF (4.00 mL x 5) under reduced pressure at 40°C, then dissolved in THF (1.10 mL) and cooled to -5~5 °C, DIAD (1 .90 M, 407 uL, 2.50 eq) (1 .90 mol / L in toluene) was added, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of compound 19 = 0.40, Rf of compound 106 = 0.48) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 4 / 1 , 3 / 1 , 0 / 1 ). Compound 106 (250 mg, crude) was obtained as a white solid, [M+H] 732.3.General procedure for preparation of compound 107106 107

[0226] TFA (385 mg, 3.38 mmol, 0.25 mL, 9.89 eq) was added to a solution of compound 106 (250 mg, 341 umol, 1.00 eq) in DCM (2.50 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of compound 106 = 0.30, Rf of compound 107 = 0.00 (PMA))indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 107 (210 mg, 281 umol, 82.4% yield, TFA) was obtained as a light-yellow solid, [M+H] 632.2.General procedure for preparation of compound 108107 108

[0227] Compound 84 (51 .1 mg, 268 umol, 1 .00 eq) was added a mixture of compound 107 (200 mg, 268 umol, 1 .00 eq, TFA) and K2CO3 (111 mg, 804 umol, 3.00 eq) powder and Nal (16.1 mg, 107 umol, 0.40 eq) in DMF (2.00 mL), then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rf of reactant 107 = 0.10, Rf of product 108 = 0.30 (PMA)) indicated -20% of compound 107 remained, and one major new spot with lower polarity was detected. H2O (20 mL) was added to the mixture, extracted with EtOAc (15 mL, 10 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. LCMS (RT = 2.502 min) indicated desired MS. Compound 108 (220 mg, crude) was obtained as a white solid, [M+H] 786.3.General procedure for preparation of Molecule 23108 Molecule 23

[0228] A solution of compound 108 (220 mg, 279 umol, 1.00 eq) in NHs / MeOH (7.00 M, 4.00 mL, 100 eq) was stirred at 15 °C for 8 h in sealed bottle. LCMS (RT of product = 1.162 min) indicated desired MS. HPLC (RT of product = 1.932 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reducedpressure at room temperature. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 28%-48%, 10.5 min). Molecule 23 (35.0 mg, 56.5 umol, 20.2% yield, 99.7% purity) was obtained as a white solid, RT = 2.632 min, [M+H] = 618.2.Synthesis of Molecule 24General procedure for preparation of compound 10919 109

[0229] Compound 19 (170 mg, 309 umol, 1.00 eq) and compound 56 (156 mg, 774 umol, 2.50 eq) and PPhs (203 mg, 774 umol, 2.50 eq) were switched with fresh THF (4.00 mL x 5) under reduced pressure at 40 °C, then dissolved in THF (1.10 mL) and cooled to -5~5 °C, DIAD (1.90 M, 407 uL, 2.50 eq) (1 .90 mol / L in toluene) was added, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of reactant 19 = 0.40, Rf of product 109 = 0.48 (PMA)) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 4 / 1 , 3 / 1 , 0 / 1 ). Compound 109 (240 mg, crude) was obtained as a white solid, [M+H] 732.3.General procedure for preparation of compound 110109 110

[0230] TFA (369 mg, 3.24 mmol, 240 uL, 9.89 eq) was added to a solution of compound 109 (240 mg, 327 umol, 1 .00 eq) in DCM (2.40 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of compound 109 = 0.30, Rf of compound 110 = 0.00 (PMA)) indicated complete conversion. The reaction was concentrated underreduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 110 (200 mg, 268 umol, 81.8% yield, TFA) was obtained as a light-yellow solid, [M+H] 632.2.General procedure for preparation of compound 111110 m

[0231] Compound 84 (48.5 mg, 254. umol, 1.00 eq) was added to a mixture of compound 110 (190 mg, 254 umol, 1.00 eq, TFA) and K2CO3 (105 mg, 764 umol, 3.00 eq) powder and Nal (15.3 mg, 102 umol, 0.40 eq) in DMF (1 .90 mL) at 15 °C, then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rf of reactant 110 = 0.10, Rf of product 111 = 0.30 (PMA)) indicated -20% of compound 110 remained, and one major new spot with lower polarity was detected. H2O (20 mL) was added to the mixture, extracted with EtOAc (15 mL, 10 mL, 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT = 2.501 min) indicated desired MS. Compound 111 (200 mg, crude) was obtained as a white solid, [M+H] 786.3.General procedure for preparation of Molecule 24111 Molecule 24

[0232] A solution of compound 111 (200 mg, 254 umol, 1.00 eq) in NHs / MeOH (7.00 M, 4.00 mL, 110 eq) was stirred at 15 °C for 8 h in sealed bottle. LCMS (RT of product = 1.162 min) indicated desired MS. HPLC (RT of product = 1.931 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reducedpressure at room temperature. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 28%-48%, 10.5 min). HPLC (RT of product = 1.932 min). Molecule 24 (30.0 mg, 48.2 umol, 18.9% yield, 99.3% purity) was obtained as a white solid, RT = 2.361 min, [M+H] = 618.2.Synthesis of Molecule 25General procedure for preparation of compound 113112 113

[0233] Pivaloyl chloride (1.80 g, 14.9 mmol, 1.83 mL, 1 .10 eq) was added drop wise to a solution of compound 112 (3.40 g, 13.5 mmol, 1 .00 eq) and TEA (1 .64 g, 16.2 mmol, 2.26 mL, 1 .20 eq) in DCM (23.8 mL) at -20 ~ -15 °C, then stirred at -20 ~ -15 °C for 2 h, then NH3-H2O (3.80 g, 27.1 mmol, 4.18 mL, 25% purity, 2.00 eq) was added drop wise and the mixture was stirred at -20 ~ -15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate (1 d AcOH) = 0 / 1 , Rf of product = 0.60, Rf of reactant = 0.50 (Ninhydrin)) indicated complete conversion. The reaction was added water (40 mL), extracted with DCM (25 mL x 6), the organic layers were washed 0.5 N NaOH (40 mL) and brine (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated isopropyl ether (10 V, 30 mL) with at 15 °C for 16 h. Compound 113 (2.75 g, 10.9 mmol, 81.2% yield) was obtained as a white solid, [M+H] 251.1.General procedure for preparation of compound 114113 114

[0234] A solution of TFAA (3.32 g, 15.8 mmol, 2.20 mL, 1 .20 eq) in DCM (6.00 mL) was added a solution of compound 113 (3.30 g, 13.2 mmol, 1 .00 eq) and dried Py (1.25 g, 15.8 mmol, 1.28 mL, 1.20 eq) in DCM (17.0 mL) at 0~5 °C, then the reaction was allowed to warm to 15 °C and stirred for 40 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.80, Rf of reactant = 0.20) indicated -10% of compound 113 remained, and one major new spot with lower polarity was detected. The reaction was quenched with saturated NH4CI (70 mL), extracted with DCM (30 mL, 15 mL, 15 mL, 15 mL, 15 mL). The combined organic layers were washed with 0.5 N HCI (50 mL) and saturated NaHCOs (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 15 / 1 , 10 / 1 , 3 / 1 ). Compound 114 (2.60 g, 11.2 mmol, 84.9% yield) was obtained as a light-yellow solid, [M+H] 233.1.General procedure for preparation of compound 115114 115

[0235] TSOH-H2O (2.87 g, 15.1 mmol, 2.50 eq) was added to a solution of compound 114 (1.40g, 6.03 mmol, 1.00 eq) in ACN (9.80mL) at 15 °C, then stirred at 15 °C for 16 h. TLC (Petroleum ether / Ethyl acetate = 3 / 1 , Rf of 115 = 0.00, Rf of 114 = 0.40 (PMA)) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The crude product was triturated with MTBE (40 mL, 10 V) at 15°C for 10 mins, then added DCM (8 mL), the precipitation was observed, filtered, the cake was washed with MTBE and concentrated under reduced pressure. Compound 115 (1.70 g, 5.59 mmol, 92.6% yield, TsOH salt) was obtained as a pink solid, [M+H] 133.0.General procedure for preparation of compound 116115 116

[0236] A solution of 75 (1 .41 g, 12.5 mmol, 993 uL, 2.00 eq) in DCM (8.00 mL) was added a solution of 115 (1 .90 g, 6.24 mmol, 1 .00 eq, TsOH) and TEA (2.53 g, 24.9 mmol, 3.48 mL, 4.00 eq) in DCM (30.0 mL) at 0~5 °C, then warmed to 15 °C and stirred at 15 °C for 4 h. TLC (DCM / MeOH = 10 / 1 , Rf of 116 = 0.77, Rf of 115 = 0.70) indicated the reaction was completed. The reaction was added water (50 mL) at 0~10 °C, extracted with DCM (20 mL x 4), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 7 / 1 , 5 / 1 ). Compound 116 (1.10 g, crude) was obtained as a yellow solid, [M+H] 209.0.General procedure for preparation of compound 11719 117

[0237] Compound 19 (200 mg, 364 umol, 1 .00 eq) and 42 (183 mg, 911 umol, 2.50 eq) and PPhs (239 mg, 911 umol, 2.50 eq) were switched with fresh THF (4.00 mL x 4) under reduced pressure at 40 °C, then dissolved in THF (1 .00 mL) and cooled to 0~10 °C, DIAD (1 .90 M, 479 uL, 2.50 eq) (1 .90 mol / L in toluene) was added, then stirred at 15 °C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of 19 = 0.40, Rf of 117 = 0.48 (UV 254 nm)) indicated -20% of 19 remained, and one major new spot with lower polarity was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 , 4 / 1 , 3 / 1 , 0 / 1 ). LCMS (RT of 117 = 1.286 min) indicated desired MS [M+H] 732.3.Compound 117 (250 mg, crude) was used in the next step without any further purification. qGeneral procedure for preparation of compound 118117 118

[0238] TFA (462 mg, 4.05 mmol, 0.30 mL, 11 .8 eq) was added a solution of 117 (250 mg, 341 umol, 1.00 eq) in DCM (3.00 mL), then stirred at 15 °C for 3 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of 118 = 0.00, Rf of 117 = 0.48) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1 ). Compound 118 (190 mg, 254 umol, 74.6% yield, TFA) was obtained as a white solid, [M+H] 632.2.General procedure for preparation of compound 119118 119

[0239] Compound 116 (50.3 mg, 241 umol, 1 .00 eq) was added to a mixture of 118 (180 mg, 241 umol, 1.00 eq, TFA) and Nal (14.5 mg, 96.5 umol, 0.40 eq) and K2CO3 (100 mg, 724 umol, 3.00 eq) powder in DMF (2.00 mL), then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rf of 118= 0.10, Rf of 119 = 0.40 (PMA)) indicated -20% of 118 remained, and one major new spot with lower polarity was detected. LCMS (RT of 119 = 1.048 min) indicated desired MS. H2O (30 mL) was added to the mixture in ice bath, extracted with EtOAc (15 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 119 (180 mg, crude) was obtained as a light-yellow solid, [M+H] 804.3.General procedure for preparation of Molecule 25119 Molecule 25

[0240] A solution of 119 (180 mg, 224 umol, 1.00 eq) in NH3 / MeOH (7.00 M, 3.60 mL, 112 eq) was stirred at 15 °C for 6 h in sealed bottle. LCMS (RT of product = 1.092 min) indicated desired MS. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at < 30 °C. HPLC (RT of Molecule 25 = 2.379 min). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-40%, 10 min). Molecule 25 (10.0 mg, 15.7 umol, 7.02% yield) was obtained as a white solid, RT = 2.346 min, [M+H] = 636.2.Synthesis of Molecule 26General procedure for preparation of compound 121120 121

[0241] TosCI (1.95 g, 10.2 mmol, 2.20 eq) was added a solution of 120 (1.00 g, 4.64 mmol, 1.00 eq) in Py (7.00 mL) at 15 °C, then stirred at 15 °C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 121 = 0.80, Rf of 120 = 0.15) indicated 120 was consumed completely. The reaction was added to H2O (20 mL) at 25 °C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (20 mL x 2) and dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue (Without further purification). Compound 121 (1.60 g, 4.33 mmol, 93.2% yield) was obtained as a white solid, [M+H] 370.2.General procedure for preparation of compound 12219 122

[0242] Compound 121 (1 .25 g, 3.37 mmol, 2.50 eq) was added a mixture of 19 (740 mg, 1 .35 mmol, 1 .00 eq) and K2CO3 (559 mg, 4.04 mmol, 3.00 eq) powder in DMF (5.00 mL) at 15 °C, then stirred at 80 °C for 16 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of 122 = 0.30, Rf of 19 = 0.24 (PMA)) indicated -80% of 19 remained, and one major new spot with lower polarity was detected. LCMS (RT of product = 1.377 min) indicated desired MS. The reaction was added to H2O (60 mL) at 0~10 °C, and extracted with EtOAc (25 mL, 20 mL, 15 mL), the organic layers were washed brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 3 / 1 , 0 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 ). LCMS (RT of product = 1.378 min) indicated desired MS. Compound 122 (120 mg, 160 umol, 11.9% yield) was obtained as a white solid, [M+H] 746.3.General procedure for preparation of compound 123122 123

[0243] TFA (185 mg, 1.62 mmol, 120 uL, 10.1 eq) was added a solution of 122 (120 mg, 161 umol, 1.00 eq) in DCM (1.20 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rfof 122 = 0.30, Rf of 123 = 0.00 (PMA)) indicated complete conversion. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1 ). Compound 123 (120 mg, 158 umol, 98.2% yield, TFA) was obtained as a pink solid, [M+H] 646.2.General procedure for preparation of compound 124123 124

[0244] 84 (27.6 mg, 145 umol, 1.00 eq) was added a mixture of 123 (110 mg, 145 umol, 1.00 eq, TFA) and K2CO3 (60.0 mg, 434 umol, 3.00 eq) powder and Nal (8.68 mg, 57.9 umol, 0.40 eq) in DMF (1.1 mL) at 15 °C, then stirred at 15 °C for 16 h. TLC (DCIWMeOH = 10 / 1 , Rfof 123 = 0.20, Rfof 124 = 0.50 (PMA)) indicated -20% of 123 remained, and one major new spot with lower polarity was detected. H2O (25 mL) was added to the mixture in ice bath, extracted with EtOAc (15 mL, 10 mL, 8 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 124 = 1.284 min) indicated desired MS. Without further purification. LCMS (RT of 124 = 0.986 min) indicated desired MS. Compound 124 (130 mg, crude) was obtained as a pink oil, [M+H] 800.3.General procedure for preparation of Molecule 26124 Molecule 26

[0245] A solution of 124 (130 mg, 162 umol, 1 .00 eq) in NH3 / MeOH (7.00 M, 2.60 mL, 112 eq) was stirred at 15 °C for 7 h in sealed bottle. LCMS (RT of Molecule 26 = 1.340 min) indicated desired MS. HPLC (RT of Molecule 26= 2.277 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-45%, 8 min). HPLC (RT of Molecule 26 = 1.787min). Molecule 26 (22.0 mg, 34.6 umol, 21.3% yield, 99.6% purity) was obtained as a white solid, RT = 2.530 min, [M+H] = 632.2.Synthesis of Molecule 27General procedure for preparation of compound 12619 126

[0246] Compound 125 was added to a mixture of compound 19 (100 mg) and CS2CO3 in dried DMF (2.8 mL) at 25 °C, then stirred at 85 °C for 16 h under N2. LCMS indicated -50% 19 remained, -50% desired MS. The reaction was cooled to 25 °C, the reaction was added to H2O (30 mL), and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound product 126 (120 mg, crude) was obtained and used in the next step without further purification.General procedure for preparation of compound 127126 127

[0247] TFA was added to a solution of compound 126 (120 mg) in DCM (2 mL) at 25 °C, then stirred at 25 °C for 2.5 h. TLC indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 127 (87 mg) was obtained as a yellow solid.General procedure for preparation of compound 128127 128

[0248] Compound 84 was added to a mixture of compound 127 (80 mg) and Nal and K2CO3 powder in dried DMF, then stirred at 25 °C for 16 h under N2. TLC indicated - 20% of compound 127 remained, and one major new spot with lower polarity was detected. H2O (30 mL) was added to the mixture, extracted with EtOAc (25 mL, 20 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS showed -60% purity. Compound 128 (60 mg, crude) was obtained as a yellow solid.General procedure for preparation of Molecule 27

[0249] A solution of compound 128 (60 mg) in NHs / MeOH was stirred at 15°C for 7 h in sealed bottle. LCMS indicated the reaction was completed. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 25%-55%, 8 min). Molecule 27 (10 mg) was obtained as a white solid. RT = 2.594 min, [M+H] = 646.3.Synthesis of Molecule 28

[0250] The process for the preparation of Molecule 28 was carried out similarly to the process described for Molecule 27.General procedure for preparation of compound 13019 130

[0251] Compound 19 (230 mg) and compound 130 (150 mg) without purification.General procedure for preparation of compound 131130 131

[0252] Compound 130 (150 mg) and compound 131 (130 mg), obtained as a yellow solid.General procedure for preparation of compound 132131 132

[0253] Compound 131 (120 mg) and compound 132 (100 mg), obtained as a yellow solid.General procedure for preparation of Molecule 28132 Molecule 28

[0254] Compound 132 (100 mg) and Molecule 28 (22 mg), obtained as a white solid. RT = 2.232 min, [M+H] = 604.4.Synthesis of Molecule 29General procedure for preparation of compound 134133 134

[0255] TEA (3.22 g, 31 .8 mmol, 4.43 mL, 4.00 eq) was added to a solution of 133 (1 .00 g, 7.96 mmol, 1.00 eq, HCI) in DCM (20 mL), the white precipitation was observed, the a solution of 75 (1 .80 g, 15.9 mmol, 1 .27 mL, 2.00 eq) in DCM (10 mL) was added dropwise to the mixture at 0~10 °C, then stirred at 0~20 °C for 2 h, the mixture was brown. TLC (DCM / MeOH = 10 / 1 , Rf of 134 = 0.77, Rr of 133 = 0.10 (PMA) indicated the reaction was completed. The reaction was added water (100 mL) at 0~10 °C, extracted with DCM (50 mL x 4), the combined organic layers were washed with brine (80 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 , 3 / 1 ). LCMS (RT of 134 = 0.389 min) indicated desired MS. Compound 134 (900 mg, 5.44 mmol, 68.3% yield) was obtained as a yellow oil, [M+H] 166.0.General procedure for preparation of compound 135118 135

[0256] Compound 134 (31.1 mg, 188 umol, 1 .00 eq) was added to a mixture of compound 118 (140 mg, 188 umol, 1.00 eq, TFA), which preparation is described in the example synthesis of Molecule 25, and K2CO3 (77.8 mg, 563 umol, 3.00 eq) powder and Nal (11 .2 mg, 75.1 umol, 0.40 eq) in DMF (1 .4 mL), then stirred at 20 °C for 16 h under N2, the mixture was yellow. TLC (DCM / MeOH = 10 / 1 , Rf of 118 = 0.10, Rf of 135 = 0.40 (PMA)) indicated ~10% of 118 was remained, and one major new spot with lower polarity was detected, LCMS (RT of product = 1 .023 min). H2O (20 mL) was added to the mixture at ice bath, extracted with EtOAc (15 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 135 (160 mg, crude) was obtained as a yellow oil. [M+H] 761.3.General procedure for preparation of Molecule 29135 Molecule 29

[0257] A solution of compound 135 (160 mg, 210 umol, 1.00 eq) in NHs / MeOH (7.00 M, 3.20 mL, 107 eq) was stirred at 20 °C for 5 h in sealed bottle. LCMS (RT of product = 2.006 min) indicated desired MS and HPLC (RT of product = 2.060 min). The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-40%, 8 min). HPLC (RT of product = 2.062 min). Molecule 29 (20.0 mg, 33.7 umol, 16.0% yield, 100% purity) was obtained as a white solid, RT = 2.241 min, [M+H] = 593.2.Synthesis of Molecule 30General procedure for preparation of compound 137136 137

[0258] TEA (2.82 g, 27.9 mmol, 3.88 mL, 4.00 eq) was added to a solution of 136 (1 .00 g, 6.97 mmol, 1.00 eq, HCI) in DCM (20 mL), the white precipitation was observed, then a solution of 75 (1.57 g, 13.9 mmol, 1.11 mL, 2.00 eq) in DCM (10 mL) was added dropwise to the mixture at 0-10 °C, then stirred at 0-20 °C for 2 h, the mixture was brown. TLC (DCM / MeOH = 10 / 1 , Rfof 137 = 0.80, Rfof 136 = 0.20 (PMA) indicated the reaction was completed. The reaction was added water (100 mL) at0~10 °C, extracted with DCM (50 mL x 4), the combined organic layers were washed with brine (100 mL), dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 ). LCMS (RT of 137 = 0.676 min) indicated desired MS. Compound 137 (1.10 g, 5.99 mmol, 86.0% yield) was obtained as a yellow oil. [M+H] 184.0.General procedure for preparation of compound 138118 138

[0259] Compound 137 (34.5 mg, 188 umol, 1.00 eq) was added to a mixture of compound 118 (from Molecule 25) (140 mg, 188 umol, 1.00 eq, TFA) and K2CO3 (77.8 mg, 563 umol, 3.00 eq) powder and Nal (11 .3 mg, 75.1 umol, 0.40 eq) in DMF (1 .4 mL), then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 118 = 0.10, Rfof 138 = 0.45 (PMA)) indicated the reaction was completed. H2O (20 mL) was added to the mixture, extracted with EtOAc (15 mL, 10 mL, 10 mL). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 138 = 1 .893 min). Compound 138 (150 mg, crude) was obtained as a yellow oil. [M+H] 779.3.General procedure for preparation of Molecule 30138 Molecule 30

[0260] A solution of 138 (150 mg, 193 umol, 1 .00 eq) in NH3 / MeOH (7.00 M, 3.00 mL, 109 eq) was stirred at 15 °C for 5 h in sealed bottle. LCMS (RT of product = 2.090 min) indicated desired MS. HPLC (RT of product = 2.293 min). The reaction was concentrated under reduced pressure and addedMeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 25%-45%,8 min). HPLC (RT of product = 2.315 min). Molecule 30 (20.0 mg, 32.7 umol, 17.0% yield, 100% purity) was obtained as a white solid, RT = 2.336 min, [M+H] = 611 .2.Synthesis of Molecule 31General procedure for preparation of compound 140139 140

[0261] TSOH-H2O (2.18 g, 11 .5 mmol, 1 .50 eq) was added to a solution of compound 139 (1.50 g, 7.64 mmol, 1.00 eq) in ACN (7.5 mL), the reaction was colorless solution, and stirred at 20 °C for 48 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of product = 0.00, Rf of reactant 139 = 0.43 (Ninhydrin) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The crude product was triturated with MTBE (30 mL, 10 V) at 20 °C for 10 min, then added DCM (6 mL) and stirred at 20 °C for 3 h, filtered, the cake was washed with MTBE and concentrated under reduced pressure. Compound 140 (1 .90 g, 7.08 mmol, 92.6% yield) was obtained as a white solid. [M+H] 97.1.General procedure for preparation of compound 142141 142

[0262] Aqueous NaOH (1 .00 M, 24.0 mL, 1 .57 eq) was added a mixture of compound 141 (2.00 g, 15.3 mmol, 1.00 eq) in dioxane (36 mL) and H2O(18 mL) (dioxane / H2O = 2 / 1 ) at 0~10 °C, subsequently a solution of BOC2O (3.99 g, 18.3 mmol, 4.20 mL, 1 .20 eq) in dioxane (6 mL) was added at 0~10 °C, then the reaction was warmed to 20 °C (colorless solution) and stirred at 20 °C for 16 h under N2, white precipitate was detected. TLC (DCM / MeOH = 10 / 1 (1 d AcOH), Rf of 142 = 0.15, Rf of 141 = 0.00 (Bromocresol green) indicated the reaction was completed. The reaction was concentrated to 30 mL and acidified with 1 N HCI to pH ~ 4 and extracted with EtOAc (100 mL x 15), the combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 142 (1.60 g, 6.92 mmol, 45.4% yield) was obtained as a yellow solid. [M+H] 232.1.General procedure for preparation of compound 143142 143

[0263] TEA (145 mg, 1 .43 mmol, 199 uL, 1.10 eq) was added to a suspension of 140 (384 mg, 1.43 mmol, 1.10 eq, TsOH) in DCM (3 mL), the white precipitation was dissolved, after stirred at 20 °C for 5 min, 142 (300 mg, 1.30 mmol, 1.00 eq), HOBt (193 mg, 1.43 mmol, 1.10 eq) and EDCI (274 mg, 1.43 mmol, 1.10 eq) were added, the reaction was clarified solution, then stirred at 20 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 (1 d AcOH), Rfof 143 = 0.54, Rfof 142 = 0.24 (Ninhydrin) indicated the reaction was completed. Saturated NaHCOs (20 mL) was added to the reaction, extracted with DCM (15 mL, 10 mL, 10 mL), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 0 / 1 , 30 / 1 , 0 / 1). LCMS (RT of product = 1.263 min) indicated desired MS. Compound 143 (230 mg, 743 umol, 57.2% yield) was obtained as a light-yellow solid. [M+H] 310.2.General procedure for preparation of compound 144143 144

[0264] TosCI (271 mg, 1 .42 mmol, 2.20 eq) was added to a solution of compound 143 (200 mg, 647 umol, 1.00 eq) in Py (1 .4 mL) at 20 °C, then the reaction was stirred at 20 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rf of 144 = 0.80, Rf of 143 = 0.50 (Ninhydrin)) indicated the reaction was completed. The reaction was added H2O (30 mL) at 25 °C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (25 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 144 (310 mg, crude) was obtained as a yellow oil. [M+H] 464.2.General procedure for preparation of compound 14519 145

[0265] Compound 144 (287 mg, 619 umol, 2.00 eq) was added to a mixture of compound 19 (170 mg, 310 umol, 1 .00 eq) and CS2CO3 (232 mg, 712 umol, 2.30 eq) in dried DMF (3.4 mL) at 25 °C, then stirred at 85 °C for 16 h under N2. LCMS (RT of 46a = 1.270 min) indicated the reaction was completed. The reaction was added to H2O (40 mL) at 15 °C, and extracted with EtOAc (15 mL, 10 mL, 10 mL), the organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 145 (350 mg, crude) was obtained as a yellow oil. [M+H] 840.3.General procedure for preparation of compound 146145 146

[0266] TFA (1.16 g, 10.1 mmol, 0.75 mL, 28.4 eq) was added to a solution of compound 145 (300 mg, 357 umol, 1 .00 eq) in dry DCM (3 mL) at 25 °C, then stirred at 25 °C for 1 .5 h. LCMS (RT of 146 = 1.010 min) indicated the reaction was completed. The reaction was concentrated under reduced pressure and added DCM (5 mL x 3) to remove TFA under reduced pressure at 45 °C. Compound 146 (300 mg crude, TFA) was obtained as a yellow oil. [M+H] 740.3.General procedure for preparation of Molecule 31146 Molecule 31

[0267] A solution of compound 146 (300 mg, 351 umol, 1.00 eq, TFA) in NH3 / MeOH (7.00 M, 6.00 mL, 120 eq) was stirred at 10-15 °C for 7 h in sealed bottle. LCMS (RT of product = 1.784 min and 1.863 min) indicated desired MS. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3under reduced pressure at room temperature. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 10%-30%, 10 min). Molecule 31 (30.0 mg, 48.2 umol, 13.7% yield, 91.9% purity) was obtained as a white solid. RT = 2.174 min, [M+H] = 572.2.Synthesis of Molecule 32General procedure for preparation of compound 148142 148

[0268] TEA (144 mg, 1 .43 mmol, 199 uL, 1.10 eq) was added to a suspension of 147 (205 mg, 1.43 mmol, 1.10 eq, HCI) in DCM (3 mL), the white precipitation was observed, after stirred at 20 °C for 5 min, 142 (from Molecule 31 ) (300 mg, 1.30 mmol, 1.00 eq), HOBt (193 mg, 1.43 mmol, 1.10 eq) and EDCI (273 mg, 1 .43 mmol, 1.10 eq) were added, the reaction was clarified solution, then stirred at 20 °C for 16 h. TLC (DCM / MeOH = 10 / 1 (1 d AcOH), Rf of 148 = 0.47, Rf of 142 = 0.35 (Bromocresol green) indicated the reaction was completed. Saturated NaHCOs (20 mL) was added to the reaction, extracted with DCM (15 mL, 10 mL, 10 mL), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 148 = 1.847 min). The residue was purified by column chromatography (SiO2, DCM / MeOH= 40 / 1 , 20 / 1 , 0 / 1 ). Compound 148 (360 mg, 1.12 mmol, 86.6% yield) was obtained as a light-yellow oil. [M+H] 321 .2.General procedure for preparation of compound 149148 149

[0269] TosCI (262 mg, 1 .37 mmol, 2.20 eq) was added to a solution of 148 (200 mg, 624 umol, 1 .00 eq) in Py (1 .4 mL) at 20 °C, then the reaction was stirred at 20 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 149 = 0.80, Rf of 148= 0.50 (Ninhydrin)) indicated the reaction was completed. The reaction was added H2O (30 mL) at 25 °C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (25 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give aresidue. Compound 149 (280 mg, crude) was obtained as a yellow oil. [M+H] 475.2.General procedure for preparation of compound 47-119 150

[0270] Compound 149 (367 mg, 774 umol, 2.50 eq) was added to a mixture of compound 19 (170 mg, 310 umol, 1 .00 eq) and CS2CO3 (232 mg, 712 umol, 2.30 eq) in dried DMF (3.4 mL) at 25 °C, then stirred at 85 °C (outside temperature) for 16 h under N2. LCMS (RT of 150 = 1.289 min (12.9%)) indicated the reaction was completed. The reaction was added to H2O (40 mL) at 15 °C, and extracted with EtOAc (15 mL, 10 mL, 10 mL), the organic layers were washed brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 150 (450 mg, crude) was obtained as a yellow oil. [M+H] 851 .3.General procedure for preparation of compound 151150 151

[0271] TFA (1.54 g, 13.5 mmol, 1 .00 mL, 28.7 eq) was added to a solution of compound 150 (400 mg, 470 umol, 1.00 eq) in dry DCM (4 mL) at 25 °C, then stirred at 25 °C for 3 h. LCMS (RT of 151 = 1.019 min (22%)) indicated the reaction was completed. The reaction was concentrated under reduced pressure and added DCM (5 mL x 3) to remove TFA under reduced pressure at 45 °C. Compound 151 (500 mg crude, TFA) was obtained as a yellow oil. [M+H] 751.2.General procedure for preparation of Molecule 32151 Molecule 32

[0272] A solution of compound 151 (500 mg, 578 umol, 1.00 eq, TFA) in NHs / MeOH (7.00 M, 10.0 mL, 121 eq) was stirred at 25 °C for 4 h in sealed bottle. LCMS (RT of Molecule 32 = 0.988 min) indicated the reaction was completed. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. HPLC (RT of Molecule 32 = 1.585 min). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 urn; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 15%-45%, 8 min). HPLC (RT of product = 1.586 min). Molecule 32 (40.0 mg, 68.3 umol, 11 .8% yield, 99.5% purity) was obtained as a white solid, RT = 2.390 min, [M+H] = 583.2.Synthesis of Molecule 33General procedure for preparation of compound 1525 152

[0273] PPh3(11 .6 g, 44.4 mmol, 1 .33 eq) and imidazole (2.85 g, 41 .9 mmol, 1 .26 eq) were added to a solution of 5 (24.4 g, 33.4 mmol, 1 .00 eq), previously prepared in the synthesis of Molecule 1 , in dried DCM (195 mL) at 25 °C, then I2 (10.5 g, 41 .5 mmol, 8.36 mL, 1 .24 eq) was added at 25 °C, the temperature was rose to 40 °C and white precipitate was detected, the mixture was stirred at 50 °C for 5 h under N2, the reaction was black mixture. TLC (DCM / MeOH = 10 / 1 , Rfof 5 = 0.50, Rfof 152 = 0.60 (PMA)) indicated the reaction was consumed completely one major new spot with lower polarity was detected. The reaction was cooled to 25 °C and pouredinto water (200 mL), extracted with DCM (120 mL, 100 mL, 80 mL). The combined organic layers were washed with 0.5 N HCI (150 mL) and brine (80 mL x 2), dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0, 50 / 1 , 30 / 1 , 20 / 1 , 0 / 1 ). Compound 152 (17.8 g, crude) was obtained as a black oil. [M+H] 549.0.General procedure for preparation of compound 153152 153

[0274] AC2O (33.1 g, 324 mmol, 30.4 mL, 10.0 eq) was added a solution of 152 (17.8 g, 32.4 mmol, 1.00 eq) and DMAP (792 mg, 6.49 mmol, 0.20 eq) in dry Py (124 mL) at 0~10 °C, then stirred at 25 °C for 15 h under N2. TLC (DCM / MeOH = 10 / 1, Rf of 153 = 1.00, Rfof 152 = 0.50 (PMA)) indicated the reaction was completed. Water (300 mL) was added to the reaction at ice bath, extracted with EtOAc (150 mL, 80 mL), the organic layers were washed brine (100 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0, 10 / 1 , 8 / 1 , 0 / 1 ). LCMS (RT of 153 = 1.491 min) indicated desired MS. Compound 153 (5.50 g, crude) was obtained as a yellow solid. [M+H] 675.1.General procedure for preparation of compound 154153 154

[0275] Wet Pd / C (2.00 g, 10.0% purity) was added to a solution of 153 (5.00 g, 7.41 mmol, 1.00 eq) and TEA (7.50 g, 74.1 mmol, 10.31 mL, 10.0 eq) in THF (30 mL) and MeOH (15 mL), then stirred at 25 °C for 24 h underH2 (15 psi). LCMS (RT of 154 = 1 .486 min) indicated the reaction was consumed completely and desired MS. The reaction was filtered, the filtrate was concentrated, then dissolved in EtOAc (300 mL), added water (150 mL) and separated, the aqueous layer was extracted with EtOAc (80 mL), the organic layers were washed with brine (100 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0, 8 / 1 , 3 / 1 , 1 / 1 , 1 / 0). HPLC (RT of 154 = 3.139 min). Compound 154 (3.80 g, crude) was obtained as a white solid. [M+H] 549.2.General procedure for preparation of compound 155154 155

[0276] H2O (121 mg, 6.74 mmol, 121 uL, 1.00 eq) was added to a solution of 154 (3.70 g, 6.74 mmol, 1.00 eq) in ACN (26 mL), then added Et3SiH (2.51 g, 21.6 mmol, 3.44 mL, 3.20 eq) and BF3-Et2O (2.30 g, 16.2 mmol, 2.00 mL, 2.40 eq) at 0~15 °C under N2, then stirred at 25 °C for 5 h. HPLC (RT of 155 = 3.062 min) indicated the reaction was consumed completely. The reaction was quenched with saturated NaHCOs (100 mL) in ice bath, extracted with EtOAc (50 mL, 40 mL, 20 mL), the layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether / Ethyl acetate = 7 / 1 (40 mL, 10 V) at 25 °C for 16 h. LCMS (RT of 155 = 1.239 min) indicated desired MS. Compound 155 (2.90 g, 5.59 mmol, 82.9% yield) was obtained as a whit solid. [M+H] 519.2.General procedure for preparation of compound 156155 156

[0277] A solution of BBr3(12.1 g, 48.2 mmol, 4.64 mL, 10.0 eq) in DCM (30 mL) was add dropwise to a solution of 155 (2.50 g, 4.82 mmol, 1.00 eq) in DCM (30 mL) at -60 - -50 °C, then stirred at -60 - -50 °C for 0.5 h and the stirred at -35 - -30 °C for 2 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 156 = 0.24, Rfof 155 = 0.43) indicated -10% of 155 was remained, and one major new spot with larger polarity was detected. The reaction was slowly poured into ice and neutralized with stirred sat. NaHCOs (350 mL) at ice bath, extracted with DCM (80 mL, 60 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0, 5 / 1 , 3 / 1 , 0 / 1 ). Compound 156 (2.20 g, crude) was obtained as a white solid. [M+H] 491.1.General procedure for preparation of Molecule 33156 Molecule 33

[0278] 156 (70.0 mg, 135 umol, 1 .00 eq) was dissolved in MeOH (1 mL), then NaOMe (4.86 mg, 26.9 umol, 30.0% purity, 0.20 eq) was added and stirred at 25 °C for 4 h under N2. LCMS (RT of Molecule 33 = 1.180 min) indicated the reaction was consumed completely and desired MS. AcOH was added to the reaction and adjust pH - 6, then concentrated under reduced pressure to give a residue at 45 °C. HPLC (RT of Molecule 33 = 2.140 min). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 8 min). LCMS (RT of Molecule 33 = 1.945 min). Molecule 33 (14 .0 mg, 38.8 umol, 28.8% yield, 99.5% purity) was obtained as a white solid. RT = 2.823 min, [M+H] = 365.1 .Synthesis of Molecule 34General procedure for preparation of compound 157156 157

[0279] PPhs (133 mg, 509 umol, 2.50 eq) and 156 (100 mg, 203 umol, 1.00 eq) and 42 (102 mg, 509 umol, 2.50 eq) were switched with THF and toluene (4.00 mL x 3) under reduced pressure, then dissolved in redistilled THF (3.00 mL) under N2, DIAD (102 mg, 509 umol, 99.0 uL, 2.50 eq) was added to above solution at 0~5 °C, the reaction was turning yellow, then stirred at 25 °C for 20 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of product = 0.50) indicated 156 was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 0 / 1 ). Compound 157 (300 mg, crude) was obtained as a yellow oil. [M+H] 674.3.General procedure for preparation of compound 158157 158

[0280] To a solution of 157 (300 mg, 444 umol, 1.00 eq) in DCM (3.00 mL) was added TFA (462 mg, 4.05 mmol, 0.300 mL, 9.11 eq). The mixture was stirred at 25 °C for 2 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of 158 = 0.00) indicated 157 was consumed completely. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 3 / 1 to 0 / 1 , DCM / MeOH =10 / 1). Compound 158 (220 mg, 319 umol, 71.8% yield, TFA) was obtained as a red oil. [M+H] 574.2.General procedure for preparation of compound 159158 159

[0281] 23 (33.8 mg, 196 umol, 0.90 eq) was added to a solution of 158(150 mg, 218 umol, 1.00 eq, TFA), K2CO3 (120 mg, 871 umol, 4.00 eq) and Nal (3.27 mg, 21.8 umol, 0.10 eq) in DMF (1.50 mL) the mixture was stirred at 25 °C for 20 h. Then 23 (7.53 mg, 43.6 umol, 0.20 eq) was added to the reaction, the mixture was stirred at 25 °C for 20 h. LCMS (RT of product = 0.979 min) showed 158 was consumed completely. Water (20 mL) was added to the reaction, extracted with EtOAc (20 mL,20 mL, 15 mL), the organic layers were washed with brine (20 mL) and dried over Na2SO4, concentrated under reduced pressure to give a residue. Without further purification. Compound 159 (120 mg, 168 umol, 77.5% yield) was obtained as an orange oil. [M+H] 710.3.General procedure for preparation of Molecule 34159 Molecule 34

[0282] A solution of 159 (120 mg, 168 umol, 1 .00 eq) in NHs / MeOH (7.00 M, 2.40 mL, 99.4 eq) was stirred at 30 °C for 9 h. LCMS (RT of product = 1 .127 min, RT of 159 = 1 .294 min) showed 159 was not consumed completely. The reaction was concentrated under reduced pressure at 25 °C, added MeOH (3 mL x 3) to remove NH3 under reduced pressure at 25 °C. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NFUHCOsJ-ACN]; B%: 20%-50%, 8 min), then the residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min). Compound Molecule 34 (3.00 mg, 5.14 umol, 3.04% yield) was obtained as a white solid. [M+H] 584.2.Synthesis of Molecule 35General procedure for preparation of compound 162160 162

[0283] Compound 160 (5.00 g, 3.85 mmol, 1.00 eq), Compound 161 (3.88 g, 3.85 mmol, 1.00 eq), Pd(OAc)2 (95.17 mg, 424 pmol,0.11 eq), RuPhos (3.79 g, 8.13 mmol, 2.11 eq) were dissolved in toluene (25 mL) and H2O (2.5 mL) , and then the mixture was stirred at 120 °C for 24 h under N2 atmosphere. TLC indicated no reactant 160 remained, and one major new spot with larger polarity was detected. The reaction mixture was concentrated under reduced pressure to give a residue, and then diluted with water (50 mL) and extracted with EtOAc (40 mL, 30 mL). The combined organic layers were washed with brine, dried over, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give desired compound as a white solid. Compound 162 (4.00 g, 1.95 mmol, 66.6% yield) was obtained as a white solid. [M+H] 513.2.General procedure for preparation of Compound 163162 163

[0284] Compound 162 (4.00 g, 1.95 mmol, 1.00 eq) was dissolved in DCM (9 mL), and added BBr3 (5.38 g, 21.5 mmol, 2.07 mL, 11 .0 eq) at - 70 °C, and then the mixture was stirred at -20 °C for 3 h underN2 atmosphere. TLC indicated no reactant 162 remained, and one major new spot was detected. The reaction mixture was quenched by addition solvent NaHCOs mL at 0 °C, and extracted with DCM (100 mL, 60 mL). The combined organic layers were washed with brine (30 mL, 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a lightyellow solid. Compound 163 (3.62 g, 1.28 mmol, 65.59% yield) was obtained as a white solid. [M+H] 485.2.General procedure for preparation of compound 164163 164

[0285] Compound 163 (0.40 g, 825 pmol, 1 .00 eq) and tert-butyl N- [(1 R,3S)-3-hydroxycyclopentyl]carbamate (199 mg, 991 pmol, 1.2 eq) was dissolved in THF (2.0 mL) ,and added PPhs (433 mg, 1 .65 mmol,2.00 eq) and DEAD (287 mg, 1.65 mmol, 300 pL, 2.00 eq) at 0 °C, and then the mixture was stirred at 20 °C for 12h under N2 atmosphere. TLC indicated no reactant remained, and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =10 / 1 to 5 / 1 ). Compound 164 (0.40 g, 599 pmol, 72.6% yield) was obtained as a white solid. [M+H] 668.3.General procedure for preparation of 165164 165

[0286] Compound 164 (0.400 g, 599 pmol, 1.00 eq) was dissolved in MeOH (3.6 mL), and added HCI / MeOH (4 M, 2.99 mL, 20 eq), and then the mixture was stirred at 20 °C for 12 hrs. TLC showed no reactantremained. One new spot was detected. The mixture was concentrated under reduced pressure to give a white solid. Compound 165 (0.25 g, 566pmol, 94.5% yield) was obtained as a white solid. [M+H] 568.3.General procedure for preparation of compound 164163 164

[0287] PPhs (3.11 g, 11.9 mmol, 2.50 eq) was added to a solution of compound 163 (1.43 g, 7.12 mmol, 1.50 eq) in THF (16.0 mL) under N2 stirred at 65 °C, DIEA (1 .53 g, 11.9 mmol, 2.07 mL, 2.50 eq) was added to above solution, the mixture was stirred at 65 °C for 20 mins. TLC indicated Reactant 1 was consumed completely and many new spots formed. The reaction was messy according to TLC. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 2:1 ). Compound 164 (2.30 g, 3.44 mmol, 72.6% yield) was obtained as a colorless oil. [M+H] 668.3.General procedure for preparation of compound 165164 165

[0288] HCI / MeOH (92.0 mL) was added a solution of compound 164 (2.30 g, 3.44 mmol, 1 .00 eq) in MeOH (2.30 mL) then stirred at 25 °C for 1 h.TLC indicated reactant was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction was concentrated under reduced pressure to give a residue. The crude product is used directly for the next step, without purification. Compound 165 (1 .60 g, 3.35 mmol, 97.2% yield, HCI) was obtained as a white oil. [M+H] 568.3.General procedure for preparation of Molecule 35165 Molecule 35

[0289] A solution of compound 84 (569 mg, 2.99 mmol, 1.20 eq) in DMF (2.50 mL) was added dropwise to a solution of compound 165 (1.10 g, 2.49 mmol, 1 .00 eq), K2CO3 (1 .03 g, 7.47 mmol, 3.00 eq) powder and Nal (149 mg, 996 pmol, 0.40 eq) in DMF (2.50 mL) under N2, then stirred at 25 °C for 2 hrs. After compound 84 (170 mg, 891 pmol, 1.10 eq) in DMF (2.50 mL) was added dropwise to a solution, under N2, then stirred at 25°C for 1 hr. TLC indicated reactant 1 was consumed completely and many new spots formed. The reaction was messy according to TLC. H2O (15.0 mL) was added to the mixture, extracted with EtOAc (10.0 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 0 / 1). Molecule 35 (170 mg, 285 pmol, 11.5% yield) was obtained as a black oil. [M+H] 596.3.General procedure for preparation of Molecule 36165 Molecule 36

[0290] Compound 165 (0.15 g, 339pmol, 1.00 eq), Compound 166 (85.0 mSg, 407pmol, 1 .20 eq), Nal (50.9 mg, 339. pmol, 1 .00 eq), K2CO3 (234 mg, 1.70 mmol, 5.00 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 12 h under N2 atmosphere. TLC indicated no reactant remained. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 m, 20 mL). Thecombined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give desired compound as a white solid. Molecule 36 (0.030 g, 48.88 pmol, 20.00% yield) was obtained as a white solid. [M+H] 614.3.Synthesis of Molecule 37General procedure for preparation of compound 121120 121

[0291] 121 was prepared according to the procedure used for the synthesis of Molecule 26.General procedure for preparation of compound 167156 167

[0292] 121 (753 mg, 2.04 mmol, 2.00 eq) was added to a solution of 156(500 mg, 1.02 mmol, 1 .00 eq) and K2CO3 (422 mg, 3.06 mmol, 3.00 eq) powder in dry DMF (4 mL) at 25 °C, then stirred at 80 °C (outside) for 19 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 167 = 0.35, Rf of 156 = 0.24) indicated -80% 156 was remained, one new spot was detected. LCMS (RT of 50A = 1.465 min) indicated desired MS. The two reactions were added to H2O (40 mL) at 25°C, and extracted with EtOAc (15 mL, 15 mL, 10 mL), the organic layers were washed brine (30 mL) and dried over Na2SO4, filtered and the organic layers and yellow precipitate were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 6 / 1 , 4 / 1 , 0 / 1 ). The residue was purified by prep-TLC (SiO2, Petroleumether / Ethyl acetate = 2 / 1 ). Compound 167 (120 mg, 174 umol, 17.1 % yield) was obtained as a white solid. [M+H] 688.3.General procedure for preparation of compound 168

[0293] TFA (616 mg, 5.40 mmol, 0.40 mL, 31 .0 eq) was added a solution of 167 (120 mg, 174 umol, 1.00 eq) in DCM (1.6 mL) at 25 °C, then stirred at 25 °C for 1 .5 h. TLC (Petroleum ether / Ethyl acetate = 3 / 1 , Rf of 167 = 0.30, Rf of 168 = 0.00 (PMA)) indicated the reaction was consumed completely. The reaction was concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO2 , Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 168 (130 mg, crude, TFA) was obtained as a brown solid. [M+H] 588.2.General procedure for preparation of compound 169168 169

[0294] 23 (29.5 mg, 171 umol, 1.00 eq) was added to a mixture of 168(120 mg, 171 umol, 1.00 eq, TFA) and Nal (10.3 mg, 68.4 umol, 0.40 eq) and K2CO3 (70.9 mg, 513 umol, 3.00 eq) powder in dried DMF (1 .2 mL) then stirred at 25 °C for 20 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 168 = 0.15, Rf of 169 = 0.43 (PMA)) indicated ~ 20% of 168 remained, and one major new spot with lower polarity was detected. H2O (25 mL) was added to the mixture at ice bath, extracted with EtOAc (15 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 169 = 2.616 min) (SM: RT = 2.326 min; byproduct: RT= 2.700 min). Compound 169 (130 mg, crude) was obtained as a yellow oil. [M+H] 724.3.General procedure for preparation of Molecule 37169 Molecule 37

[0295] A solution of 169 (130 mg, 180 umol, 1 .00 eq) in NHs / MeOH (7.00 M, 2.60 mL, 101 eq) was stirred at 25 °C for 8 h in sealed bottle. LCMS (RT of molecule 37 = 1.136 min) indicated desired MS. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. HPLC (RT of product = 2.492 min). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min). Molecule 37 (16.0 mg, 26.8 umol, 14.9% yield, 100% purity) was obtained as a white solid. LCMS: RT = 2.706 min, [M+H] = 598.3.Synthesis of Molecule 38General procedure for preparation of compound 171170 171

[0296] Aqueous Na2CO3 (1 .00 M, 6.28 mL, 4.00 eq) was added to a mixture of compound 170 (260 mg, 1.57 mmol, 1.00 eq, HCI) in THF (3.38 mL), then the mixture was stirred at 25 °C for 10 min, BOC2O (411 mg, 1.88 mmol, 433 uL, 1 .20 eq) was added, then stirred at 25 °C for 20 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 170 = 0.00, Rf of 171 = 0.20 (Ninhydrin)) indicated the reaction was consumed completely. H2O (30 mL)was added to the mixture, extracted with EtOAc (20 mL, 10 ml_, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 , 5 / 1 , 0 / 1 ). Compound 171 (380 mg, crude) was obtained as a colorless oil. [M+H] 230.2.General procedure for preparation of compound 172171 172

[0297] TosCI (640 mg, 3.36 mmol, 2.20 eq) was added to a solution of compound 171 (350 mg, 1.53 mmoi, 1.00 eq) and DMAP (186 mg, 1.53 mmol, 1.00 eq) in dry Py (3.5 mL) at 0-15 °C, then the reaction was stirred at 25 °C for 20 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 172 = 0.50, Rf of 171 = 0.10 (Ninhydrin)) indicated -20% 171 remained, one major new spot with lower polarity was detected. The reaction was added H2O (30 mL) at 25 °C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 172 = 1.291 min). The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 , 10 / 1 , 0 / 1 ). Compound 172 (500 mg, 1.30 mmol, 85.4% yield) was obtained as a white solid. [M+H] 384.2.General procedure for preparation of compound 17319 173

[0298] Compound 172 (225 mg, 587 umol, 2.30 eq) was added to a mixture of compound 19 (140 mg, 255 umol, 1.00 eq) and CS2CO3 (208 mg, 638 umol, 2.50 eq) in dried DMF (2.8 mL) at 25 °C, then stirred at 85 °C for16 h under N2. LCMS (RT of (1 ) = 1.332 min, RT of 19 = 1.192 min) indicated ~50% 19 remained, ~50% desired MS. The reaction was cooled to 25 °C, the reaction was added to H2O (30 mL), and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (20 mL) and dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue. Compound product (1 ) (350 mg, crude) was obtained as a yellow oil. (2) Ac2O (211 mg, 2.07 mmol, 194 uL, 4.00 eq) was added to a solution of product (1 ) (350 mg, 518 umol, 1 .00 eq) and DMAP (19.0 mg, 155 umol, 0.30 eq) in dried Py (3.5 mL) at 25 °C, then stirred at 25 °C for 20 h under N2. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of 173 = 0.70 (PMA)) indicated the reaction was completed. The reaction was added H2O (30 mL) at 25 °C, and extracted with EtOAc (20 mL, 15 mL, 10 mL), the organic layers were washed brine (15 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate = 10 / 1 , 5 / 1 , 3 / 1 , 0 / 1 ). Compound 173 (200 mg, 155 umol, 30.0% yield, 59.0% purity) was obtained as a yellow oil. LCMS (RT of 173 = 2.959 min) showed ~59.0% purity. [M+H] 760.3.General procedure for preparation of compound 174173 174

[0299] TFA (770 mg, 6.75 mmol, 0.50 mL, 25.7 eq) was added to a solution of compound 173 (200 mg, 263 umol, 1 .00 eq) in DCM (2 mL) at25 °C, then stirred at 25 °C for 1 .5 h. TLC (Petroleum ether / Ethyl acetate =2 / 1 , Rf of 173 = 0.50, Rf of 174 = 0.00 (PMA)) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 174 (120 mg, 155 umol, 58.9% yield, TFA) was obtained as a light-yellow solid. [M+H] 660.2.General procedure for preparation of compound 175174 175

[0300] Compound 84 (27.1 mg, 142 umol, 1 .00 eq) was added to a mixture of compound 174 (110 mg, 142 umol, 1 .00 eq, TFA) and Nal (8.52 mg, 56.8 umol, 0.40 eq) and K2CO3 (58.9 mg, 426 umol, 3.00 eq) powder in dried DMF (2.2 mL), then stirred at 25 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 174 = 0.10, Rfof 175 = 0.40 (PMA)) indicated ~ 20% of compound 174 remained, and one major new spot with lower polarity was detected. H2O (30 mL) was added to the mixture, extracted with EtOAc (25 mL, 20 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. LCMS (RT of 175 = 1.958 min) showed ~60% purity. Compound 175 (140 mg, crude) was obtained as a yellow oil. [M+H] 814.3.General procedure for preparation of Molecule 38175 Molecule 38

[0301] A solution of compound 175 (140 mg, 172 umol, 1.00 eq) in NHs / MeOH (7.00 M, 3.00 mL, 122 eq) was stirred at 25 °C for 5 h in sealed bottle. LCMS (RT of product = 1.086 min) indicated the reaction was completed. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. HPLC (RT of product = 2.300 min). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobilephase: [water (10 mM NH4HCO3) - ACN]; B%: 25%-55%, 8 min). HPLC (RT of product = 2.308 min). Molecule 38 (34.0 mg, 52.6 umol, 30.6% yield, 100% purity) was obtained as a white solid. LCMS: RT = 2.581 min, [M+H] = 646.3.Synthesis of Molecule 39General procedure for preparation of compound 177176 177

[0302] To a mixture of 176 (7.1 g, 38.9 mmol, 1 eq) in THF (49.7 mL) and H2O (12.4 mL) was added LiOH.H2O (6.54 g, 156 mmol, 4 eq) and the mixture was heated to 60°C and stirred for 2 h. TLC (Petroleum ether / Ethyl acetate = 3 / 1 ) indicated the reaction was completed. The mixture was cooled to room temperature and concentrated under reduced pressure, then adjust pH=3 with aqueous HCI (2.0 N). The mixture was extracted with ethyl acetate (20 mLx5). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4, filtered and concentrated to give 177 (6.56 g) as yellow oil without further purification. [M+H] 169.1 .General procedure for preparation of compound 178177 178

[0303] TEA (3.31 g, 32.7 mmol, 4.55 mL, 1 eq), DPPA (9.0 g, 32.7 mmol, 1 eq) and t-BuOH (48.5 g, 654 mmol, 62.6 mL, 20 eq) were added to a solution of 177 (5.5 g, 32.7 mmol, 1 eq) in dioxane (82.5 mL), then stirred at 80°C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 ) indicatedthe reaction was completed. The reaction was cooled to 25°C and poured into water (20 mL), extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 8 / 1 , 2 / 1 , 0 / 1 ) to give 178 (1.88 g, 7.86 mmol, 24% yield) as white solid. [M+H] 240.2.General procedure for preparation of compound 179178 179

[0304] 178 (500 mg, 2.09 mmol, 1 eq) was dissolved in MeOH (5 mL) and cool to 0°C under N2. Add NaBH4 (158 mg, 4.18 mmol, 2 eq) and stir the solution at 0~10°C for 1 h. TLC (Petroleum ether / Ethyl acetate=1 / 1 ) indicated the reaction was completed. The mixture was added water (10 mL) and extract with ethyl acetate (3 x 10 mL), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =10 / 1 , 8 / 1 , 4 / 1 , 0 / 1 ) to give 179 (487 mg) as white solid. [M+H] 242.2.General procedure for preparation of compound 180179 180

[0305] TosCI (660 mg, 3.46 mmol, 2.2 eq) was added to a solution of 179(380 mg, 1.57 mmol, 1 eq) and DMAP (192 mg, 1.57 mmol, 1 eq) in dry Py (3.5 mL) at 0-15°C, then the reaction was stirred at 25°C for 20 h under N2 TLC (Petroleum ether / Ethyl acetate=1 / 1 ) indicated the reaction wascompleted. The reaction was added water (20 mL) at 25°C, and extracted with EtOAc (20 mLx3), the organic layers were wished brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=30 / 1 , 20 / 1 (product), 10 / 1 , 0 / 1 ) to give 180 (500 mg, crude) as colorless oil. [M+H] 396.2.General procedure for preparation of compound 18119 181

[0306] 180 (331 mg, 838 umol, 2.3 eq) was added to a mixture of 19 (200 mg, 364 umol, 1 eq) and CS2CO3 (297 mg, 911 umol, 2.5 eq) in dried DMF (4 mL) at 25°C, then stirred at 85°C for 16 h under N2. The reaction was added water (20 mL) at 25°C, and extracted with EtOAc (20 mLx3), the organic layers were wished brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give 181 (400 mg) as yellow oil without further purification. [M+H] 772.3.General procedure for preparation of compound 182181 182

[0307] TFA (1.17 g, 10.3 mmol, 0.76 mL) was added to a solution of 181 (230 mg, 298 umol, 1 eq) in DCM (2.3 mL) at 25°C, then stirred at 25 °C for 2.5 h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue at 45°C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1 , 0 / 1 ) to give 182 (95 mg, TFA salt) as light-yellow solid. [M+H] 672.2.General procedure for preparation of compound 183182 183

[0308] 84 (20.6 mg, 108 umol, 1 eq) was added to a mixture of 182 (85 mg, 108 umol, 1 eq, TFA salt) and Nal (6.48 mg, 43.3 umol, 0.4 eq) and K2CO3 (44.8 mg, 324 umol, 3 eq) in dry DMF (1.7 mL), then stirred at 25°C for 16 h under N2. The reaction was added H2O (20 mL) at 25°C, and extracted with EtOAc (15 mLx3), the organic layers were washed brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give 183 (70 mg) as yellow oil without further purification. [M+H] 826.3.General procedure for preparation of Molecule 39183 Molecule 39

[0309] A solution of 183 (70 mg, 84.7 umol, 1 eq) in NHs / MeOH (7 M, 3 mL) was stirred 25°C for 5 h in a sealed bottle. The reaction was concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCOs)-ACN]; B%: 25%-50%, 8 min) to give Molecule 39 (15 mg, 99.2% purity) as white solid. LCMS: RT = 2.653 min, [M+H] = 658.3.Synthesis of Molecule 40General procedure for preparation of compound 57a

[0310] 7A (170 mg, 346 umol, 1.00 eq) and 3A (376 mg, 1.73 mmol, 5.00 eq) and PPhs (227 mg, 866 umol, 2.50 eq) were switched with redistilled THF / redistil led toluene ((2.5 mL / 2.5 mL) x 3) under reduced pressure, then dissolved in redistilled THF (1 .2 mL), DIAD (175 mg, 866 umol, 2.50 eq) was added at 25 °C, then stirred at 25 °C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 7A = 0.24, Rf of 57a = 0.60 (PMA)) indicated the was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0, 10 / 1 , 8 / 1 , 6 / 1 , 1 / 0). The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 ). LCMS (ET20981 -475-P1 P, RT of 57a = 1.336 min) indicated desired MS. Compound 57a (240 mg, crude) was obtained as a colorless oil. [M+H] 690.3.General procedure for preparation of compound 57b

[0311] TFA (924 mg, 8.10 mmol, 0.60 mL, 23.3 eq) was added a solution of 57a (240 mg, 348 umol, 1 .00 eq) in DCM (2.4 mL) at 25 °C, then stirred at 25 °C for 1 .5 h. TLC (Petroleum ether / Ethyl acetate = 2 / 1 , Rf of 57a = 0.50, Rf of 57b = 0.00 (PMA)) indicated the reaction was consumed completely. The reaction was concentrated under reduced pressure at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 , DCM / MeOH = 10 / 1). Compound 57b (230 mg, crude, TFA) was obtained as a brown solid. [M+H] 590.2.General procedure for preparation of compound 57c

[0312] 1X (53.9 mg, 312 umol, 1 .00 eq) was added to a mixture of 57b (220 mg, 312 umol, 1.00 eq, TFA) and Nal (18.7 mg, 125 umol, 0.40 eq) and K2CO3 (129 mg, 937 umol, 3.00 eq) powder in dried DMF (2.2 mL), then stirred at 25 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 57b = 0.10, Rf of 57c = 0.50 (PMA)) indicated - 20% of 57b was remained, and one major new spot with lower polarity was detected. H2O (25 mL) was added to the mixture at ice bath, extracted with EtOAc (15 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (ET20981 -478-P1A, RT of 57c = 1.126 min) showed -50% purity. Compound 57c (230 mg, crude) was obtained as a light brown oil. [M+H] 726.3.General procedure for preparation of ACH-001873

[0313] A solution of 57c (230 mg, 317 umol, 1.00 eq) in NHs / MeOH (7.00 M, 5 mL, 110 eq) was stirred at 25 °C for 10 h in sealed bottle. LCMS (ET20981-482-P1 B, RT of ACH-001873 = 1.151 min) indicated the reaction was consumed completely and desired MS. The reaction was concentrated under reduced pressure and added MeOH (5 mL x 3) to remove NH3 under reduced pressure at room temperature. HPLC (ET20981-482-P1 C, RT of ACH-001873 = 2.652 min). The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 3 min). HPLC (ET20981-482-PJ1 , RT of ACH-001873 = 2.640 min). ACH-001873 (25.0 mg, 40.9 umol, 12.9% yield, 98.4% purity) was obtained as a white solid. LCMS: ET20981-482-P1 P, RT = 2.781 min, [M+H] = 600.3.General procedure for preparation of ACH-001875

[0314] Compound 5’ (100 mg, 219 pmol, 1 .00 eq) and Compound 5A (56.6 mg, 328 pmol, 1.50 eq) was dissolved in DMF (2.40 mL), and added Nal (32.8 mg, 219 pmol, 1.00 eq) and K2CO3 (151 mg, 1.09 mmol, 5 .OOeq), and then the mixture was stirred at 20 °C for 12 hrs. TLC indicated reactant 1 was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give desired compound as a white solid. Compound ACH-001875 (33 mg, 55.6 pmol, 33.0% yield) was obtained as a white solid. [M+H] 594.3.General procedure for preparation of compound 59a

[0315] 3-De (200 mg) was carried out as described for synthesis of 57a to give 59a (280 mg) as yellow solidGeneral procedure for preparation of compound 59b

[0316] 59a (280 mg) was carried out as described for synthesis of 57b to give 59b (230 mg) as TFA saltGeneral procedure for preparation of compound 59c

[0317] 59b (220 mg) was carried out as described for synthesis of 57c to give 59c (200 mg) without purification.General procedure for preparation of ACH-001876

[0318] 59c (200 mg) was carried out as described for synthesis ofMolecule 59C to give ACH-001876 (10 mg) as white solid by pre-HPLC.LCMS: ET20981-570-P1 P2, RT = 2.711 min, [M+H] = 600.3.General procedure for preparation of compound 60-1

[0319] 3-Da (170 mg) was carried out as described for synthesis of 49-1 to give 60-1 (230 mg).General procedure for preparation of compound 60-3

[0320] 60-1 (230 mg) was carried out as described for synthesis of 49-2 to give 60-2 (220 mg) as TFA salt.General procedure for preparation of compound 60-3

[0321] 60-2 (210 mg) was carried out as described for synthesis of 49-3 to give 60-3 (200 mg) without purification.General procedure for preparation of ACH-001877

[0322] 60-3 (210 mg) was carried out as described for synthesis ofMolecule 60-3 to give ACH-001877 (7 mg) after pre-HPLC. RT = 2.568 min, [M+H] = 584.2.General procedure for preparation of compound 61 A

[0323] Compound 7A (200 mg, 407 umol, 1 .00 eq) and compound 3A (443 mg, 2.04 mmol, 5.00 eq) and PPh3(267 mg, 1.02 mmol, 2.50 eq) were switched with redistilled TH F / redistilled toluene ((4 mL / 4 mL) x 4) under reduced pressure, then dissolved in redistilled THF (2 mL), DIAD (206 mg, 1 .02 mmol, 198 uL, 2.50 eq) was added at 15 °C, then stirred at 15 °C for 16 h under N2. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of 7A = 0.24, Rf of 61 A = 0.45 (PMA)) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 7 / 1 , 6 / 1 (P), 0 / 1 (PPh3)). LCMS (ET20981 -578-P1A, RT of 61 A = 1.530 min), HPLC (ET20981-578-P1 B1 , RT of 61 A = 4.806 min). The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30 mm*5u m; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50%-80%, 8 min). Compound 61 A (200 mg, 290 umol, 71.1 % yield) was obtained as a white solid. [M+H] 690.3.General procedure for preparation of compound 61 B

[0324] TFA (770 mg, 6.75 mmol, 0.50 mL, 23.3 eq) was added to a solution of compound 61 A (200 mg, 290 umol, 1 .00 eq) in DCM (2 mL) at 15 °C, then stirred at 15 °C for 1 h. TLC (Petroleum ether / Ethyl acetate = 3 / 2, Rf of 61 A = 0.40, Rf of 61 B = 0.00 (PMA)) indicated the reaction was consumed completely. The reaction was concentrated under reduced pressure to give a residue. Compound 61 B (210 mg, crude, TFA) was obtained as a light brown oil. [M+H] 590.2.General procedure for preparation of compound 61 C

[0325] Compound 32X (54.1 mg, 284 umol, 1 .00 eq) was added to a mixture of compound 61 B (0.20 g, 284 umol, 1.00 eq, TFA) and K2CO3 (118 mg, 852 umol, 3.00 eq) powder and Nal (17.0 mg, 114 umol, 0.40 eq) in DMF (2 mL), then stirred at 15 °C for 16 h under N2. TLC (DCM / MeOH = 10 / 1 , Rfof 61 B = 0.10, Rfof 61 C = 0.40 (PMA)) indicated - 20% of 61 B was remained, and one major new spot with lower polarity was detected. H2O (20 mL) was added to the mixture at ice bath, extracted with EtOAc (15 mL, 15 mL, 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. LCMS (ET20981 -584-P1A, RT of 61C = 2.653 min) indicated -70% desired MS. Compound 61 C (230 mg, crude) was obtained as a light green oil. [M+H] 744.3.General procedure for preparation of ACH-001878

[0326] A solution of compound 61 C (0.23 g, 309 umol, 1 .00 eq) inNHs / MeOH (7.00 M, 4.60 mL, 104 eq) was stirred at 15 °C for 11 h in sealedbottle, the reaction was concentrated under reduced pressure to give a residue, then dissolved in NHs / MeOH (7.00 M, 4.60 mL, 104 eq), and stirred at 15 °C for 8 h in sealed bottle. LCMS (ET20981 -586-P1A4, RT of ACH- 001878 = 1.277 min) indicated desired MS. HPLC (ET20981-586-P1A5, RT of ACH-001878 = 2.954 min) showed ~78% purity. The reaction was concentrated under reduced pressure to give a residue (< 30 °C). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 8 min). ACH-001878 (67.5 mg, 106 umol, 34.3% yield, 97.1 % purity) was obtained as a white solid. LCMS: ET20981 -586-P1 P1 , RT = 2.468 min, [M+H] = 618.3.General procedure for preparation of compound 10n

[0327] t-BuOK (4.38 g, 39.0 mmol, 1 .20 eq) was added at 0 °C to a compound 10m (15.0 g, 32.5 mmol, 1.00 eq, HCI) in THF (150 mL). After 20 mins, the reaction mixture was filtrated through a celite pad and rinsed with EtOAc. Solvents were removed in vacuo, and the residue was suspended in dry hexane (285 mL). The triethyl borane (1 .0 M, 39.0 mL, 1 .20 eq) was added to the carbene suspension at 0 °C and the resulting solution was allowed to warm to 25 °C for 16 hrs. The solvents were evaporated to deliver the expected complexes after appropriate purification. LC-MS (ET56420-16- P1 A1 ) showed was consumed completely and one main peak with desired. The reaction was concentrated under reduced pressure to remove solvent. Compound 10n (16.1 g, 32.4 mmol, 99.7% yield, 98% purity) was obtained as a yellow solid, m / z 486.4.General procedure for preparation of compound 2

[0328] Compound 10n (4.22 g, 8.67 mmol, 1.50 eq), compound 1 (3.00 g, 5.78 mmol, 1.00 eq), RuPhos (863 mg, 1.85 mmol, 0.32 eq) and diacetoxypalladium (221 mg, 983 pmol, 0.17 eq) in Tol. (37.5 mL) and H2O (3.75 mL) at 25 °C was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 24 h sunder N2 atmosphere.LC-MS (ET73809-10-P1A1 , product: RT = 2.17 min; start material: RT =2.04 min) showed ~0% of reactant 1 remained. Several new peaks were shown on LC-MS and ~90.9% of desired compound was detected. H2O (12.0 mL) was added to the mixture, extracted with EtOAc (20.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiC>2, Petroleum ether / Ethyl acetate=20 / 1 to 8 / 1 ). Compound 2 (2.94 g, 5.74 mmol, 99.2% yield) was obtained as a white solid. [M+H] 513.2.General procedure for preparation of compound 3

[0329] A solution of BBrs (5.86 g, 23.4 mmol, 2.26 mL, 10.0 eq) in dried DCM (24.0 mL) was add dropwise to a solution of compound 2 (1 .20 g, 2.34 mmol, 1.00 eq) in dried DCM (12.0 mL) at -70°C, then stirred at -70 °C for 0.5 h and -10°C for 0.5 hrs. TLC indicated compound 2 was consumed completely and new spot formed. The reaction was poured into ice andneutralized with sat. NaHCOs (100 ml_) and solid NaHCOs in ice-bath, separated and the aqueous layer was extracted with DCM (250 mL, 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 6 / 1 ). Compound 3 (970 mg, 2.00 mmol, 85.5% yield) was obtained as a white solid. [M+H] 485.2.General procedure for preparation of compound 4

[0330] PPhs (812 mg, 3.10 mmol, 2.50 eq) was added to a solution of compound 3 (600 mg, 1 .24 mmol, 1 .00 eq) and compound C (538 mg, 2.48 mmol, 2.00 eq) in THF (3.50 mL) at 60 °C under N2, DIAD (626 mg, 3.10 mmol, 600 pL, 2.50 eq) was added to above solution, the mixture was stirred at 70 °C for 3 hrs. LC-MS (ET78380-17-P1A1 , product: RT = 2.17 min; start material: RT =1 .85 min) showed -0% of reactant 1 remained.Several new peaks were shown on LC-MS and -18.7% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, Petroleum ether / Ethyl acetate = 2:1 ). Compound 4 (800 mg, 1.17 mmol, 94.48% yield) was obtained as a colorless oil. [M+H] 684.4.General procedure for preparation of compound 5

[0331] HCI / MeOH (10.0 mL) was added a solution of compound 4 (800 mg, 1.17 mmol, 1.00 eq) in MeOH (1.00 mL) then stirred at 25 °C for 1 hr. LC-MS (ET78380-3-P1A3, product: RT = 2.17 min; start material: RT= 1.36 min) showed -0% of reactant 1 remained. Several new peaks wereshown on LC-MS and ~89.7% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. ACN was added to remove HCI / MeOH under reduced pressure. The crude product is used directly for the next step, without purification. Compound 5 (790 mg, 1.02 mmol, 87.1 % yield, 59.0% purity) was obtained as a white oil. [M+H] 458.3.General procedure for preparation of compound ACH-001879

[0332] A solution of compound D (170 mg, 891 pmol, 1 .10 eq) in DMF (2.00 mL) was added dropwise to a solution of compound 5’ (400 mg, 810 pmol, 1 .00 eq, HCI), K2CO3 (336 mg, 2.43 mmol, 3.00 eq) powder and Nal (48.5 mg, 324 pmol, 0.40 eq) in DMF (2.00 mL) under N2, then stirred at 25 °C for 2 hrs. After compound D (170 mg, 891 pmol, 1.10 eq) in DMF (2.00 mL) was added dropwise to a solution, under N2, then stirred at 25 °C for 12 hrs. LC-MS (ET78380-9-P1 A1 , product: RT = 1.70 min; start material: RT =1.29 min) showed ~0% of reactant 1 remained. Several new peaks were shown on LC-MS and -38.6% of desired compound was detected. H2O (12.0 mL) was added to the mixture, extracted with EtOAc (20.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [H2O (10mM NH4HCOS)-ACN]; gradient: 30.0%-60.0% B over 8.0 min). Compound ACH- 001879 (0.11 g, 179.81 pmol, 55.00% yield) was obtained as a white solid. [M+H] 612.3.General procedure for preparation of compound 62-1

[0333] PPh3 (267 mg, 1 .02 mmol, 2.5 eq) and 7A (200 mg, 407 umol, 1 eq), 7b1 (205 mg, 1 .02 mmol, 2.5 eq) were switched with a mixture of redistilled THF and toluene (4 mL / 4 mL x 3). Then dissolved in THF (1 .4 mL) under N2, DIAD (206 mg, 1 .02 mmol, 2.5 eq) was added to above solution at 0~5°C, then stirred at 15°C for 20 h. TLC (Petroleum ether: Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Kromasil C18 (250*50mm*10 urn); mobile phase: [water (10mM NH4HCO3) - ACN]; B%: 55%-85%, 10 min) to give 62-1 (182 mg, 66% yield) as a white solid. [M+H] 674.3.General procedure for preparation of compound 62-2

[0334] TFA (311 mg, 2.73 mmol, 202.22 uL, 10.12 eq) was added to a solution of 62-1 (182 mg, 270 umol, 1 eq) in DCM (1 mL), then stirred at 15°C for 2 h. TLC (Petroleum ether : Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give 62-2 (185 mg, TFA salt) as yellow oil without purification. [M+H] 574.2.General procedure for preparation of compound 62-3

[0335] 62-3 (185 mg, 269 umol, 1 eq, TFA salt), K2CO3 (111 mg, 807 umol, 3 eq) and Nal (4.03 mg, 26.9 umol, 0.1 eq) in DMF (1.8 mL) at 0~5°C, then stirred at 15°C for 16 h. TLC (Dichloromethane: Methanol =10:1) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (20 mL) at 15°C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 62-3 (230 mg, crude) as yellow oil without purification. [M+H] 728.3.General procedure for preparation of ACH-001881

[0336] 62-3 (230 mg, 316 umol, 1 eq) was dissolved in NH3 / MeOH (7 M,6 mL, 133 eq) in a seal tube and stirred at 15°C for 12 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-50%, 8 min) to give ACH-001881 (45 mg, 23% yield, 99% purity) as white solid. LCMS: ET29323-56-P1 O1 , RT = 2.644 min, [M+H] = 602.2.General procedure for preparation of compound 62-4

[0337] PPh3(267 mg, 1.02 mmol, 2.5 eq) and 7A (200 mg, 407 umol, 1 eq), 7c1 (205 mg, 1.02 mmol, 2.5 eq) were switched with a mixture of redistilled THF / toluene (4 mL / 4 mL x 3). Then dissolved with THF (1 .4 mL) under N2, DIAD (206 mg, 1 .02 mmol, 2.5 eq) was added to above solution at 0~5°C, then stirred at 15°C for 20 h. TLC (Petroleum ether : Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Kromasil C18 (250*50 mm*10 urn); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 55%-85%, 10 min), to give 62-4 (230 mg, 84% yield) as white solid. [M+H] 674.3.General procedure for preparation of compound 62-5

[0338] TFA (616 mg, 5.40 mmol, 0.4 mL, 16 eq) was added to a solution of 62-4 (230 mg, 341 umol, 1 eq) in DCM (2 mL), then stirred at 15°C for 1 h. TLC (Petroleum ether: Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give 62-5 (234 mg, TFA salt) as yellow oil without purification. [M+H] 574.2.General procedure for preparation of compound 62-6

[0339] K2CO3 (141 mg, 1.02 mmol, 3 eq), Nal (5.10 mg, 34.0 umol, 0.1 eq) and 32X (64.8 mg, 340 umol, 1 eq) were added to a solution of 62-6 (234 mg, 340 umol, 1 eq, TFA salt) in DMF (2.3 mL), then stirred at 15°C for 16 h under N2. TLC (Dichloromethane: Methanol = 10:1 ) indicated the reaction was completed. The reaction mixture was quenched by addition of H2O (20 mL) at 15 °C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 62-6 (310 mg) as yellow oil without purification. [M+H] 728.3.General procedure for preparation of ACH-001882

[0340] 62-6 (310 mg, 426 umol, 1 eq) was dissolved in NHs / MeOH (7 M,5 mL) in a sealed tube and stirred at 15°C for 12 h. The reaction was concentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 21 %-41 %,8 min) to give ACH-001882 (45 mg, 99% purity) as white solid. LCMS: ET29323-59- P101 , RT = 2.643 min, [M+H] = 602.2.General procedure for preparation of compound 62-7

[0341] PPh3(267 mg, 1.02 mmol, 2.5 eq) and 7A (200 mg, 407 umol, 1 eq), 7d1 (205 mg, 1 .02 mmol, 2.5 eq) were switched with a mixture of redistilled THF / toluene (4 mL / 4 mL x 3), then dissolved in THF (1 .4 mL) under N2, DIAD (206 mg, 1 .02 mmol, 2.5 eq) was added to above solution at 0~5°C, then stirred at 15°C for 16 h. TLC (Petroleum ether : Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to give 62-7 (210 mg, 76 % yield) as white solid. [M+H] 674.3.General procedure for preparation of compound 62-8

[0342] TFA (616 mg, 5.40 mmol, 0.4 mL, 17eq) was added to a solution of 62-7 (210 mg, 311 umol, 1 eq) in DCM (1.8 mL), then stirred at 15°C for 2 h. TLC (Petroleum ether: Ethyl acetate = 2:1) indicated the reaction was completed. The reaction was concentrated under reduced pressure to give 62-8 (250 mg, TFA salt) as yellow oil without purification. [M+H] 574.2.General procedure for preparation of compound 62-9

[0343] K2CO3 (129 mg, 933 umol, 3 eq), Nal (4.66 mg, 31.1 umol, 0.1 eq) and 32X(59.3 mg, 311 umol, 1 eq) were added to a solution of 62-8 (214 mg, 311 umol, 1 eq, TFA salt) in DMF (2 mL), then stirred at 15°C for 16 h. TLC (Dichloromethane: Methanol = 10:1 ) indicated the reaction was completed. The reaction mixture was quenched by addition of H2O (20 mL) at 15°C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 62-9 (240 mg) as yellow oil without purification. [M+H] 728.3.General procedure for preparation of ACH-001883

[0344] 62-9 (240 mg, 330 umol, 1 eq) was dissolved in NHs / MeOH (7 M,5 mL) in a sealed tube and stirred at 15°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-55%, 8 min) to give ACH-001883 (46 mg, 99% purity) as white solid. LCMS: ET29323- 63-P1O1 , RT = 2.639 min, [M+H] = 602.2.General procedure for preparation of compound 62-10

[0345] PPh3(267 mg, 1.02 mmol, 2.5 eq), 7e (205 mg, 1.02 mmol, 2.5 eq) and 7A (200 mg, 407 umol, 1 eq) were switched with redistilledTHF / toluene (4 mL / 4 mL x 3), then dissolved in THF (1.4 mL) under N2, DIAD (206 mg, 1 .02 mmol, 2.5 eq) was added to above solution at 0~5°C, then stirred at 15°C for 16 h. TLC (Petroleum ether: Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50%-70%, 8 min) to give 62-10 (175 mg, 63% yield) as white solid. [M+H] 674.3.General procedure for preparation of compound 62-11

[0346] TFA (616. mg, 5.40 mmol, 0.4 mL) was added to a solution of 62- 10 (175 mg, 260 umol, 1 eq) in DCM (1.8 mL), then stirred at 15°C for 1h.TLC (Dichloromethane: Methanol = 10:1 ) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 62-11 (240 mg, TFA salt) as yellow solid without purification. [M+H] 574.2.General procedure for preparation of compound 62-12

[0347] K2CO3 (107 mg, 776 umol, 3 eq), Nal (3.88 mg, 25.9 umol, 0.1 eq) and 1X (49.3 mg, 259 umol, 1 eq) was added to a solution of 62-11 (178 mg, 259 umol, 1 eq, TFA) in DMF (2 mL), then stirred at 15°C for 16 h. The reaction mixture was quenched by addition of H2O (20 mL) at 15°C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 62-12 (240 mg) as yellow solid without purification. [M+H] 728.3.General procedure for preparation of ACH-001884

[0348] 62-12 (240 mg, 330 umol, 1 eq) was dissolved in NHs / MeOH (7 M,5 mL), then the sealed and stirred at 15°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-50%, 8 min) to give ACH-001884 (30 mg, 100% purity) as white solid. LCMS: ET29323-74-P101 , RT = 2.638 min, [M+H] = 602.2.General procedure for preparation of compound 63-1

[0349] K2CO3 (845 mg, 6.11 mmol, 3 eq), 34A-2 (1.73 g, 4.68 mmol, 2.3 eq) was added to a solution of 7A (1 g, 2.04 mmol, 1 eq) in DMF (7 mL) at 15°C, then stirred at 80°C for 16 h. TLC (Petroleum ether: Ethyl acetate = 2:1 ) indicated ~70% reactant 1 was remained. The reaction mixture was quenched by addition of H2O (80 mL) at 15 °C and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1.5:1 ) to give 63-1 (260 mg, 18% yield) as whited solid. [M+H] 688.3.General procedure for preparation of compound 63-2

[0350] TFA (1.23 g, 10.8 mmol, 800 uL) was added to a solution of 63-1 (270 mg, 392 umol, 1 eq) in DCM (3 mL) at 15°C, then stirred at 15°C for 1 h. TLC (Dichloromethane: Methanol = 10:1 ) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 63-2 (310 mg, crude, TFA salt) as yellow oil. [M+H] 588.2.General procedure for preparation of compound 63-3

[0351] K2CO3 (162 mg, 1.18 mmol, 3 eq), Nal (23.5 mg, 157 umol, 0.4 eq) and 32X (74.7 mg, 392 umol, 1 eq) was added to a solution of 62-2 (275 mg, 392 umol, 1 eq, TFA salt) in DMF (2.7 mL) at 15°C, then stirred at 15°C for 16 h. TLC (Dichloromethane: Methanol = 10:1 ) indicated the reaction was completed. The reaction mixture was quenched by addition of H2O (20 mL) at 15 °C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20m L), dried over Na2SO4, filtered and concentrated under reduced pressure to give 62-3 (370 mg) as yellow solid without purification. [M+H] 742.3.General procedure for preparation of ACH-001885

[0352] 63-3 (370 mg, 499 umol, 1 eq) was dissolved in NH3 / MeOH (7 M,6 mL) at 15°C, then stirred at 15°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3um; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 22%-42%, 6 min) to give ACH-001885 (60 mg, 19.% yield, 100% purity) as white solid. LCMS: ET29323-78-P1J1 , RT = 2.690 min, [M+H] = 616.3.General procedure for preparation of compound 64-4

[0353] 64a (265 mg, 1 .39 mmol, 1 .2 eq) was added to a solution of 64-3(816 mg, 1.16 mmol, 1 eq, TFA salt), K2CO3 (481 mg, 3.48 mmol, 3 eq) and Nal (69.5 mg, 463 umol, 0.4 eq) in DMF (8 mL) at 15°C, then stirred at 15°C for 16 h. The reaction mixture was quenched by addition of H2O (80 mL) at 15 °C and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 64-4 (1 g) as yellow solid without purification. [M+H] 744.3.General procedure for preparation of ACH-001886

[0354] 64-4 (1 g, 1.34 mmol, 1 eq) was dissolved in NHs / MeOH (7 M,20.00 mL) at 15°Cin a sealed tube and stirred at 15°C for 7 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre HPLC (column: Waters Xbridge C18 150*50 mm* 10 um; mobile phase: [water (10 mM NH4HCOs)-ACN]; B%: 30%-60%, 10 min) to give ACH-001886 (260 mg) as white solid. LCMS: ET29323-303- P1J1 , RT = 2.890 min, [M+H] = 618.2.General procedure for preparation of compound 6-8

[0355] K2CO3 (1.28 g, 3.93 mmol, 2.30 eq) and Nal (25.6 mg, 171 umol, 0.10 eq) were added to a solution of compound 6_7 (707 mg, 1.71 mmol, 1 .00 eq) and compound 7a (504 mg, 1 .03 mmol, 0.60 eq) dissolved in DMF (4.60 mL) to a 100 mL three-neck round flask the mixture was stirred at 86 °C for 16 hrs. LC-MS (ET60682-58-P1A1 , product: RT = 2.53 min; start material: RT = 1.91 min) showed reactant 1 was consumed completely and one main peak with desired m / z or desired mass was detected. The reaction was added to H2O (10.0 mL) at 25°C, and extracted with EtOAc (10.0 mL), the organic layers were washed brine (10.0 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 1 / 1 ). Compound 6_8 (341 mg, 466 umol, 27.2% yield) was obtained as a white solid. [M-H] 590.2.General procedure for preparation of compound 6-11

[0356] To a solution of compound 6_8 (1 .87 g, 3.09 mmol, 1 .00 eq) was charged ACN (10.0 mL) to a 100 mL three-neck round flask was added TEA (2.50 g, 24.7 mmol, 3.44 mL, 8.00 eq) and then was added AC2O (1 .89 g, 18.5 mmol, 1.73 mL, 6.00 eq) and DMAP (37.7 mg, 308 umol, 0.10 eq) at 35 °C over 6 hrs. The mixture was stirred at 25 °C for 14 hrs. TLC (PE: EtOAc = 1 : 1 , Rf = 0.76) showed the starting material was consumed completely. The reaction was added H2O (1.00 mL) at 5~10°C, extracted with EtOAc (5.00 mL, 5.00 mL, 5.00 mL), the organic layers were washedbrine (10.0 mL x 2) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 1 / 1).Compound 6_11 (917 mg, 1 .25 mmol, 40.6% yield) was obtained as a green oil. [M-H] 716.2.General procedure for preparation of compound 6-12

[0357] Compound 6_11 (115 mg, 160 umol, 1 .00 eq) and DCM (3.45 mL) to the 100 mL three-necked round bottom flask and stirred N2 atmosphere, then was added DMF (1.17 mg, 16.0 umol, 1.23 uL, 0.10 eq) oxalyl dichloride (24.4 mg, 192 umol, 16.8 uL, 1 .20 eq) at 0- 5 °C, then stirred at 20 °C for 20 mins, then the miture was added THIAZOLIDINE (17.1 mg, 192 umol, 15.2 uL, 1.20 eq)stirred at 15- 20 °C for 2 h under N2 atmosphere. LC- MS (ET60682-90-P1A1 , product: RT = 0.94min; start material: RT = 2.3 min) showed no reactant 1 remained. Several new peaks were shown on LC-MS and 4.00% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 6_12 (120 mg, 152 umol, 94.9% yield) was obtained as a white solid. [M+H] 788.3.General procedure for preparation of compound 6-12

[0358] Compound 6_12 (140 mg, 177 umol, 1.00 eq) in HCI / MeOH (0.70 mL) and MeOH (0.70 mL) the mixture was stirred at 25 °C for 3 h. LC-MS(ET60682-94-P1 A1 , product: RT = 2.58 min; start material: RT = 0.94 min) showed no reactant 1 remained. Several new peaks were shown on LC-MS and 46.0% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 6_13 (100 mg, 145 umol, 81 .8% yield) was obtained as a white solid. [M+H] 689.2.General procedure for preparation of compound ACH-001888

[0359] Compound 6_13 (100 mg, 145 umol, 1 .00 eq) in NH3 / MeOH (0.70 mL) the mixture was stirred at 25°C for 3 hrs. LC-MS (ET60682-95- P1A1 , product: RT = 2.90 min; start material: RT = 0.94 min) showed 0% of Reactant 1 remained. Several new peaks were shown on LC-MS and 92.0% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 80*40mm*3 urn; mobile phase:[water (HCI)-ACN]; B%: 20%-35%, 7min). Compound ACH-001888 (16.0 mg, 28.4 umol, 19.6% yield) was obtained as a white solid. [M+H] 563.2.General procedure for preparation of ACH-001887

[0360] Compound 13X (24.3 mg, 127 umol, 1.00 eq) was added to a mixture of compound 5 (67.0 mg, 127 umol, 1.00 eq, HCI) and Nal (5.73 mg, 38.2 umol, 0.30 eq) and K2CO3 (88.0 mg, 637 umol, 5.00 eq) powder in anhydrous DMF (0.70 mL), then stirred at 25 °C for 16 hrs under N2. LCMS(ET60682-166-P1A1 , product: RT = 1.417 min; start material: RT = 1.319 min) showed 0% of Reactant 1 remained. Several new peaks were shown on LCMS and 83% of desired compound was detected. H2O (5.00 mL) was added to the mixture at ice bath, extracted with EtOAc (10.0 mL, 5.00 mL, 5.00 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue at 45 °C. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCI)-ACN]; B%: 20%-45%, 8min). Compound ACH-001887 (43.0 mg, 66.8 umol, 53.7% yield) was obtained as a white solid. [M+H] 644.3.General procedure for preparation of compound 65-4

[0361] 65a (254 mg, 1 .22 mmol, 1 .05 eq) was added to a solution of 64-3(816 mg, 1.16 mmol, 1 eq, TFA salt), K2CO3 (480 mg, 3.48 mmol, 3 eq) and Nal (69.5 mg, 464 umol, 0.4 eq) in DMF (2 mL) at 15°C, then stirred at 15°C for 16 h. The reaction mixture was quenched by addition of H2O (80 mL) at 15°C and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (40mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 65-4 (800 mg) as yellow solid without purification. [M+H] 762.3.General procedure for preparation of ACH-001890

[0362] 65-4 (1 g, 1.31 mmol, 1 eq) was dissolved in NHs / MeOH (7 M, 18 mL) at 15°C, then the sealed and stirred at 15°C for 7 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Phenomenex Gemini-NX 80*40mm*3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give Molecule 36 (200 mg, 23.49% yield, 98% purity) as pink solid. RT = 2.869 min, [M+H] = 636.3.General procedure for preparation of Compound 7-1

[0363] Compound 6 (1 .80 g, 3.47 mmol, 1 .00 eq), compound 1 b (615 mg, 4.16 mmol, 1.20 eq), Ruphos (142.39 mg, 346.83 pmol, 0.10 eq), Pd(OAc)2 (389 mg, 1.73 mmol, 0.50 eq) and K2CO3 (1 .44 g, 10.4 mmol, 3.00 eq) were dissolved in dioxane (12 mL) and H2O (2 mL) ,and then the mixture was stirred at 90 °C for 12 hrs. LCMS indicated no reactant 1 was remained. The reaction mixture was diluted with ACN (20 mL), filtered and concentrated under reduced pressure to give a residue. Compound 7-1 (0.5 g, 953.11 pmol, 27.48% yield) was obtained as a yellow oil. [M+H] 525.2.General procedure for preparation of Compound 7-2

[0364] Compound 7-1 (0.50 g, 953 pmol, 1.00 eq), Pd / C (202 mg, 95.3 pmol, 5% purity, 0.10 eq) were dissolved in EtOH (3.2 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 20 °C for 3 h under H2 atmosphere. LCMS indicated no reactant 1 was remained. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 7-2 (0.45 g, 854.51 pmol, 89.66% yield) was obtained as a yellow oil. [M+H] 527.3.General procedure for preparation of Compound 7-3

[0365] Compound 7-2 (0.45 g, 854 pmol, 1.00 eq) was dissolved in DCM (3 mL), and added BBrs (2.35 g, 9.40 mmol, 905 pL, 11 .0 eq) at -70 °C and then the mixture was stirred at -40 °C for 2 h under N2 atmosphere. LCMS indicated no reactant 1 was remained. The reaction mixture was quenched by addition solvent NaHCOs mL at 0 °C, and extracted with DCM (100 mL, 50 mL, 20 mL). The combined organic layers were washed with brine (30 mL, 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a light-yellow solid. Compound 7-3 (0.40 g, 802 pmol, 93.8% yield) was obtained as a white solid. [M+H] 499.2.General procedure for preparation of Compound 7-4

[0366] Compound 7-3 (0.4 g, 802.31 pmol, 1.00 eq), Compound 3a (87.2 mg, 401 pmol, 0.50 eq), and PPh3 (420 mg, 1 .60 mmol, 2.00 eq) were dissolved in THF (2 mL) ,and added DEAD (279 mg, 1.60 mmol, 292 pL, 2.00 eq) at 65°C,and then the mixture was stirred at 65 °C for 12 hrs. TLC indicated no reactant 1 was remained. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 7 / 1 ). Compound 7-4 (0.36 g, 515 pmol, 64.3% yield) was obtained as a white solid. [M+H] 698.4.General procedure for preparation of Compound 7-5

[0367] Compound 7-4 (0.36 g, 515 pmol, 1.00 eq) was dissolved in MeOH (5 mL), and added HCI / MeOH (4 M, 3.87 mL, 30.0 eq), and then the mixture was stirred at 20 °C for 12 hrs. TLC indicated no reactant 1 was remained. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCI condition) to give desired compound as a white solid. Compound 7-5 (0.16 g, 314 pmol, 57.1% yield, HCI) was obtained as a white solid. [M+H] 472.3.General procedure for preparation of ACH-001898

[0368] A mixture of Compound 7-5 (0.16 g, 339 pmol,1 .00 eq), Compound D (70.8 mg, 339 pmol, 1 .00 eq), Nal (50.9 mg, 339 pmol, 1 .00 eq), K2CO3 (234 mg, 1.70 mmol, 5.00 eq) in DMF (1 .5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 20 °C for 12hr under N2 atmosphere. LCMS indicated no reactant 1 was remained. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 m, 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition) to give desired compound as a white solid. Compound ACH- 001898 (0.041 g, 63.7 pmol, 13.7% yield) was obtained as a white solid. [M+H] 644.3.General procedure for preparation of 3c_2- ,

[0369] NaH (971 mg, 24.3 mmol, 60% purity, 1.50 eq) was added in THF (30 mL), and added THF solution of Compound 867-13-0 (9.08 g, 40.5 mmol, 8.03 mL, 2.50 eq) at 0 °C, and then TFH solution of compound 3c_1 (3.00 g, 16.2 mmol, 1.00 eq) at -78 °C. The mixture was stirred at 20 °C for 3 h under N2 atmosphere. TLC indicated no reactant 1 was remained. The reaction mixture was quenched by addition NH4CI (30 mL) at 0 °C, and then diluted with H2O (50 mL) and extracted with EtOAc (80 mL, 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S iO2 , Petroleum ether / Ethyl acetate=1 / 0 to 10 / 1 ). Compound 3c_2 (1.2 g, 4.70 mmol, 29.02% yield) was obtained as a white solid. [M+H] 242.1 .General procedure for preparation of 3c

[0370] Compound 3c_2 (0.5 g, 1 .96 mmol, 1 .00 eq) was dissolved in THF (5 mL), and added LiBH4 / THF (2 M, 9.79 mL, 10.0 eq) at 0 °C, and then the mixture was stirred 20 °C for 12 hrs. TLC indicated no reactant 1 was remained. The reaction mixture was quenched by addition cold H2O (10 mL) at 0 °C, and extracted with EtOAc (50 mL, 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 3c (0.40 g, crude) was obtained as a white solid. [M+H] 216.2.General procedure for preparation of 8-1

[0371] Compound 6-3 (0.25 g, 515 pmol, 1.00 eq), compound 3c (133 mg, 619pmol, 1 .20 eq) and PPhs (270.66 mg, 1 .03 mmol, 2.00 eq) was dissolved in THF (2.5 mL), and added DEAD (179 mg, 1 .03 mmol, 187pL, 2.00 eq) at 65 °C and then the mixture was stirred at 65 °C for 1 hr. TLC indicated no reactant 1 was remained. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA= 2:1 ). Compound 8-1 (0.2 g, 293.34 pmol, 56.85% yield) was obtained as a white oil. [M+H] 682.4.General procedure for preparation of 8-2

[0372] Compound 8-2 (0.28 g, 410 pmol, 1.00 eq) was dissolved in MeOH (2 mL), and added HCI / MeOH (4 M, 3.08 mL, 30.0 eq), and then the mixture was stirred at 20 °C for 12 hrs. LCMS indicated no reactant 1 was remained. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 8-2 (0.20 g, crude) was obtained as a white oil. [M+H] 582.3.General procedure for preparation of ACH-001899

[0373] A mixture of Compound 8-2 (0.20 g, 439 pmol,1 .00 eq), compound D (137 mg, 658 pmol, 1 .50 eq), Nal (65.8 mg, 439 pmol, 1 .00 eq), K2CO3 (303 mg, 2.19 mmol, 5.00 eq) in DMF (4 mL) wasdegassed and purged with N 2 for 3 times, and then the mixture was stirred at 20 °C for 6hr under N2 atmosphere. LCMS indicated no reactant 1 was remained. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (FA condition) to give desired compound as a white solid.Compound ACH-001899 (0.043 g, 68.5 pmol, 28.7% yield) was obtained as a white solid. [M+H] 634.2.General procedure for preparation of compound 3d-2HO / ' \ IBX(1.5 eq)3 hrs

[0374] Compound 3d-1 (1.80 g, 8.36 mmol, 1 .00 eq) was dissolved in ACN (36 mL), and added IBX (3.51 g, 12.5 mmol, 1.50 eq), and then the mixture was stirred at 80 °C for 3 hrs. TLC indicated no reactant 1 was remained. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 3d_2 (0.90 g, crude) was obtained as a yellow solid. [M+H] 214.1.General procedure for preparation of compound 3d-3

[0375] NaH (890 mg, 22.2 mmol, 60% purity, 2.50 eq) was added in THF(20 mL), and added THF solution of 867-13-0 (4.99 g, 22.2 mmol, 4.42 mL, 2.50 eq) at 0°C, and then TFH solution of Compound 3d_2 (1 .90 g, 8.91 mmol, 1 .00 eq) at -78 °C. The mixture was stirred at 20 °C for 3hr under N2 atmosphere. TLC indicated no reactant 1 was remained. The reaction mixture was quenched by addition NH4CI (1 mL) at 0 °C, and then diluted with H2O (3 mL) and extracted with EtOAc (10 mL, 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered andconcentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 10 / 1 ). Compound 3d_3 (2.24 g, 7.91 mmol, 88.7% yield) was obtained as a white solid. [M+H] 270.2.General procedure for preparation of compound 3d_4

[0376] Pd / C (123 mg, 58.2 pmol, 5% purity, 0.03 eq) was added EtOH (5.5 mL), and added Compound 3d_3 (0.55 g, 1 .94 mmol, 1 .00 eq), and then the mixture was stirred at 20 °C for 3 h under H2 atmosphere. TLC indicated no reactant 1 was remained. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 3d_4 (0.51 g, 1.79 mmol, 92.1 % yield) was obtained as a white solid. [M+H] 272.2.General procedure for preparation of compound 3d

[0377] Compound 3d_4 (0.51 g, 350.41 pmol, 1.00 eq) was dissolved in THF (3 mL), and added LiBH4 / THF (2 M, 876 pL, 3.50 eq) at 0 °C, and then the mixture was stirred at 20 °C for 12 hrs. TLC indicated no reactant 1 was remained. The reaction mixture was quenched by addition cold H2O (10 mL) at 0 °C, and extracted with EtOAc (50 mL, 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA = 2:1 ). Compound 3d (0.30 g, 205 pmol, 58.6% yield) was obtained as a white solid. [M+H] 244.2.General procedure for preparation of compound 9-1

[0378] Compound 6-2 (0.30 g, 619 pmol, 1.00 eq), compound 3d (180 mg, 742 pmol, 1 .20 eq) and PPhs (324 mg, 1 .24 mmol, 2.00 eq) were dissolved in THF (1 mL), and added DEAD (215 mg, 1 .24 mmol, 225 pL, 2.0 eq) at 70 °C, and then the mixture was stirred at 70 °C for 1 hr. LCMS indicated no reactant 1 was remained. The reaction mixture was reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA= 2:1). Compound 9-1 (0.4 g, 563.49 pmol, 91.01 % yield) was obtained as a yellow oil. [M+H] 710.4.General procedure for preparation of 9-2

[0379] Compound 9-1 (0.400 g, 599 pmol, 1.00 eq) was dissolved in MeOH (3.6 mL), and added HCI / MeOH (4 M, 2.99 mL, 20.0 eq), and then the mixture was stirred at 20 °C for 12 hrs. TLC showed no reactant1 remained. One new spot was detected. The mixture was concentrated under reduced pressure to give a white solid. Compound 9-2 (0.25 g, 566pmol, 94.5% yield) was obtained as a white solid. [M+H] 484.3.General procedure for preparation of ACH-001900

[0380] Compound 9-2 (0.15 g, 339pmol, 1.00 eq), Compound D (85.0 mg, 407pmol, 1 .20 eq), Nal (50.9 mg, 339. pmol, 1 .00 eq), K2CO3 (234 mg,1 .70 mmol, 5.00 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 h underN2 atmosphere. TLC indicated no reactant 1 was remained. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 m, 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition) to give desired compound as a white solid. Compound ACH-001900 (0.06 g, 91 ,5pmol, 20.0% yield) was obtained as a white solid. [M+H] 662.3.General procedure for preparation of compound ACH-001895

[0381] A solution of compound D (169 mg, 810 pmol, 1 .00 eq) in DMF (2.00 mL) was added dropwise to a solution of compound 5 (400 mg, 810 pmol, 1 .00 eq, HCI), K2CO3 (336 mg, 2.43 mmol, 3.00 eq) powder and Nal (48.5 mg, 324 pmol, 0.40 eq) in DMF (2.00 mL) under N2, then stirred at 25°C for 2 h, after compound D (169 mg, 810 pmol, 1 .00 eq) in DMF (2.00 mL) was added dropwise to a solution, under N2, then stirred at 25°C for 12 hrs. LC-MS (ET78380-8-P1A1 , product: RT = 1.81 min; start material: RT = 1.29 min) showed ~0% of reactant 1 remained. Several new peaks were shown on LC-MS and ~38.6% of desired compound was detected. H2O (12.0 mL) was added to the mixture, extracted with EtOAc (20.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [H2O (10mM NH4HCO3)-can]; gradient: 30.0%-60.0% B over 8.00 min). Compound ACH- 001895 (0.11 g, 174.68 pmol, 58.18% yield) was obtained as a white solid. [M+H] 630.3.General procedure for preparation of compound 5

[0382] To a solution of compound 4 (1 .70 g, 3.32 mmol, 1 .00 eq) in DCM (17.0 mL) was added BBr3 (8.30 g, 33.2 mmol, 3.20 mL, 10.0 eq). The mixture was stirred at -70 - 10 °C for 1 .5 h. TLC indicated compound 4 was consumed completely and new spot formed. The reaction was poured into ice and neutralized with sat.NaHCO3 (100 mL) and solid NaHCO3 in icebath, separated and the aqueous layer was extracted with DCM (250 mL, 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S iO2 , Petroleum ether / Ethyl acetate = 20 / 1 to 1 / 1 ). Compound 5 (1 .40 g, 2.90 mmol, 87.1 % yield) was obtained as a white solid. [M-H] 470.2.General procedure for preparation of compound 6

[0383] To a solution of compound 5 (900 mg, 1 .90 mmol, 1 .00 eq) and compound C (1 .00 g, 4.80 mmol, 2.50 eq) in THF (6.30 mL) was added DIAD (967 mg, 4.80 mmol, 0.90 mL, 2.50 eq) and PPh3 (1.25 g, 4.80 mmol, 2.50 eq). The mixture was stirred at 70 °C for 3 hrs. TLC (Petroleum ether / Ethyl acetate = 2: 1) indicated compound 5 was consumed completely and one new spot formed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 15 / 1 to 0 / 1 ). Compound 6 (1 .60 g, crude) was obtained as a white solid. [M+H] 670.4.General procedure for preparation of compound 7

[0384] To a solution of compound 6 (500 mg, 746 pmol, 1.00 eq) in HCI / MeOH (4.00 M, 12.5 mL, 67.0 eq). The mixture was stirred at 25 °C for 12 hrs. LC-MS (ET79186-8-P1A3, product: RT=0.356 min) showed compound 6 was consumed completely and one main peak with desired m / z was detected. The reaction was concentrated under reduced pressure to give a residue. The crude product used into the next step without further purification. Compound 7 (600 mg, crude) was obtained as a yellow oil. [M+H] 444.3.General procedure for preparation of ACH-001897

[0385] A solution of compound D (174 mg, 833 pmol, 2.00 eq) in DMF (1 .00 mL) was added dropwise to a solution of compound 7 (200 mg, 417 pmol, 1 .00 eq, HCI), K2CO3 (173 mg, 1 .25 mmol, 3.00 eq) powder and Nal (25.0 mg, 166 pmol, 0.40 eq) in DMF (1.00 mL) under N2, then stirred at 25 °C for 12 hrs. LC-MS (ET79186-9-P1A2, product: RT =1.731 min) showed compound 7 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was extracted with EtOAc (5.00 ml, 3.00 ml) and water (5.00 mL, 3.00 mL). The combined organic layers were washed with brine (5.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*70mm*10um; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 35%-65% B over 20.0 min). Compound ACH-001897 (220 mg, 357 pmol, 44.0% yield) was obtained as a white solid. [M+H] 616.3.General procedure for preparation of compound 1

[0386] A 100 mL three-necked round bottom flask equipped with magnetic stirrer, addition funnel and thermometer were charged with compound LX-4211 (200 mg, 471 umol, 1.00 eq), RuPhos (70.3 mg, 150 umol, 0.32 eq), and Pd(OAc)2 (21 .1 mg, 94.1 umol, 0.20 eq) in toluene (2.50 mL) and H2O (0.25 mL) at 25 °C was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 24 h under N2 atmosphere. LCMS (ET60682-105-P1 A3, product: RT = 1.746 min) showed showed 0% of Reactant 1 remained. Several new peaks were shown on LC-MS and 63% of desired compound was detected. The reaction was added H2O (10.0 mL) at 5~10 °C, extracted with EtOAc (10.0 mL, 5.50 mL), the organic layers were washed brine (10.0 mL x 3) and dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S iO2 , Petroleum ether / Ethyl acetate = 15 / 1 to 0 / 1). Compound 1 (198 mg, 383 umol, 81.4% yield, 81 .0% purity) was obtained as a black solid. [M+H] 419.2.General procedure for preparation of compound 2

[0387] To a solution of Compound 1 (290 mg, 693 umol, 1 .00 eq) in DCM (11.0 mL) was added dropwise Py (658 mg, 8.31 mmol, 671 uL, 12.0 eq), Ac2O (849 mg, 8.31 mmol, 779 uL, 12.0 eq) and DMAP (6.77 mg, 55.4 umol, 0.08 eq) at 20 °C. The resulting mixture was stirred at 20 °C for 1 hr. LCMS (ET60682-111-P1A1 , product: RT = 2.372 min; start material: RT = 1.746 min) showed 0% of Reactant 1 remained. Several new peaks were shown on LCMS and 81.0% of desired compound was detected. Thereaction mixture was concentrated under reduced pressure to give a residue, and then the residue was diluted with MTBE (30.0 mL) and washed with 1 M. HCI (8.00 mL * 2), saturated aqueous solution NaHCO3 (8.00 mL). The combined organic layers were washed with brine (8.00 mL), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether / Ethyl acetate = 15 / 1 to 5 / 1). Compound 2 (266 mg, 488 umol, 70.5% yield) was obtained as a white solid. [M+H] 545.2.General procedure for preparation of compound 3

[0388] A solution of BBr3 (14.3 g, 56.9 mmol, 5.48 mL, 10.0 eq) and dried DCM (31.0 mL) was added dropwise to a solution of compound 2 (3.10 g, 5.69 mmol, 1 .00 eq) in dried DCM (43.4 mL) at -70 °C, then stirred at - 70 °C for 1 .5 hrs and -30 °C for 3 hrs. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf of product = 0.53) indicated compound 2 (3.10 g, 5.69 mmol, 1 .00 eq) was consumed completely. The reaction was slowly poured into stirred sat.NaHCO3 (200 mL) and NaHCO3 (18.0 g) and DCM (200 mL) at 0 °C, extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1 ). Compound 3 (1 .45 g, 2.81 mmol, 49.3% yield) was obtained as a green solid. [M+H] 517.2.General procedure for preparation of compound 4

[0389] To a solution of compound 3 (2.10 g, 4.07 mmol, 1.00 eq) andCompound 3A (883 mg, 4.07 mmol, 1.00 eq) in THF (21 .0 mL) was addeddropwise PPh3 (1.28 g, 4.88 mmol, 1.20 eq) and DEAD (849 mg, 4.88 mmol, 886 uL, 1 .20 eq) at 55 °C. The resulting mixture was stirred at 55 °C for 12 hrs. LCMS (ET60682-140-P1 A1 , product: RT = 2.405 min; start material: RT = 1.909 min) showed 2% of Reactant 1 remained. Several new peaks were shown on LCMS and 84% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 urn; mobile phase: [water (HCI)-ACN]; B%: 80%-95%, 10min). Compound 4 (246 mg, 344 umol, 8.45% yield) was obtained as a white solid. [M+H] 716.3.General procedure for preparation of compound 5

[0390] Compound 4 (196 mg, 274 umol, 1 .00 eq) in HCI / MeOH (4.00 mL) and MeOH (2.00 mL) the mixture was stirred at 25 °C for 12 hrs. LCMS (ET60682-160-P1A3, product: RT = 1.319 min; start material: RT = 1.977 min) showed 0% of Reactant 1 remained. Several new peaks were shown on LCMS and 95% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue at 45 °C. The crude product was used into the next step without further purification. Compound 5 (200 mg, 266 umol, 97.2% yield, 70.0% purity, HCI) was obtained as a green oil. [M+H] 490.3.General procedure for preparation of compound ACH-001892

[0391] Compound 9 (31 .7 mg, 152 umol, 1 .00 eq) was added to a mixture of compound 5 (80.0 mg, 152 umol, 1.00 eq, HCI) and Nal (6.84 mg, 45.6 umol, 0.30 eq) and K2CO3 (105 mg, 760 umol, 5.00 eq) powder inanhydrous DMF (0.80 mL), then stirred at 25 °C for 16 h under N2. LCMS (ET60682-163-P1A1 , product: RT = 1.417 min; start material: RT = 1.319 min) showed 0% of Reactant 1 remained. Several new peaks were shown on LCMS and 95% of desired compound was detected. H2O (5.00 mL) was added to the mixture at ice bath, extracted with EtOAc (10.0 mL, 5.00 mL, 5.00 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue at 45 °C. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water(HCI)-ACN];B%: 5%-40%,8min). Compound ACH-001892 (76.0 mg, 115 umol, 95.0% yield) was obtained as a white solid. [M+H] 662.3.General procedure for preparation of compound 1-1

[0392] To a solution of compound 1 (100 g, 578 mmol, 1 .00 eq) in THF (1.45 L) was added compound 1A (165 g, 635 mmol, 1.10 eq) and Cs2CO3 (377 g, 1.16 mol, 2.00 eq) then the mixture was stirred at 40 °C for 12 hrs. PPh3 (860 mg, 3.28 mmol, 1.20 eq) was added to a solution of compound 1 a (1 .34 g, 2.73 mmol, 1 .00 eq) and compound 7a (900 mg, 2.73 mmol, 1.00 eq) and THF (9.00 mL) to a 100 mL three-neck round flask the mixture was stirred at 50°C and DIAD (571 mg, 3.28 mmol, 596 uL, 1.20 eq). Stir the mixture at 50 °C for 2 hrs. LC-MS (ET60682-29-P1 A1 , product: RT = 2.30 min; start material: RT = 1.80 min) showed 30.0% of reactant 1 remained. Several new peaks were shown on LC-MS and 15.0% of desired compound was detected. The reaction was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 65%-95%,8min). Compound 1-1(508 mg, 633 umol, 23.1 % yield) was obtained as a white solid. [M+H]802.3.General procedure for preparation of compound 1-2

[0393] A solution of compound 1 -1 (250 mg, 312 umol, 1.00 eq) in MeOH (1.25 mL) and HCI / MeOH (1.25 mL) to a 100 mL three-neck round flask, the mixture was stirred at 25°C for 3 hrs. LC-MS (ET60682-41-P1 A1 , product: RT = 1.42 min) showed reactant 1 was consumed completely and one main peak with desired m / z. The reaction was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 1 -2 (200 mg, 284 umol, 91.4% yield) was obtained as a white solid. [M+H] 702.2.General procedure for preparation of ACH-001893

[0394] A solution of compound 1 -2 (200 mg, 285 umol,1.00 eq) in NH3 / MeOH (7.00 M, 3.66 mL, 90.0 eq) to a 100 mL three-neck round flask and stirred at 25 °C for 3 hrs. TLC (Rf = 0.46) indicated Reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 30%-60%, 8min). Compound ACH-001893 (120 mg, 208 umol, 73.1 % yield) was obtained as a white solid. [M+H] 576.2.General procedure for preparation of compound 2

[0395] To a solution of compound 1 (4.00 g, 12.1 mmol, 1.00 eq) in DCM (24.0 mL) was added Dess-Martin (10.3 g, 24.3 mmol, 7.52 mL, 2.00 eq) at 0 °C in a 100 mL three-necked round bottom flask. The mixture was stirred at 20 °C for 4 hrs. TLC (Rf = 0.46) indicated Reactant 1 was consumed completely and one new spot formed. The mixture extracted with DCM (40 mL) and H2O (20 mL) twice. The combined organic layers were washed with brine (20.0 mL) or water and dried over Na2SO4, concentrated under vacuum. Without further purification. Compound 2 (2.50 g, 7.64 mmol, 62.9% yield) was obtained as a white solid. [M+H] 328.1 .General procedure for preparation of compound 3

[0396] A solution in which PPh3(CH3)Br (14.7 g, 41 .2 mmol, 2.70 eq) is stirred in a 100 mL three-neck round flask, and n-BuLi (2.50 M, 17.1 mL, 2.80 eq) at 0° C. were added to the compound 2 (5.00 g, 15.3 mmol, 1 .00 eq) in THF (85.0 mL) followed by stirring for 0.5 hours at 0° C. LC-MS (ET60682-17-P1A1 , product: RT = 1.54 min; start material: RT = 1.43 min) showed reactant 1 was consumed completely and one main peak with desired m / z. The reaction was quenched with a saturated aqueous solution of NH4CI (20 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 10 / 1 ). Compound 3 (2.20 g, 6.76 mmol, 44.3% yield) was obtained as a yellow solid. [M+H] 326.1.General procedure for preparation of compound 4

[0397] To a solution of compound 3 (1 .05 g, 3.23 mmol,1 .00 eq) and THF (4.40 mL) to a 100 mL three-neck round flask was added BH3-Me2S (10.0 M, 323 uL, 1.00 eq) under N2. The mixture was stirred at 5-10 °C for 4 hrs. Then to the mixture was added EtOH (1 .21 mL) and NaOH (3.00 M, 3.23 mL, 3.00 eq) at 5-10 °C. The mixture was added H2O2 (2.93 g, 25.8 mmol, 2.48 mL, 30.0% purity, 8.00 eq)) at 5-10 °C for 16 hrs. LC-MS (ET60682-30-P1A1 , product: RT = 1.42 min; start material: RT = 1.85 min) showed no reactant 1 remained. Several new peaks were shown on LC-MS and 84.0% of desired compound was detected. The reaction mixture was separated and the aqueous phase was extracted with MTBE (6.00 mL, 5.00 mL). The combined organic phase was washed with sat NaHSO3 (50.0 mL). The mixture was separated and organic phase was dried and concentrated under reduced to give the crude. The crude product was used into the next step without further purification. Compound 4 (1 .86 g, 5.42 mmol, 83.9% yield) was obtained as a white solid. [M+H] 344.2.General procedure for preparation of compound 5

[0398] Compound 4 (1 .76 g, 5.13 mmol, 1 .00 eq) was dissolved in DCM (35.0 mL) to a 100 mL three-neck round flask and imidazole (523 mg, 7.69 mmol, 1 .50 eq) and I2 (1 .56 g, 6.15 mmol, 1 .24 mL, 1 .20 eq) were added thereto, followed by cooling to 0°C. Subsequently, PPh3 (1.61 g, 6.15 mmol, 1 .20 eq) was added, and the mixture was stirred at 25° C. for 2 hours. LC- MS (ET60682-36-P1A1 , product: RT = 2.23 min) showed Reactant 1 was consumed completely and one main peak with desired m / z. The reactionwas then quenched with 50.0 ml_ of water, and the resulting product was extracted twice with 30.0 mL of dichloromethane and washed with 50.0 mL of water Dichloromethane was distilled off from the organic phases under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 8 / 1 ). Compound 5 (1.30 g, 2.87 mmol, 55.9% yield) was obtained as a white solid. [M+H] 436.1.General procedure for preparation of compound 6

[0399] A 100 mL three-necked round bottom flask equipped with magnetic stirrer, addition funnel and thermometer were charged with compound 5 (0.99 g, 2.18 mmol, 1.00 eq) and compound 4a (750 mg, 1.53 mmol, 0.70 eq) was dissolved in DMF (5.00 mL) and K2CO3 (453 mg, 3.28 mmol, 1 .50 eq) was added thereto, the mixture was stirred at 60 °C for 12 hours. LC-MS (ET60682-46-P1A2, product: RT = 2.65 min) showed no reactant 1 remained. Several new peaks were shown on LC-MS and 11 .0% of desired compound was detected. The reaction was then quenched with 20.0 mL of water, and the resulting product was extracted twice with 10.0 mL of dichloromethane and washed with 20.0 mL of watet dichloromethane was distilled off from the organic phases under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 55%-85%, 8min). Compound 6 (120 mg, 147 umol, 6.73% yield) was obtained as a white solid. [M+H] 816.3.General procedure for preparation of compound 7

[0400] A 100 mL three-necked round bottom flask equipped with magnetic stirrer, addition funnel and thermometer were charged with compound 6 (110 mg, 134 umol, 1 .00 eq) in MeOH (0.50 mL) and HCI / MeOH (0.50 mL), the mixture was stirred at 25°C for 3 hrs. LC-MS (ET60682-54-P1 A4, product: RT = 1.53 min; start material: RT = 2.04 min) showed Reactant 1 was consumed completely and one main peak with desired m / z or desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 7 (80.0 mg, 112 umol, 82.9% yield) was obtained as a white solid. [M+H] 716.2.General procedure for preparation of ACH-001894

[0401] A 100 mL three-necked round bottom flask equipped with magnetic stirrer, addition funnel and thermometer were charged with compound 7 (80.0 mg, 112 umol, 1.00 eq) in NH3 / MeOH (7.00 M, 1.44 mL, 90.0 eq) was stirred at 25 °C for 4 hrs. TLC (Rf = 0.45) indicated reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 30%-60%, 8min). Compound ACH-001894 (58.0 mg, 98.3 umol, 88.0% yield) was obtained as a white solid. [M+H] 590.2.General procedure for preparation of compound 66-4

[0402] 33X (80.2 mg, 435 umol, 1 .5 eq) was added to a solution of 64-3(204 mg, 290 umol, 1 eq, TFA salt), K2CO3 (120 mg, 869 umol, 3 eq) and Nal (17.4 mg, 116 umol, 0.4 eq) in DMF (2 mL) at 15°C, then stirred at 15°C for 16h. The reaction mixture was quenched by addition of H2O (20 mL) at 15 °C and extracted with EtOA (10 mL * 3). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 66-4 (300 mg) as yellow oil without purification. [M+H] 738.3.General procedure for preparation of ACH-001902

[0403] 66-4 (300 mg, 406 umol, 1 eq) was dissolved in NHs / MeOH (7 M,5 mL) in a sealed tube and stirred at 15°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 urn; mobile phase: [water (10 mM NF HCOsJ-ACN]; B%: 25%-55%, 10 min) to give ACH-001902 (52.9 mg, 21 .27% yield, 100% purity) as whited solid. [M+H] 612.3.General procedure for preparation of compound 2

[0404] TsOH.H2O (3.99 g, 20.9 mmol, 0.10 eq) was added to a solution of compound 1 and dimethoxymethylbenzene (51.1 g, 335 mmol, 50.6 mL,1 .60 eq) in DCM (300 mL) at 25 °C, then stirred at 25 °C for 2 h under N2. TLC (Dichloromethane: Methanol = 10:1 , Rf of 1 = 0.20, Rf of 2 = 0.50) indicated the reaction was completed. The reaction mixture was quenched by addition Et3N, and then diluted with H2O (1000 mL) and extracted with EtOAc (300 mLx3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (300 mL) at 25 oC for 30 min. Compound 2 (54.0 g, 165 mmol, 78.8% yield) was obtained as a white solid. [M+H] 327.1.General procedure for preparation of compound 3

[0405] NaH (19.9 g, 496 mmol, 60% purity, 3.00 eq) was added to a solution of compound 2 (54.0 g, 165 mmol, 1.00 eq) in DMF (1080 mL) at 0 °C, then stirred at 0 °C for 30 min and BnBr (84.9 g, 496 mmol, 59.0 mL, 3.00 eq) was added at 0 °C, the solution of stirred at 25 °C for 16 h. TLC (Dichloromethane: Methanol =10:1 , Rf of 1 = 0.20) indicated the reaction was completed. The reaction mixture was quenched by addition NH4CI (1000 mL) at 0 °C and filtered and filtrate was concentrated under reduced pressure to give a residue, then residue was dissolved in EtOAc (1000 mL) and organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with i-Pr20 (1000 mL) at 25 oC for 30 min. Compound 3 (79.0 g, 156 mmol, 94.2% yield) was obtained as a white solid. [M+H] 507.2.General procedure for preparation of compound 4

[0406] Compound 3 (26.3 g, 51.9 mmol, 1 .00 eq) was partially dissolved in acetone (296 mL) and H2O (33 mL) at 25 °C, then was added NBS (8.78 g, 49.3 mmol, 0.95 eq), then the solution was stirred at 25 °C for 5 min. An orange color was immediately observed and rapidly dissipated in moment. TLC (Petroleum ether : Ethyl acetate = 2:1 , Rf of 4 = 0.30) indicated the reaction was completed. The reaction mixture was quenched by addition NaHCO3 (300 mL) at 25 °C and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1 ). Compound 4 (45.0 g, 100 mmol, 64.4% yield) was obtained as a white solid. [M+H] 449.2.General procedure for preparation of compound 5

[0407] Compound 4 (40.0 g, 44.6 mmol, 1 .00 eq) was dissolved in DMSO (128 mL), then Ac2O (64 mL) was added, the solution was stirred at 25 °C for 16 h. TLC (Petroleum ether : Ethyl acetate = 1 :1 , Rf of product = 0.80) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (2000 mL) at 0~10 °C and extracted with EtOAc mL (150 mLx3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 , 7 / 1 , 5 / 1 (product), 2 / 1 ). Compound 5 (32.0 g, 71.7 mmol, 80.4% yield) was obtained as a white solid. [M+H] 447.2.General procedure for preparation of compound 6

[0408] To a solution of 4-bromo-1 -chloro-2-[(4- ethoxyphenyl)methyl]benzene (19.7 g, 60.5 mmol, 1.50 eq) in THF (180 mL) was added n-BuLi (2.5 M, 24.2 mL, 1 .50 eq) at -65--60 °C, the solution was stirred at -65~-60 °C for 30 min, then a solution of compound 5 (18.0 g, 40.3 mmol, 1 .00 eq) in THF (30 mL) was added at -65-~60 °C, then the reaction was stirred at -65--60 °C for 2 h under N2. TLC (Petroleum ether : Ethyl acetate = 2:1 , Rf of 6 = 0.70) indicated the reaction was completed. The reaction mixture was quenched by addition NH4CI (300 mL) at 0 °C and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1 ). Compound 6 (49.0 g, 70.7 mmol, 87.6% yield) was obtained as a white solid. [M+H] 693.3.General procedure for preparation of compound 8

[0409] Et3SiH (12.7 g, 109 mmol, 17.4 mL, 3.00 eq) was added to a solution of compound 6 (25.2 g, 36.3 mmol, 1 .00 eq) in DCM (151 mL) at 0 °C, then BF3.Et2O (15.5 g, 109 mmol, 13.5 mL, 3.00 eq) was added at 0°C under N2, then the solution was stirred at 0 °C for 1 h. TLC (Petroleum ether: Ethyl acetate = 1 :1) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (50 mL) at 0 °C and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 , 4 / 1 (product), 0 / 1 ). Compound 8 (13.0 g, 22.1 mmol, 60.7% yield) was obtained as a white solid. [M+H] 589.2.General procedure for preparation of compound 8a

[0410] TosCI (7.57 g, 39.7 mmol, 1.80 eq) was added to a solution of compound 8 (13.0 g, 22.1 mmol, 1 .00 eq) in Py (78 mL) at -20°C, then the reaction was stirred at 30 °C for 16 h under N2. TLC (Petroleum ether: Ethyl acetate = 2:1 , Rf of 8 = 0.40, Rf of 8a = 0.20) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (50 mL) at 0 °C and extracted with EtOAc (20 mLx3). The combined organic layers were washed with NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 , 6 / 1 (product), 0 / 1 ). Compound 8a (11.4 g, 15.3 mmol, 69.5% yield) was obtained as a white solid. [M+H] 743.2.General procedure for preparation of compound 10

[0411] To a solution of LiAIH4 (3.51 g, 92.6 mmol, 4.00 eq) in THF (104 mL) was added a solution of compound 8a (17.2 g, 23.1 mmol, 1.00 eq) in THF (30 mL) at 0 °C, after stirred at 0 °C for 30 min, the solution was heated to 65 °C and stirred for 2 h under N2. TLC (Petroleum ether : Ethyl acetate = 3:1 , Rf of 8a = 0.40, Rf of 10 = 0.41 ) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (4.64 mL), 15% NaOH (4.64m L), H2O (14 mL) at 0 °C, then Na2SO4 was added and stirred for 20 min at 15 °C, then the mixture was filtered and filtrated was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 0 / 1 ). Compound 10 (10.2 g, 17.8 mmol, 76.9% yield) was obtained as a white solid. [M+H] 573.2.General procedure for preparation of compound 10-1

[0412] To a solution of compound 10 (6.0 g, 10.5 mmol, 1.00 eq) in DCM (60 mL) and Py (24 mL) was added Tf20 (5.91 g, 20.9 mmol, 3.45 mL, 2.00 eq) at -15 °C, then stirred for 15min at -15 °C and for 1 h at 15 °C under N2. TLC (Petroleum ether : Ethyl acetate = 4:1 , Rf of 10 = 0.25, Rf of 10-1 = 0.45) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 10-1 (7.38 g, 10.5 mmol,) was obtained as a yellow solid. [M+H] 705.2.General procedure for preparation of compound 11

[0413] TBAF (1 M, 104.6 mL, 10.0 eq) was added to a solution of compound 10-1 (7.38 g, 10.5 mmol, 1.00 eq) in THF (44.3 mL), then stirred at 15 °C for 16 h. TLC (Petroleum ether: Ethyl acetate = 5:1 , Rf of 10-1 = 0.30, Rf of 11 = 0.70) indicated the reaction was completed. The reaction mixture was quenched by H2O (100 mL) and extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =100 / 1 , 70 / 1 , 50 / 1 , 30 / 1 (product), 0 / 1 ).Compound 11 (3.50 g, 6.09 mmol, 58.1 % yield) was obtained as a colorless oil. [M+H] 575.2.General procedure for preparation of compound 12

[0414] Compound 11 (3.50 g, 6.09 mmol, 1 .00 eq) was dissolved in ethanethiol (38.2 g, 615 mmol, 45.5 mL, 101 eq) and BF3.Et2O (26.2 g, 184 mmol, 22.8 mL, 30.3 eq), then stirred at 25 °C for 3 h. TLC (Petroleum ether : Ethyl acetate = 4:1 , Rf of 11 = 0.40, Rf of 12 = 0.00) indicated the reaction was completed. The reaction solution was poured into NaHCO3 (100 mL) and extracted with EtOAc (30mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 12 (2.40 g, crude) was obtained as a yellow oil. [M+H] 395.1.General procedure for preparation of compound 13

[0415] DMAP (74.2 mg, 608 umol, 0.10 eq) and Ac2O (3.72 g, 36.5 mmol, 3.42 mL, 6.00 eq) were added to a solution of compound 12 (2.40 g, 6.08 mmol, 1.00 eq) in Py (24 mL) at 0~10 °C, then stirred at 25 °C for 16h. TLC (Dichloromethane : Methanol = 10:1 , Rf of 12 = 0.30, Rf of 13 = 0.90) indicated the reaction was completed. The reaction mixture was poured H2O (20 mL) at 15 °C and extracted with EtOAc (10 mLx2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 , 50 / 1 , 30 / 1). Compound 13 (1.90 g, 3.97 mmol, 65.2% yield) was obtained as a white solid. [M+H] 479.2.General procedure for preparation of compound 13a

[0416] A solution of BBr3 (9.94 g, 39.6 mmol, 3.82 mL, 10.0 eq) in DCM (4 mL) was dropwise to a solution of compound 13 (1 .90 g, 3.97 mmol, 1 .00 eq) in DCM (12 mL) at -65 °C~-60 °C and stirred for 0.5 h, then stirred at -35~-30 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 3:1 , Rf of 13 = 0.40, Rf of 13a = 0.10) indicated the reaction was completed. The reaction mixture was quenched by addition NaHCO3 (100 mL) at 0 °C and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 , 10 / 1 , 0 / 1 ). Compound 13a (1.70 g, 3.77 mmol, 95.0% yield) was obtained as a white solid. [M+H] 451.1.General procedure for preparation of compound 13b

[0417] Compound 13a (700 mg, 1.55 mmol, 1.00 eq), 3A (1.69 g, 7.76 mmol, 5.00 eq) and PPh3 (1 .02 g, 3.88 mmol, 2.50 eq) were switched with anhydrous THF / anhydrous toluene ((1 mL / 1mL) x 3), then dissolved in THF (7 mL), DIAD (785 mg, 3.88 mmol, 754 uL, 2.50 eq) was added to above solution at 0~5 °C and stirred at 15 °C for 16 h under N2. TLC (Petroleum ether: Ethyl acetate = 3:1 , Rf of 13a = 0.40, Rf of 13b = 0.60) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 , 12 / 1 (product), 0 / 1 ). The residue was purified by pre- HPLC (column: Kromasil C18 (250*50 mm*10 urn); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 65%- 95%, 10 min). Compound 13b (850 mg, 1.31 mmol, 84.2% yield) was obtained as a white solid. [M+H] 650.3.General procedure for preparation of compound 14

[0418] TFA (385 mg, 3.38 mmol, 250 uL, 22.0 eq) was added to a solution of compound 13b (100 mg, 154 umol, 1 .00 eq) in DCM (1 mL) at 15 °C, then stirred at 15 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 4:1 , Rf of 13b = 0.50, Rf of 14 = 0.00) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 14 (102 mg, 153 umol, TFA) was obtained as a yellow oil. [M+H] 550.2.General procedure for preparation of compound 15

[0419] K2CO3 (63.7 mg, 461 umol, 3.00 eq), Nal (9.21 mg, 61 .4 umol, 0.40 eq) and 14x (26.51 mg, 153 umol, 1.00 eq) were added to a solution of compound 14 (102 mg, 154 umol, 1.00 eq, TFA) in DCM (1 mL), then stirred at 15 °C for 16 h. LCMS (ET29323-260-P1A1 ) indicated the reaction was completed. The reaction mixture was quenched by H2O (20 mL) and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 15 (104 mg, 153 umol,) was obtained as a yellow oil. [M+H] 686.3.General procedure for preparation of ACH-001903

[0420] Compound 15 (104 mg, 151 umol, 1 .00 eq) was dissolved inNH3 / MeOH (7 M, 1.50 mL, 69.3 eq) at 15 °C, then sealed and stirred at 15 °C for 6 h. LCMS (ET29323-263-P1A4) indicated the -42% desired compound. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mMNH4HCO3)-ACN]; B%: 35%-65%, 8 min). ACH-001903 (12.5 mg, 20.3 umol, 13.4% yield, 98% purity) was obtained as a white solid. [M+H] 602.3.General procedure for preparation of compound 16

[0421] K2CO3 (154 mg, 1.11 mmol, 3.00 eq), Nal (22.2 mg, 148 umol,0.40 eq) and 14a (70.7 mg, 371 umol, 1.00 eq) were added to a solution of compound 14 (204 mg, 371 umol, 1.00 eq) in DMF (2 mL), then stirred at 15 °C for 16 h. LCMS (ET29323-265-P1A1 ) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 16 (261 mg, crude) was obtained as a yellow solid. [M+H] 704.3.General procedure for preparation of ACH-001904

[0422] Compound 16 (261 mg, 370 umol, 1 .00 eq) was dissolved in NH3 / MeOH (7 M, 3 mL, 56.6 eq), then sealed and stirred at 15 °C for 6 h. LCMS (ET29323-268-P1A2) indicated ~57% desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-60%, 8 min). ACH-001904 (82.0 mg, 132 umol, 35.6% yield) was obtained as a white solid. RT = 3.042 min, [M+H] = 620.3.General procedure for preparation of compound 17

[0423] K2CO3 (154 mg, 1.11 mmol, 3.00 eq), Nal (22.2 mg, 148 umol,0.40 eq) and compound 14b (70.7 mg, 370 umol, 1.00 eq) were added to a solution of compound 14 (204 mg, 370 umol, 1 .00 eq) in DMF (2 mL), then stirred at 15 °C for 16 h. LCMS (ET29323-266-P1A1 ) indicated -22% reactant 1 and -68% desired compound. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 17 (261 mg, crude) was obtained as a brown oil. [M+H] 704.2.General procedure for preparation of ACH-001905

[0424] Compound 17 (261 mg, 370 umol, 1.00 eq) was dissolved in NH3 / MeOH (7 M, 3 mL, 56.6 eq), then the solution was sealed and stirred at 15 °C for 6 h. LCMS (ET29323-269-P1A2) indicated -35% desired compound. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 urn; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%, 8 min). ACH-001905 (34.5 mg, 55.6 umol, 15.0% yield) was obtained as a white solid. RT = 3.130 min, [M+H] = 620.2.General procedure for preparation of compound 71-12

[0425] TsOH.H2O (390 mg, 2.05 mmol, 0.10 eq) was added to a solution of compound 71 -12a (4.50 g, 20.5 mmol, 1 .00 eq) and ethylene glycol (5.09 g, 82.0 mmol, 4.59 mL, 4.00 eq) in toluene (27 mL) at 20 °C, then stirred at 120 °C for 5 h. TLC (Petroleum ether: Ethyl acetate = 5:1 , Rf of 71 -12a = 0.60 Rf of 71-12 = 0.50) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (50 mL) and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 0 / 1 ). Compound 71 -12 (5.50 g, crude) was obtained as a colorless liquid.General procedure for preparation of compound 71 -13b

[0426] TsOH.H2O (4.36 g, 22.9 mmol, 1 .50 eq) was added to a solution of compound 71-13a (3.00 g, 15.3 mmol, 1 .00 eq) in DCM (18 mL) at 20 °C, then stirred at 20 °C for 16 h. TLC (Petroleum ether : Ethyl acetate = 4:1 , Rf of 71 -13a = 0.60) indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (20 mL) at -30 oC for 1 h. Compound 71 -13b (3.40 g, 12.6 mmol, 82.8% yield, TsOH) was obtained as a white solid. [M+H] 97.1 .General procedure for preparation of compound 71-13

[0427] A solution of compound 71 -13c (2.82 g, 8.20 mmol, 1.10 eq) in DMF (14 mL) was added HATU (5.67 g, 14.9 mmol, 2.00 eq) and DIPEA (4.82 g, 37.2 mmol, 6.49 mL, 5.00 eq), then stirred at 15 °C for 30 min and then compound 71 -13b (2.0 g, 7.45 mmol, 1.00 eq, TsOH) was added, then stirred at 15 °C for 16 h. LCMS (ET29323-305-P1A1 ) indicated the reaction was completed. The reaction mixture was quenched by addition H2O (140 mL) and extracted with EtOAc mL (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 0 / 1 ). Compound 71 -13 (2.90 g, 6.87 mmol, 92.1% yield) was obtained as a yellow oil. [M+H] 422.1 .General procedure for preparation of compound 71 -13d

[0428] A solution of tricyclohexylphosphane (192 mg, 686 umol, 222 uL, 0.10 eq) and Pd(dba)2 (395 mg, 686 umol, 0.10 eq) in dioxane (5 mL) were added to a solution of compound 71-13 (2.90 g, 6.87 mmol, 1.00 eq), KOAc (1 .01 g, 10.3 mmol, 1 .50 eq) and compound 71x (2.62 g, 10.30 mmol, 1 .50 eq) in dioxane (21 mL) at 90 °C for 3 h. LCMS (ET29323-331-P1 A1) indicated the reaction was completed. The reaction mixture was filtered, and filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S iO2 , Petroleum ether / Ethyl acetate = 15 / 1 , 10 / 1 , 7 / 1 (product), 5 / 1 ). Compound 71 -13d (2.70 g, 5.75 mmol, 83.7% yield) was obtained as a yellow solid. [M+H] 470.3.General procedure for preparation of compound 71-13e

[0429] To a solution of compound 71 -13d (2.80 g, 5.97 mmol, 1 .00 eq) in THF (28 mL) and H2O (7 mL) was added NalO4 (3.83 g, 17.9 mmol, 991 uL, 3.00 eq), then stirred at 25 °C for 0.5 h. Then HCI (4 M, 2.98 mL, 2.00 eq) was added and stirred at 25 °C for 2.5 h. TLC (Petroleum ether : Ethyl acetate = 2:1 ) indicated the reaction was completed. The reaction mixture was filtered, filter cake was washed with THF, filtrate was washed with brine (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge C18 150*50 mm* 10 urn; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%-45%, 10 min). Compound 71-13e (1.40 g, 3.62 mmol, 60.6% yield) was obtained as a yellow solid. [M+H] 388.2.General procedure for preparation of compound 71-2

[0430] IMIDAZOLE (28.1 g, 412 mmol, 2.00 eq) and PPh3 (81.1 g, 309 mmol, 1.50 eq) were added to a solution of compound 71 -1 (40 g, 206 mmol, 1.00 eq) in THF (240 mL), and then I2 (78.4 g, 309 mmol, 62.2 mL, 1 .50 eq) in THF (100 mL) was added dropwise at 85 °C. The solution was stirred at 85 °C for 16 h. TLC (DCM / MeOH / H2O / NH3.H2O = 10 / 5 / 1 / 0.5, Rf of product = 0.50) indicated the reaction was completed. The reaction mixture was filtered, and filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH =20 / 1 to 0 / 1 ). Compound 71-2 (31.8 g, crude) was obtained as a yellow solid. [M+H] 305.1.General procedure for preparation of compound 71-3

[0431] A molecular sieves was added to a solution of compound 71-2 (26 g, 85.5 mmol, 1 .00 eq) and benzyl 2,2,2-trichloroethanimidate (86.4 g, 342. mmol, 64.0 mL, 4.00 eq) in dioxane (520 mL), then the mixture was cooled at 0 °C with an ice bath, then TfOH (6.42 g, 42.7 mmol, 3.77 mL, 0.50 eq) was added dropwise (pH = 2), the mixture was stirred at 0 °C for 10 min.TLC (Dichloromethane : Methanol = 10:1 , Rf of reactant = 0.20) indicated the reaction was completed. The reaction mixture was quenched by addition NaHCO3 (100 mL) at 20 °C, and then diluted with H2O (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 0 / 1 ).

[0432] Compound 71-3 (38.0 g, 66.1 mmol, 77.3% yield) was obtained as a colorless oil. [M+H] 575.1 .General procedure for preparation of compound 71-4

[0433] TEA (66.9 g, 661 mmol, 92.1 mL, 10.0 eq) and compound 71-3 (38.0 g, 66.1 mmol, 1.00 eq) was added to a solution of Pd / C (3.80 g, 10% purity) in MeOH (200 mL) and THF (100 mL), then stirred at 25 °C for 24 h under H2 (20 Psi). LCMS (ET29323-294-P1 A1) indicated the reaction was completed. The reaction mixture was filtered, and filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1 ). Compound 71-4 (20.0 g, 44.6 mmol, 67.4% yield) was obtained as a colorless oil. [M+H] 449.2.General procedure for preparation of compound 71-5

[0434] Compound 71-4 (10.0 g, 22.3 mmol, 1 .00 eq) was added to a solution of CI2Sr.H2O (594 mg, 2.23 mmol, 0.10 eq) in AcOH (70 mL), then the solution was heated to 70 °C and HCI (5 M, 10.00 mL, 2.24 eq) was added, then stirred at 70 °C for 6 h. TLC (Petroleum ether: Ethyl acetate = 4:1 , Rf of R1 = 0.40, Rf of P1 = 0.20) indicated the reaction was completed. The reaction mixture was quenched by addition NaHCO3 (150 mL) at 0 °C and extracted with DCM (40 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 0 / 1 ). Compound 71-5 (3.00 g, 6.90 mmol, 30.9% yield) was obtained as a white solid. [M+H] 435.2.General procedure for preparation of compound 71-6

[0435] Ac20 (6 mL) was added to a solution of compound 71-5 (3.00 g, 6.90 mmol, 1 .00 eq) in DMSO (30 mL), then stirred at 25 °C for 16 h. TLC (Petroleum ether: Ethyl acetate = 4:1 , Rf of reactant 1 = 0.40) indicated the reaction was completed. The reaction mixture was quenched by addition NaHCO3 (100mL) at 0 °C, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 20 / 1 to 0 / 1 ). Compound 71-6 (2.10 g, 4.86 mmol, 70.3% yield) was obtained as a yellow oil. [M+H] 433.2.General procedure for preparation of compound 71-7

[0436] To a solution of 2-(5-bromo-2-chloro-phenyl)-1 ,3-dioxolane (1 .54 g, 5.83 mmol, 1 .20 eq) in THF (12 mL) was added n-BuLi (2.5 M, 2.33 mL, 1 .20 eq) at -65~-60 °C and stirred at -65~60 °C for 15 min, then a solution of compound 71 -6 (2.10 g, 4.86 mmol, 1.00 eq) in THF(10 mL) at -65~-60 °C and stirred for 1 h under N2. TLC (Petroleum ether: Ethyl acetate = 3:1 ) indicated the reaction was completed. The reaction mixture was quenched by addition NH4CI (50 mL) at 0 °C and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 0 / 1 ). Compound 71 -7 (2.20 g, 3.56 mmol, 73.4% yield) was obtained as a colorless oil. [M+H] 617.2.General procedure for preparation of compound 71-8

[0437] HCI (6 M, 5.10 mL, 11.1 eq) was added to a solution of compound 71 -7 (1 .70 g, 2.75 m...

Claims

Claims

1. A COMPOUND characterized in that it has the general Formula I:[Chem 1.] Compound of Formula Ior its pharmaceutically acceptable salts, isomers, crystals, hydrates, prodrugs, metabolites or solvates, wherein: dotted line indicates the presence, or not, of an aliphatic cyclic ring; n is selected from zero or 1 ;P is absent or selected from hydrogen, CH2, C-alkyl linear or branched chain (C1-C20), 0, S, NH or N-alkyl linear or branched chain (C1-C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1-C20), OH, 0- or NH-alkyl linear or branched chain (C1-C20) or NH2; B is absent or selected from hydrogen, C-alkyl linear or branched chain (C1-C20), 0, NH, O- or NH-alkyl linear or branched chain (C1- C20) or NH2;Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1-C20), C-alkyl linear or branched chain (C1-C20), OH, F, Cl, Br, I, 0- or NH-alkyl linear or branched chain (C1-C20) or NH2;M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH- alkyl, wherein the alkyl is linear or branched chain (C1-C20);W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, wherein the alkyl is linear or branched chain (C1- C20);K is selected from CH2, CH-alkyl linear or branched chain (C1- C20), 0, NH, N-alkyl linear or branched chain (C1 -C20) or S;A is absent or selected from 0, S, NH, CH2, NH- or CH-alkyl chain (C1 -C20);D is absent or selected from hydrogen, carbon or sulfur;LT is selected from hydrogen, methyl or fluorine;U is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, wherein the alkyl is linear or branched chain (C1- C20);Z is absent or selected from methyl, CH2OH, S-Me, -CH20C(0)0- alkyl, -CH2OC(O)-alkyl or -CH2OC(O)N-alkyl; optionally, Z or P together can form a cycloalkyl ring;X is a linker space selected from the following, including its isomers:[Chem. 1] radical moieties iY is absent or it is a heterocyclic aliphatic moiety selected from the following, including its isomers:[Chem. 1] radical moieties ii

2. The compound, according to claim 1 , characterized in that the compound of Formula I optionally has the following meanings:P is absent or selected from hydrogen, CH2, 0, S or NH;L is H or -CH2-;B is absent or -0;Q is CH2, ethyl, methyl, isopropyl or chlorine;LT is independently selected from H, fluorine or methyl;U is selected from fluorine, OH or -OC(O)alkyl, wherein the alkyl is linear or branched chain (C1-C20);Z is absent, methyl, -SMe or -CH20H;W is H, OH or -OC(O)alkyl, wherein the alkyl is linear or branched chain (C1-C20).

3. The compound, according to claim 1 , characterized in that the compound has optionally the general formula XV:Formula XV or its pharmaceutically acceptable salts, isomers, crystals, hydrates, prodrugs, metabolites or solvates, wherein: n is selected from zero or 1 ;L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1 -C20), OH, O- or NH-alkyl linear or branched chain (C1-C20) or NH2;B is absent or selected from hydrogen, C-alkyl linear or branched chain (C1-C20), O, NH, 0- or NH-alkyl linear or branched chain (C1- C20) or NH2;P is absent or selected from CH2, C-alkyl linear or branched chain (C1 -C20), 0, S, NH or N-alkyl linear or branched chain (C1 -C20);R2 is selected from C-alkyl linear or branched chain (C1 -C20), OH, F,Cl, Br, I, 0- or N-alkyl linear or branched chain (C1 -C20) or NH2;Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0- alkyl, -CH20C(0)-alkyl or -CH20C(0)N-alkyl; optionally, Z and P together can form a cycloalkyl ring;J is a “linker space” selected from the following, including its isomers:Y is a “heterocyclic aliphatic moiety” selected from the following, including its isomers:

4. The compound, according to any one of claims 1 to 3, characterized in that the compound is preferably selected from:(2R,3R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol;(S)-N-(4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylbutan-2-yl)-2 -cyanopyrrolidine-1 -carboxamide;(S)-N-(5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)-2 -cyanopyrrolidine-1 -carboxamide;(S)-1-((2-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)ethyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-((4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)butyl)glycyl)pyrrolidine-2-carbonitrile;(2S)-1-((3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 R,3R)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 R,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 S,3R)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(2S)-1-((3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-((4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile; (S)-3-((4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylbutan-2-yl)glycyl)thiazolidine-4-carbonitrile;(S)-3-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)thiazolidine-4-carbonitrile;(S)-1-((3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)propyl)glycyl)pyrrolidine-2-carbonitrile;((2R,3S,4R,5R,6S)-6-(4-chloro-3-(4-((4-((2-((S)-2-cyanopyrrolidin-1 - yl)-2-oxoethyl)amino)-4-methylpentyl)oxy)benzyl)phenyl)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)methyl ethyl carbonate;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(1 S,3S,5S)-2-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile;(S)-1-(((1 R,4R)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 S,4S)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-(((1S,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1 R,3R)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(25.45)-1-(((1 R,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1S,3R)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(S)-1-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4,4-difluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1 R,4R)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-((4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-1- methylcyclohexyl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(25.45)-1-(2-(3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)pyrrolidin-1-yl)acetyl)-4-fluoropyrrolidine-2-carbonitrile;2-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)amino)-1 -((S)-3-fluoropyrrolidin-1- yl)ethan-1 -one;2-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)amino)-1 -(3,3-difluoropyrrolidin-1- yl)ethan-1 -one;(S)-1-((2S,4S)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)pyrrolidine-2-carbonyl)pyrrolidine-2 -carbonitrile; ((2S,4S)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)pyrrolidin- 2-yl)(3,3-difluoropyrrolidin-1-yl)methanone;(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- methyltetrahydro-2H-pyran-3,4,5-triol;(S)-1-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-(((1S,3S)-3-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(S)-1-(((1 S,3S)-3-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)cyclopentyl)glycyl)- 4,4-difluoropyrrolidine-2-carbonitrile;(S)-1-(((1 R,4R)-4-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy- 6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-(((1 R,4R)-4-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)-1 -methylcyclohexyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)bicyclo[2.2.2]octan-2-yl)glycyl)-4-fluoropyrrolidine- 2-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)pyrrolidine-2 -carbonitrile;(S)-1-((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-(((1 S,3S)-3-(4-(2-chloro-5-((2S,3R,5S,6R)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4-fluoropyrrolidine-2 -carbonitrile;(25.45)-1-((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4-fluoropyrrolidine-2 -carbonitrile;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(25.45)-1-(((1S,3S)-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1S,3R)-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1 R,3S)-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1 R,3R)-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclopentyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(25.45)-1-(((1 R,4R)-4-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)cyclohexyl)glycyl)-4-fluoropyrrolidine-2- carbonitrile;(S)-3-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)thiazolidine-4-carbonitrile;(S)-3-((5-(4-(2-ethyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)thiazolidine-4-carbonitrile;((2S,4S)-4-((4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)methyl)pyrrolidin-2- yl)(thiazolidin-3-yl)methanone;(S)-3-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)thiazolidine-4-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;(S)-1-((5-(4-(2-ethyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;(2S,3R,4S,5S,6R)-2-(3-(4-(((3R,5S,6R)-5-amino-6-(2,5- difluorophenyl)tetrahydro-2H-pyran-3-yl)oxy)benzyl)-4-chlorophenyl)- 6-methyltetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4S,5S,6R)-2-(3-(4-(((3R,5S,6R)-5-amino-6-(2,5- difluorophenyl)tetrahydro-2H-pyran-3-yl)methoxy)benzyl)-4- chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol;(S)-1-((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;2-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)amino)-1-(3,3-difluoropyrrolidin-1 -yl)ethan-1 -one;(S)-4,4-difluoro-1-((2-methyl-5-(4-(2-methyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)pentan-2-yl)glycyl)pyrrolidine-2-carbonitrile;(S)-4,4-difluoro-1-((5-(4-(2-isopropyl-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)pyrrolidine-2-carbonitrile;(S)-1-((1-(3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2- yl)benzyl)phenoxy)propyl)cyclopropyl)glycyl)-4,4-difluoropyrrolidine- 2-carbonitrile;(S)-1-((1-(3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- m ethyltetrahydro-2 H-pyran-2- yl)benzyl)phenoxy)propyl)cyclopentyl)glycyl)-4,4-difluoropyrrolidine- 2-carbonitrile;(S)-1-(N-(5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)-N-methylglycyl)-4,4-difluoropyrrolidine-2 -carbonitrile;(1 S,3S,5S)-2-((5-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan- 2-yl)glycyl)-2-azabicyclo[3.1 ,0]hexane-3-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-5-fluoro-3,4- dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(S)-3-((5-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)thiazolidine-4-carbonitrile;(S)-1-((S)-2-amino-3-(4-(2-chloro-5-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)benzyl)phenyl)propanoyl)pyrrolidine-2-carbonitrile;(S)-1-((5-(4-(2-chloro-5-((2S,3R,4R,6R)-5,5-difluoro-3,4-dihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)pyrrolidine-2-carbonitrile;(25.45)-1-((5-(4-(2-chloro-5-((2S,3R,4R,6R)-5,5-difluoro-3,4- dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2- methylpentan-2-yl)glycyl)-4-fluoropyrrolidine-2-carbonitrile;(S)-3-((5-(4-(2-chloro-5-((2S,3R,4R,6R)-5,5-difluoro-3,4-dihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)thiazolidine-4-carbonitrile;(S)-1 -((5-(4-(2-ethyl-5-((1 S,2S,3S,4R,5S)-2,3,4-trihydroxy-1 -methyl-6,8-dioxabicyclo[3.2.1 ]octan-5-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4,4-difluoropyrrolidine-2-carbonitrile;(S)-4,4-difluoro-1-((2-methyl-5-(4-((6-((2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)-2,3-dihydro-1 H-inden-4- yl)methyl)phenoxy)pentan-2-yl)glycyl)pyrrolidine-2 -carbonitrile;(S)-1-((5-(4-(2-ethyl-5-((5S,6R,7R,8S)-6,7,8-trihydroxy-4- oxaspiro[2.5]octan-5-yl)benzyl)phenoxy)-2-methylpentan-2-yl)glycyl)- 4,4-difluoropyrrolidine-2-carbonitrile;(2S,3S,4S,5R,6R)-2-(3-(4-(3-(3-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)amino)oxetan-3-yl)propoxy)benzyl)- 4-ethylphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate;(2S,3S,4S,5R,6R)-2-(3-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)amino)-4-methylpentyl)oxy)benzyl)-4-ethylphenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate;(1 R,3S,4S)-2-((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-2-azabicyclo[2.2.1 ]heptane-3-carbonitrile;(2S,4S)-1-((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan-2- yl)glycyl)-4-(fluoromethyl)pyrrolidine-2-carbonitrile; or (2S,3aS,6aS)-1 -((5-(4-(2-ethyl-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy- 6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenoxy)-2-methylpentan- 2-yl)glycyl)octahydrocyclopenta[b]pyrrole-2-carbonitrile.

5. A PROCESS FOR THE PREPARATION OF THE COMPOUNDS of general Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites, isomers or solvates thereof, characterized in that it comprises the following general steps: a) reacting a compound of formula II under protecting group reaction that form a product comprising the formula III:Formula II Formula III b) treating the compound of formula III under conditions that form a product comprising the formula IV:Formula IV c) react a compound of formula IV with a compound of formula V under conditions that form a product comprising the formula VI:Formula V Formula VI d) optionally, react the compound of formula VI under mild-basic hydrolysis conditions to form a compound of Formula I:[Chem.1] Compound of Formula Iwherein, dotted line indicates the presence, or not, of an aliphatic cyclic ring; n is selected from zero or 1 ;P is absent or selected from CH2, C-alkyl linear or branched chain (C1 -C20), 0, S, NH or N-alkyl linear or branched chain (C1 -C20);L is selected from hydrogen, CH2, C-alkyl linear or branched chain (C1 -C20), 0, N-alkyl linear or branched chain (C1-C20) or NH;B is absent or selected from C-alkyl linear or branched chain (C1- C20), 0, NH, O- or NH-alkyl linear or branched chain (C1 -C20) or NH2;Q is selected from hydrogen, CH3, CH2, alkyl linear or branched chain (C1-C20), C-alkyl linear or branched chain (C1 -C20), OH, F, Cl, Br, I, 0- or NH-alkyl linear or branched chain (C1 -C20) or NH2;W is selected from hydrogen, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1 -C20);M is selected from hydrogen, -C(O)alkyl, -C(O)O-alkyl, or -C(O)NH- alkyl, alkyl being linear or branched chain (C1-C20);V is selected from CH2-CI or CH2-Br;K is selected from CH2, CH-alkyl linear or branched chain (C1 -C20), 0, NH, N-alkyl linear or branched chain (C1 -C20) or S;A is absent or selected from 0, S, NH, CH2, NH- or CH-alkyl chain (C1 -C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silyl derivativesLT is selected from hydrogen, methyl or fluorine;II is selected from fluorine, OH, -OC(O)alkyl, -OC(O)O-alkyl, or - OC(O)NH-alkyl, alkyl being linear or branched chain (C1 -C20);Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0- alkyl, -CH20C(0)-alkyl or -CH20C(0)N-alkyl; optionally Z or P together can form a cycloalkyl ring;D is absent or selected from hydrogen, carbon or sulfur;T is selected from hydrogen, methyl, ethyl, or a C-alkyl linear or branched chain (C1-C20);E is an “amino-linker space” selected from the following, including its isomers:X is a linker space selected from the following, including its isomers:Y is absent or it is a heterocyclic aliphatic moiety selected the following, including its isomers:

6. THE PROCESS FOR THE PREPARATION OF THE COMPOUNDS, according to claim 5, characterized in that it comprises the following general steps: a) reacting a compound of formula VII with protecting groups under conditions that form a product of formula VIIIFormula VII Formula VIII b) treat the compound of formula VIII under carbon-carbon couplingconditions to form a reactional product of formula IXFormula IX c) react the compound of formula IX with dealkylating reagents under conditions to form a reactional product of formula XFormula X d) reacting the compound of formula X with a compound of formula XI under conditions that form a compound of formula XIIFormula XI Formula XII e) react a compound of formula XII with a compound of formula XIII under conditions that form a reactional product of formula XIVFormula XIII Formula XIV f) optionally react a compound of formula XIV under mild-basic hydrolysis reactions to form a compound of formula XVFormula XV wherein, n is selected from zero and 1 ;A is selected from O, S, NH, CH2, CH-alkenyl chain (C1-C20);P is absent or selected from CH2, C-alkyl linear or branched chain (C1 -C20), 0, S, NH or N-alkyl linear or branched chain (C1 -C20);PG - is selected from any protecting group; preferably, PG is selected from acetyl, tosyl, C-alkyl linear or branched chain (C1-C20), silyl derivatives.R1 is selected from methyl or ethyl;R2 is selected from C-alkyl linear or branched chain (C1-C20), OH, 0- or N-alkyl linear or branched chain (C1 -C20) or NH2;Z is absent or selected from methyl, CH20H, S-Me, -CH20C(0)0- alkyl; optionally, Z and P together can form a cycloalkyl ring;JH is an “amino-linker space” selected from the following, including its isomers:J is a “linker space” selected from the following, including its isomers:is a “heterocyclic aliphatic moiety” selected from the following, including its isomers:

7. AN INTERMEDIATE COMPOUND in the synthesis of the compound, as defined in claim 1 , characterized in that it is a general intermediate of formula IV or VI:Formula IVFormula VI wherein n, B, L, Q, PG, W, U, U’, P, Z, K, E, X, D, A and Y have the same meanings as those defined in claim 5.

8. A PHARMACEUTICAL COMPOSITION characterized in that it comprises at least one compound of general Formula I, as defined in claim 1 , or its pharmaceutically acceptable salts, isomers, crystals, hydrates, prodrugs, metabolites or solvates, optionally together with at least one pharmaceutically acceptable excipient.

9. A PHARMACEUTICALLY ACCEPTABLE SALT of compound of general Formula I, as defined in claim 1 , or any hydrates, prodrugs, metabolites or solvates thereof, characterized in that the salt is selected from the group comprising inorganic or organic salts selected from hydrochloride, hydrobromide, hydroiodide, hemisulfate, sulfate, lactate, carbonate, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, decanoate, 2,2-dichloroacetate, digluconate, dodecylsulfate, ethane-1 ,2-disulfonate, ethanesulfonate, formate, phosphate, fumarate, galactarate, gentisate, glucoheptanoate, gluconate, glucuronate, glutamate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2- hydroxyethane-sulfonate, isobutyrate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, 3-phenylpropionate, phosphate, L- pyroglutamate, pivalate, propionate, salicylate, sebacate, hydrogensebacate, stearate, succinate, tannate, tartrate, hydrogen tartrate, tosylate, or undecanoate salt.

10. A COMBINATION characterized in that it comprises (i) at least one compound of general Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof; and (ii) one or more agents selected from drugs that are useful for treating cardiovascular diseases, renal diseases, metabolic diseases, diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, and diabetic retinopathy.

11. A COMBINATION, according to claim 10, characterized in that it comprises (i) at least one compound of general Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof; and (ii) one or more agents selected from the list comprising antidiabetics, antihypertensives, lipid-lowering, anti-atherosclerotic, anti-obesity and / or antiplatelet drugs.

12. A MEDICAMENT characterized in that it comprises at least one compound of general Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof, for use in treating human diseases.

13. A MEDICAMENT, according to claim 12, characterized in that it comprises at least one compound of general Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof, for use in treating cardiovascular diseases, metabolic diseases, renal diseases, diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, or diabetic retinopathy.

14. USE of a compound of Formula I, as defined in claim 1 , or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof, characterized in that it is for preparation of a medicament for treating a human or animal disease.

15. USE of a compound of Formula I or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof, according to claim 14, characterized in that the disease is a cardiovascular disease, a metabolic diseases, a renal disease, diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, or diabetic retinopathy.

16. A METHOD OF TREATMENT of a disease characterized in that it comprises to apply an effective amount of compound of Formula I or any pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites or solvates thereof as defined in claim 1 in a human or animal in need.

17. THE METHOD, according to claim 16, characterized in that the disease is a cardiovascular disease, a metabolic diseases, a renal disease, diabetes mellitus, heart failure, stroke, chronic kidney disease, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, hyperlipidemia,hypertriglyceridemia, insulin resistance, hyperglycemia, atherosclerosis, coronary heart disease, peripheral vascular disease, nephropathy, hypertension, neuropathy, diabetic nephropathy, or diabetic retinopathy.

18. THE METHOD, according to claim 16, characterized in that the amount of compound of Formula I is from 0.1 mg to 10,000 mg per day.

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