WO2025245591A1

WO2025245591A1 - Compounds, process for obtaining the compounds, intermediate compounds, reagent compounds, pharmaceutical compositions, pharmaceutical combinations, medicaments, uses and methods of treatment

Info

Publication number: WO2025245591A1
Application number: PCT/BR2024/050227
Authority: WO
Inventors: Hatylas Felype Zaneti DE AZEVEDO; Alessandra MASCARELLO; Marcos Antonio FERREIRA JUNIOR; Fernando Henrique De Souza Gama; Mariana Celestina Frojuello Costa Bernstorff DAMIÃO; Bruno Vinicius MOTTA TEODORO; Cristiano Ruch Werneck GUIMARÃES
Original assignee: Ache Laboratorios Farmaceuticos SA
Current assignee: Ache Laboratorios Farmaceuticos SA
Priority date: 2024-05-31
Filing date: 2024-05-31
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30
Also published as: WO2025245601A1

Abstract

The present invention relates to novel compounds of formula I or any pharmaceutically acceptable salt, crystal, stereoisomer, hydrate, solvate, prodrug, metabolite or solvate thereof. Among other properties, the compounds of the invention exhibit long-acting muscarinic antagonism (LAMA) or dual pharmacological activity at the muscarinic M3 receptor and the beta-2 adrenergic receptor (MABA), which are useful for the treatment of respiratory conditions, such as asthma, chronic obstructive pulmonary disease (COPD) and rhinitis for example. The invention encompasses the compounds, reagent and intermediate compounds, processes for obtaining the compounds of the invention, pharmaceutical compositions, combinations and medicaments containing them and their therapeutic uses and methods for the treatment of human diseases in which such receptors are involved.

Description

COMPOUNDS, PROCESS FOR OBTAINING THE COMPOUNDS, INTERMEDIATE COMPOUNDS, REAGENT COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, PHARMACEUTICAL COMBINATIONS, MEDICAMENTS, USES AND METHODS OF TREATMENT

Field of the Invention

[0001] The present invention relates to novel compounds of formula I or any pharmaceutically acceptable salt, crystal, stereoisomer, hydrate, solvate, prodrug, metabolite or solvate thereof with long-acting muscarinic receptor antagonism activity (herein referred to as LAMA) or as dual muscarinic M3 receptor antagonists and beta-2 adrenergic receptor agonists (herein referred to MABA), which are useful for the treatment of respiratory disorders. The invention encompasses the compounds, reagent and intermediate compounds, processes for obtaining the compounds of the invention, pharmaceutical compositions, combinations and medicaments containing them and their therapeutic uses and methods for the treatment of human diseases in which such receptors are involved.

Background of the Invention

[0002] Respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis, represent a significant global health burden, affecting millions of individuals worldwide. These conditions are characterized by airway inflammation, bronchoconstriction, and in the case of allergic rhinitis, nasal congestion, all of which contribute to impaired respiratory function and reduced quality of life for affected individuals. Upper and lower respiratory tract disorder, such as allergic rhinitis and asthma often coexist, suggesting shared underlying pathophysiological mechanisms and potential for overlapping treatment approaches.

[0003] Current treatment options for these respiratory conditions primarily target specific pathways involved in airway inflammation, bronchoconstriction and/ or allergic response. Beta-2 adrenergic agonists, such as salbutamol, formoterol, and salmeterol, are widely used bronchodilators that act by stimulating beta-2 adrenergic receptors on bronchial smooth muscle cells, leading to relaxation of the airways and improved airflow, thus alleviating symptoms and improving lung function in asthma and COPD. Muscarinic receptor antagonists, particularly those targeting the M3 subtype, are effective bronchodilators that inhibit the vagal cholinergic tone of airway smooth muscle, thereby also promoting airway dilation. For allergic rhinitis, beta-2 adrenergic agonists have demonstrated efficacy in relieving nasal congestion, which is associated with bronchodilation of nasal vasculature. Similarly, M3 muscarinic receptor antagonists also alleviate symptoms of nasal congestion and rhinorrhea in patients with allergic rhinitis by its airway dilation effect.

[0004] Several approved muscarinic M3 antagonists and beta-2 adrenergic agonists for inhaled or nasal use need to be administered several times per day due to their limited duration of action. Even the approved long- acting beta-2 adrenergic agonists (LABAs) and LAMAs, such as formoterol and aclidinium, still require twice-daily dosing via inhalation for the treatment respiratory disorders. This pharmacokinetics profile may result in poor treatment adherence by the patients and thus impair the treatment efficacy. Therefore, there is a need for novel molecules with prolonged effect in the lungs and nasal cavity.

[0005] Additionally, systemic side effects due to exposure to muscarinic antagonists or beta-2 adrenergic agonists are a concern for the management of respiratory diseases. Although inhaled and nasal administrations reduce systemic exposure compared to oral dosing, adverse effects such as dry mouth, urinary retention, blurred vision, tachycardia, tremor, and palpitations still occur due to systemic absorption. Therefore, there is a need for novel compounds with reduced systemic exposure and an improved safety profile. [0006] Despite the relevant pharmacological effect of beta-2 adrenergic agonists and muscarinic M3 antagonists as monotherapies for respiratory diseases, there are patients that continue to experience symptoms and exacerbations, which require the use of drug combinations in the clinic to simultaneously target multiple pathways involved in the disease pathophysiology. For COPD and asthma management, the guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Global Initiative for Asthma (GINA) recommend the combination of antimuscarinic agents with beta-2 agonists for selected patient populations, thus highlighting the need of dual bronchodilation for effective disease control in these subgroups. Selected patients also need the bronchodilation therapy to be administered in combination with anti-inflammatory agents, such as corticosteroids, cysteinyl leukotriene receptor antagonists and phosphodiesterase 4 inhibitors. For rhinitis, a nasal formulation of the muscarinic M3 antagonist ipratropium is approved for the management of rhinorrhea symptoms. Similarly, due to the complexity of the rhinitis condition, M3 antagonists are used in the clinic in combination with other medicines, such as intranasal corticosteroids and antihistamines.

[0007] Although combination of mechanisms of action are required for effective management of respiratory diseases, the development of fixed- dose combination formulations incorporating two or more active ingredient for pulmonary and nasal delivery poses 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. Moreover, achieving optimal drug delivery and deposition of the drugs in the lungs or the nasal cavity poses greater challenges in formulation design and device engineering, potentially compromising the uniformity and consistency of drug delivery. Therefore, there remains a need for improved molecules that combine the bronchodilation effects of both antimuscarinic and adrenergic activities. Although MABAs have been described in the literature (W02004074246, WO2013068554), no drug with this pharmacological profile has been approved by any regulatory agency yet.

[0008] Novel compounds with long-acting muscarinic antagonism (LAMAs) or with dual activity at the muscarinic M3 receptor and the beta-2 adrenergic receptor (MABAs) represent promising approaches for the treatment of respiratory diseases, in particular, compounds also exhibiting long-acting activity to enable once daily dosing and low systemic exposure for an optimized safety. In addition, MABAs would also provide advantages in terms of formulation development either as a product containing a single molecule with dual pharmacology or as a fixed-dose combination with another drug, thus resulting in a single product with triple mode of action. Such compounds are expected to be efficacious for the treatment of respiratory diseases, such asthma, COPD and rhinitis, and to provide higher efficacy, safety and treatment adherence compared with existing therapies.

Summary of the Invention

[0009] The present invention describes compounds that are useful for the treatment of respiratory diseases. Among other properties, the compounds of the invention exhibit long-acting muscarinic antagonism (LAMAs) or dual activity at the muscarinic M3 receptor and the beta-2 adrenergic receptor (MABAs). The compounds may also present long-acting local modulation of the receptors and low systemic exposure.

[0010] Therefore, this invention provides novel compounds of general Formula I or pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof, said compounds comprising the formula I:

[0011] [Chem. 1] - Formula I

wherein:

• a is an integer from 0 to 2;

• each of R3, R4, R5, R6, R7, R9 e R10 is independently selected from hydrogen, (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-10C)cycloalkyl, cyano, or halo;

• the symbol * indicates a chiral center at the carbon atom;

• R8 is independently selected from (1 -4C)alkyl, (3-10C)cycloalkyl, -CH2- phenyl, -CH2-CH2-phenyl or -CH2-(3-10C)cycloalkyl;

• W is independently carbon or nitrogen;

• the 0 attached to the phenyl ring is at ortho, meta or para position;

• R1 is selected from anyone of: a) [Chem. I] - Radical i wherein: o b is an integer from 1 to 4; c is an integer from 1 to 3; o A is -NR18C(0)- or -C(0)NR19- where R18 or R19 is independently hydrogen or (1-4C)alkyl; o each R11 , R12, R13 and R14 is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, or halogen; o R11 and R12 optionally form together -CH=CH-S-; -S-CH=CH-; -CH2- CH2-CH2-; -CH2-CH2-CH2-CH2-; -CH=CH-CH=CH-; -CH=CH-NH-; - NH-CH=CH-; -NH-CH=N-; -CH=CH-O-; -O-CH=CH-; -N=CH-O-; -0- CH=N-; -NH-N=N- ; -N=CH-CH=CH-; -CH=N-CH=CH-; -CH=CH- N=CH-; -CH=CH-CH=N-; -N=CH-CH=N-; -CH=N-CH=N-; -N=CH- N=CH-; -CH=CH-N=N-; -CH=N-N=CH- or -N=N-CH=CH- o each Y or Z is independently selected from carbon or nitrogen, where when Z or Y is nitrogen, R13 and/or R14 is an empty value; b) -(CH2)2-(phen-1 ,4-ylene)-CH2- or -(CH2)2-(OCO)-(phen-1 ,4-ylene)- CH2- c) -R15-X-; o where R15 is (1 -1 OC)Alkyl or (1-10C)-alkoxy and o X is independently hydrogen, NH, N-Boc or 0 d) -CH2-CH2-NH(CO)-CH2-(phen-1 ,4-ylene)-(CH2)d-NH- o where d is an integer from 1 to 3 e) -(CH2)e-(phen-1 ,4-ylene)-(CH2)f-NH-

-(CH2)e-(phen-1 ,3-ylene)-(CH2)f-NH- or

-(CH2)e-(phen-1 ,2-ylene)-(CH2)f-NH- o where e is an integer from 1 to 4 and o f is an integer from 1 to 2; f) [Chem. I] - Radical ii o where g is an integer from 1 to 3; o A’ is -NR20C(O)- or -C(0)NR21- where R20 and R21 are independently hydrogen or (1 -4C)alkyl; o X is independently selected from carbon or oxygen; o W’ is independently hydrogen, (1-4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, or halogen; g) [Chem. I] - Radical iii

X’ is independently nitrogen or CO and

Y’ is independently oxygen, nitrogen or sulfur h) additionally, R1 can be selected from: o -(CH2)2-(CO)NH-(CH2)2-NH- o -(CH2)2-(CO)NH-(CH2)3-NH- o -CH2-(CO)NH(CH2)3-NH- o -(CH2)3-(CO)N(CH3)-(CH2)-NH- o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : R isomer o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : S isomer o -CH2-*CH(CH3)-CH2-(CO)NH-CH2-NH- : R isomer o -CH2-*CH(CH3)-(CH2)-(CO)NH-(CH2)-NH- : S isomer o -(CH2)2-NH(CO)-CH2-NH- o -(CH2)2-NH(CO)-(CH2)2-NH- o -(CH2)3-NH(CO)-*CH(NH2)-CH2- R isomer o -(CH2)3-NH(CO)-*CHNH2)-CH2- S isomer o -(CH2)3-NH(CO)- C(CH3)2-NH- o -(CH2)3-NH(CO)- (CH2)2-NH- o -(CH2)3-C(CH3)2-NH(CO)-(CH2)-NH- o -CH2-C(CH3)2-CH2-NH(CO)-(CH2)-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-CH2-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-CH2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-0-(phen-1 ,4-ylene)-(CH2)3-NH-

• R2 is independently selected from hydrogen or a particular value by the formula iv:

[0012] [Chem. I] - Radical iv wherein:

• R16 is hydrogen, -NR16a CR16b(O), -CR16cR16dOR16e and

• R17 is hydrogen, -CR17aR17bOR17c, -NR17dCR17e(O) ; or

• R16 and R17 together form -NR17fC(O)-CR17g=CR17h-, -CR17i=CR17j- C(O)-NR17k-, -NR17IC(O)-CR17mR17n- CR17oR17p-, -CR17q, R17r- CR17sR17t-C(O)- NR17u- or -NR17vC(O)-CR17xR17y-O-;

• each of R16a, R16b, R16c, R16d and R16e is independently hydrogen or (1- 4C)alkyl; and

• each of R17a, R17b, R17c, R17d, R17e, R17f, R17g, R17h, R17i, R17j, R17I, R17m, R17n, R17o, R17p, R17q, R17r, R17s, R17t, R17u, R17v, R17x or R17y is independently selected from hydrogen or (1 -4C)alkyl;

• R15 is independently selected from hydrogen or OH attached on the phenyl ring at ortho, meta or para position;

• optionally, R2 can be selected from formula v: [0013] [Chem. I] - Radical v

wherein: a) the amide moiety is attached on the six-membered ring at ortho, meta or para position; b) R22 and R23 are independently selected from hydrogen or (1 -4C)alkyl. [0014] The present invention is also directed to processes, reagent or intermediate compounds, 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.

[0015] The compounds of the present invention can be prepared by a process comprising: a. reacting a general reagent compound 1 or a salt thereof: [0016] [Chem. 2] - Reagent compound 1 b. with a general reagent compound 2:

[0017] [Chem. 3] - Reagent compound 2 wherein Nu represents a nucleophile, and P1 represent a hydrogen atom or an amino-protecting group; and c. removing the protecting group P1 to provide a compound of formula I; and optionally, forming a pharmaceutically acceptable salt thereof.

[0018] Compounds of formula I can be prepared by deprotecting an intermediate a:

[0019] [Chem. 4] - Intermediate a wherein P1 represents an amino-protecting group, such as a Boc, Fmoc, benzyl or acetyl. Examples of particular values for P1 are tert-butoxycarbonyl group or fluorenylmethoxycarbonyl group. In this process, amino-protecting groups are conveniently removed by treating the protected compound with trifluoroacetic acid, hydrochloric acid or formic acid. Generally, this reaction is conducted in DCM or dioxane, at room temperature until the reaction is substantially complete. The reaction product is then isolated after neutralization using conventional procedures, such as extraction, recrystallization, and/or chromatography.

[0020] For example, compounds of formula 1 can be prepared from commercially available starting materials and reagents using well-known procedures. In process (b), i.e. , the reaction between the reagents of formula 1 and 2, the nucleophile can be represented by a primary or secondary amine, and the reaction can be performed under conventional amide coupling conditions. By way of illustration, this step involves combining about one equivalent of the amine compound of reagent compound of formula 2 with one or more equivalents of the carboxylic acid reagent compound of formula 1 , in the presence of one or more equivalents of an amine-carboxylic acid coupling reagent, and one or more equivalents of an organic base to form an intermediate a. [0021] Compounds of formula 1 can be prepared by various procedures described herein or by procedures that are well-known to those skilled in the art. For example, the ester group of a reagent compound of formula 3 below, can be readily converted into the corresponding carboxylic acid using well- known reagents and procedures. By way of illustration, the carboxylic acid can be obtained under acid conditions using TFA or HCI. Generally, this reaction is conducted in an inert diluent, such as DCM or THF, at a temperature ranging from 25° C to 40° C until the reaction is substantially complete. The reaction product is then isolated using conventional procedures, such as extraction, recrystallization, and/or chromatography.

[0022] [Chem. 5] - reagent compound 3

[0023] Reagent compound of formula 3 in which b is an integer of 2 can be prepared by reduction of a reagent compound of formula 4:

[0024] [Chem. 6] - reagent compound 4

[0025] By way of illustration, the alkene can be readily reduced to alkane using, for example, hydrogen metal catalyst, such as palladium on carbon, or platinum dioxide.

[0026] Reagent compound of formula 4 can be prepared by reacting a reagent compound of formula 5:

[0027] [Chem. 7] - Reagent compound 5

[0028] with an alkyne such as tert-butyl prop-2-ynoate in presence of a base.

[0029] Reagent compound of formula 5 can be prepared by reacting a reagent compound of formula 6 with a ketone in presence of a reducing agent:

[0030] [Chem. 8] - Reagent compound of formula 6

[0031 ] Referring to the reaction of a reagent compound of formula 6 with a ketone, any suitable reducing agent may be used in this reaction. For example, the reducing agent may be a metal hydride reagent, such as sodium triacetoxyborohydride or cyanoborohydride. Typically, this reduction reaction is conducted in an inert diluent and a protic solvent, such as methanol, at a temperature in the range of 0 °C to 100 °C until the reaction is substantially complete.

[0032] Reagent compound of formula 6 can be prepared by deprotecting a reagent compound of formula 7:

[0033] [Chem. 9] - Reagent compound of formula 7

wherein P2 represents an amino-protecting group, such as a Boc, Fmoc, tosyl or mesyl, and P3 represents a methyl group. Referring to process, i.e., a p- toluenesulfonyl group and methoxyl group can be simultaneously removed by treating the protected compound with one or more equivalents of 4-hydroxy benzoic acid and a HBr/AcOH solution. This reaction will generate the desired phenol reagent compound of formula 6.

[0034] Reagent compound of formula 7 can be prepared by reacting a reagent compound of formula 8:

[0035] [Chem. 10] - Reagent compound of formula 8 with a reagent compound of formula 9:

[0036] [Chem. 11 ] - Reagent compound of formula 9 wherein X1 represents a leaving group, and P2 represent a hydrogen atom or an amino protecting group;

[0037] Reagent compound of formula 8 can be prepared by deprotecting a reagent compound of formula 10:

[0038] [Chem. 12] - Reagent compound of formula 10

wherein P4 represents an amino-protecting group, such as a Boc, Fmoc, tosyl or mesyl. Reagent compound of formula 8 can be prepared using the conditions described in method (a).

[0039] Reagent compound of formula 10 may be prepared by oxidizing the corresponding thioether reagent compound of formula 11 :

[0040] [Chem. 13] - Reagent compound of formula 11

[0041 ] Referring to the process, a reagent compound of formula 11 is treated with a suitable oxidizing agent such as 3-chloroperbenzoic acid. This reaction is typically conducted in an inert diluent such as DCM, at a temperature in the range from about 0 °C to 25° C until the oxidation is substantially complete.

[0042] Reagent compound of formula 11 may be prepared by protection of reagent compound of formula 12:

[0043] [Chem. 14] - Reagent compound 12

[0044] Referring to the process, a reagent compound of formula 12 treated with one or more equivalents of di-tert-buty I dicarbonate, and a base such as triethylamine. The reaction is typically conducted in DCM, at a temperature in the range from about 0 °C to 25° C until the starting material is completely consumed.

[0045] Reagent compound of formula 12 can be prepared by removal of the te/Y-butanesulfinyl group present in reagent compound of formula 13:

[0046] [Chem. 15] - Reagent compound 13

[0047] By way of illustration, the sulfinyl group can be readily removed by treating the protected compound with HCI/dioxane solution. This reaction will generate the desired amine reagent compound of formula 12.

[0048] Reagent compound of formula 13 can be prepared by reacting a reagent compound of formula 14:

[0049] [Chem. 16] - Reagent compound 14 with a Grignard reagent compound in anhydrous DCM. The Grignard reagent compound can be represented by the molecular formula R5MgBr wherein R5 represents the following groups (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3- 10C)cycloalkyl.

[0050] Reagents of formula 14 are generally known in the art or can be prepared from commercially available starting materials and reagents using well-known procedures. For example, reagent compound of formula 14 can be prepared by reacting a reagent compound of formula 15 with tert- butanesulfinamide:

[0051 ] [Chem. 17] - Reagent compound 15

[0052] The reaction of a reagent compound of formula 15 with tert- butanesulfinamide is carried out in the presence of a base such as potassium carbonate or cesium carbonate. The reaction is typically conducted in an inert diluent such as DCM, at a temperature in the range from about 0 °C to 25° C until the carbonyl compound is completely consumed.

[0053] Reagent compound of formula 2 are generally known in the art or can be prepared from commercially available starting materials and reagents using well-known procedures.

[0054] For example, reagent compounds of formula 2 can be prepared by deprotecting a reagent compound of formula 16:

[0055] [Chem. 18] - Reagent compound 16 wherein Nu represents a nucleophile, such as a primary or secondary amine, and P5 represents a hydroxyl-protecting group such as trimethylsilyl, tertbutyldimethylsilyl, or triisopropylsilyl.

[0056] Reagents of formula 16 can be prepared by protection of a reagent compound of formula 17:

[0057] [Chem. 19] - Reagent compound 17

[0058] Reagents of formula 16 can be prepared using conditions similar as described before.

[0059] Reagents of formula 17 in which c is an integer of 1 can be prepared by reacting of a reagent compound of formula 18:

[0060] [Chem. 20] - Reagent compound 18 pound of formula 19: m. 21 ] - Reagent compound 19:

[0062] Reagent compound of formula 17 can be prepared by reacting a reagent compound of formula 18 with an aldehyde in presence of a reducing agent using the conditions described before.

[0063] In another aspect of the invention, it is provided a general intermediate a:

[0064] [Chem. 4] - intermediate a:

wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an aminoprotecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect.

[0065] A reagent compound for the preparation of compounds of formula

I is also claimed wherein the reagent compound is selected from:

[0066] [Chem. 2] - Reagent compound 1 wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an aminoprotecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect. [0067] The present invention is also directed to a pharmaceutical composition comprising at least one compounds of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, defined in the first aspect, and at least one pharmaceutically acceptable excipient.

[0068] 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, enantiomers, diastereomers or solvates thereof for the treatment of diseases, optionally for the treatment of human diseases comprising respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, rhinitis), pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders (such as urinary incontinence), and gastrointestinal disorders (e.g., irritable bowel syndrome, spastic colitis).

[0069] 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 thereof for the manufacture of a medicament for treating a disease comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[0070] The present invention is also directed to method of treatment of a disease comprising the administration of a therapeutically effective amount of at least one compound of general Formula I to a patient in need.

[0071] Said disease comprises respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis. [0072] The present invention is also directed to a combination for simultaneous, separate, or sequential use, which comprises: 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 agents selected from the list comprising a non-steroidal glucocorticoid receptor agonist; a PDE4 inhibitor; a modulator of chemokine receptor function; a corticosteroid; a histamine receptor modulator; an adrenergic agonist; and an inhibitor of p38 kinase function.

It is another aspect of the invention to provide a medicament comprising a compound of general Formula I for use in treating a disease, said disease comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[0073] Other aspects of the invention comprise the intermediate and reagent compounds used in the preparation of the compound of formula I, according to the first aspect.

Detailed Description of the Invention

Definitions

[0074] Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

[0075] 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.

[0076] “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 sulfur atoms 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.

[0077] “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.

[0078] “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.

[0079] “Alkoxy” means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention can be optionally substituted.

[0080] “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 along with 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, and other). 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.

[0081 ] “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.

[0082] “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, and others.

[0083] “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”).

[0084] “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 X and 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.

[0085] “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.

[0086] “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.

[0087] “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.

[0088] “Carbamoyl” means the radical -OC(O)NRR', wherein R and R' are each independently hydrogen or further substituents.

[0089] “Carbocycle” means a ring consisting of carbon atoms.

[0090] “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.

[0091] “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.

[0092] “Cyano” means the radical -CN.

[0093] “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 (ClO)cycloalkyl.

[0094] “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.

[0095] “Halo” means fluoro, chloro, bromo or iodo.

[0096] “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)alkyl. 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.

[0097] “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, imidazo[l,5-a]pyridine, pyrazolo[1 ,5-a]pyridine, imidazo[1 ,2-a]pyrimidine, imidazo[1 ,2-c]pyrimidine, imidazo[1 ,5-a]pyrimidine, 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]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[1 ,5-a]pyridine, pyrrolo[1 ,2-b]pyridazine, pyrrolo[1 ,2c]pyrimidine, pyrrolo[1 ,2-a]pyrimidine, 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.

[0098] “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.

[0099] “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-)=, -O-, -S- or -S(O)2-, wherein R is hydrogen or a further substituent. [0100] “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 with another 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.

[0101] “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.

[0102] “Heterocycloalkyl” means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently fromN, O, 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.

[0103] “Hydroxy” means the radical -OH.

[0104] “IC50” means the molar concentration of an inhibitor that produces

50% inhibition of the target enzyme.

[0105] “Imino” means the radical -CR(=NR') and/or -C(=NR')-, wherein R and R' are each independently hydrogen or a further substituent.

[0106] “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). [0107] “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.

[0108] “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.

[0109] “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.

[0110] “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.

[0111] “Oxy” means the radical -0- or -OR, wherein R is hydrogen or a further substituent. Accordingly, it is noted that the oxy radical may be further substituted with a variety of substituents to form different oxy groups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

[0112] “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.

[0113] “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 acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 4, 4'-methylenebis(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.

[0114] 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.

[0115] “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.

[0116] “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.

[0117] “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.

[0118] “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). [0119] “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. Examples include 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- methoxybenzyloxycarbonyl, 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)CO-], 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 carbon atom 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 [3,[3,[3-trichloroethoxycarbonyl and [3- iodoethoxycarbonyl).

[0120] “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 -10)alkyl, hydroxy(C1 -10)alkyl, carbonyl(C1- 10)alkyl, thiocarbonyl(C1 -10)alkyl, sulfonyl(C1 -10)alkyl, sulfinyl(C 1 -10)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)alky I , 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)alkyl, (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)alky I , 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.

[0121 ] “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.

[0122] “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.

[0123] “Thio” denotes replacement of an oxygen by a sulfur and includes, but is not limited to, -SR, -S- and =S containing groups.

[0124] “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.

[0125] “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.

[0126] “Treatment” or “treating” means any administration of a compound of the present invention and includes: a) 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, b) 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 c) 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).

[0127] 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 Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a (Ci )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 (C-i )alkyls. Similarly, terms such as alkylamino or similar comprise dialkylamino or similar.

[0128] As a first object of the invention, it is revealed a compound of general Formula I:

[0129] [Chem.1 ] - Formula I or pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites, enantiomers, diastereomers or solvates thereof, wherein:

• a is an integer from 0 to 2;

• the symbol * indicates a chiral center at the carbon atom, meaning either R or S configuration can be selected for the compounds of the present invention and its radicals;

• R8 is independently selected from (1 -4C)alkyl, (3-10C)cycloalkyl, -CH2- phenyl, -CH2-CH2-phenyl or -CH2-(3-10C)cycloalkyl; • W is independently carbon or nitrogen;

• the 0 attached to the phenyl ring is at ortho, meta or para position;

• R1 is selected from anyone of:

[0130] [Chem. I] - Radical i: wherein: o b is an integer from 1 to 4; c is an integer from 1 to 3; o A is -NR18C(O)-, -C(O)NR19- -C(O)O- or -OC(O)-, wherein R18 or R19 is independently hydrogen or (1 -4C)alkyl; o each R11 , R12, R13 and R14 is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, or halogen; o R11 and R12 optionally form together -CH=CH-S-; -S-CH=CH-; -CH2- CH2-CH2-; -CH2-CH2-CH2-CH2-; -CH=CH-CH=CH-; -CH=CH-NH-; - NH-CH=CH-; -NH-CH=N-; -CH=CH-O-; -O-CH=CH-; -N=CH-O-; -0- CH=N-; -NH-N=N- ; -N=CH-CH=CH-; -CH=N-CH=CH-; -CH=CH- N=CH-; -CH=CH-CH=N-; -N=CH-CH=N-; -CH=N-CH=N-; -N=CH- N=CH-; -CH=CH-N=N-; -CH=N-N=CH- or -N=N-CH=CH- o each Y or Z is independently selected from carbon or nitrogen, where when Z or Y is nitrogen, R13 and/or R14 is an empty value; a) -(CH2)2-(phen-1 ,4-ylene)-CH2- or -(CH2)2-(OCO)-(phen-1 ,4-ylene)- CH2- b) -R15-X-; o where R15 is (1 -10C)Alkyl or (1-10C)-alkoxy and o X is independently hydrogen, NH, N-Boc or 0 c) -CH2-CH2-NH(CO)-CH2-(phen-1 ,4-ylene)-(CH2)d-NH- o where d is an integer from 1 to 3 d) -(CH2)e-(phen-1 ,4-ylene)-(CH2)f-NH- -(CH2)e-(phen-1 ,3-ylene)-(CH2)f-NH- or -(CH2)e-(phen-1 ,2-ylene)-(CH2)f-NH- o where e is an integer from 1 to 4 and o f is an integer from 1 to 2; e) [Chem. I] - Radical ii: o wherein g is an integer from 1 to 3; o A’ is -NR20C(O)- or -C(0)NR21- where R20 or R21 is independently hydrogen or (1 -4C)alkyl; o X is independently selected from carbon or oxygen; o W’ is independently hydrogen, (1-4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, or halogen; f) [Chem. I] - Radical iii: o where h is an integer from 1 to 3; o X’ is independently nitrogen or CO and o Y’ is independently oxygen, nitrogen or sulfur g) additionally, R1 can be selected from: o -(CH2)2-(CO)NH-(CH2)2-NH- o -(CH2)2-(CO)NH-(CH2)3-NH- o -CH2-(CO)NH(CH2)3-NH- o -(CH2)3-(CO)N(CH3)-(CH2)-NH- o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : R isomer o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : S isomer o -CH2-*CH(CH3)-CH2-(CO)NH-CH2-NH- : R isomer o -CH2-*CH(CH3)-(CH2)-(CO)NH-(CH2)-NH- : S isomer o -(CH2)2-NH(CO)-CH2-NH- o -(CH2)2-NH(CO)-(CH2)2-NH- o -(CH2)3-NH(CO)-*CH(NH2)-CH2- R isomer o -(CH2)3-NH(CO)-*CHNH2)-CH2- S isomer o -(CH2)3-NH(CO)- C(CH3)2-NH- o -(CH2)3-NH(CO)- (CH2)2-NH- o -(CH2)3-C(CH3)2-NH(CO)-(CH2)-NH- o -CH2-C(CH3)2-CH2-NH(CO)-(CH2)-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-CH2-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-CH2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-(CH2)3-NH-

• R2 is independently selected from hydrogen or a particular value by the radical iv, which can assume a R or S configuration:

[0131] [Chem. I] - Radical iv: wherein: o R16 is hydrogen, -NR16a CR16b(O), -CR16cR16dOR16e and o R17 is hydrogen, -CR17aR17bOR17c, -NR17dCR17e(O) ; or o R16 and R17 together form -NR17fC(O)-CR17g=CR17h-, -CR17i=CR17j- C(O)-NR17k-, -NR17IC(O)-CR17mR17n- CR17oR17p-, -CR17q, R17r- CR1 7sR17t-C(0)- NR17u- or -NR17vC(O)-CR17xR17y-O-; o each of R16a, R16b, R16c, R16d and R16e is independently hydrogen or (1 -4C)alkyl; and o each of R17a, R17b, R17c, R17d, R17e, R17f, R17g, R17h, R17i, R17j, R17I, R17m, R17n, R17o, R17p, R17q, R17r, R17s, R17t, R17u, R17v, R17x or R17y is independently selected from hydrogen or (1 -4C)alkyl; o R15 is independently selected from hydrogen or OH attached on the phenyl ring at ortho, meta or para position;

• optionally, R2 can be selected from radical of formula v:

[0132] [Chem. I] - Radical v: wherein: c) The amide moiety is attached on the six-membered ring at ortho, meta or para position; d) R22 and R23 is independently selected from hydrogen or (1 -4C)alkyl.

[0133] In one optional embodiment, R⁷ and R⁹ together form -CH2-CH2-.

[0134] In an embodiment, the compound of formula I is a compound selected from the molecule examples 1 to 205, as described in Table 1 below.

[0135] The present invention is also directed to processes, reagent and intermediate compounds, which are useful to obtain the compounds of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof.

[0136] The compounds of the present invention can be prepared by a process comprising: a. reacting a general reagent compound 1 or a salt thereof:

[0137] [Chem. 2] - Reagent compound 1 b. with a general reagent compound 2:

[0138] [Chem. 3] - Reagent compound 2 wherein Nu represents a nucleophile, and P1 represent a hydrogen atom or an amino-protecting group; and c. removing the protecting group P1 to provide a compound of formula I; and optionally, forming a pharmaceutically acceptable salt thereof.

[0139] Compounds of formula I can be prepared by deprotecting an intermediate a:

[0140] [Chem. 4] - Intermediate a wherein P1 represents an amino-protecting group, such as a Boc, Fmoc, benzyl or acetyl. Referring to process (a), examples of particular values for P1 are tertbutoxycarbonyl group orfluorenylmethoxycarbonyl group. In this process, amino- protecting groups are conveniently removed by treating the protected compound with trifluoroacetic acid, hydrochloric acid or formic acid. Generally, this reaction is conducted in DCM or dioxane, at room temperature until the reaction is substantially complete. The reaction product is then isolated after neutralization using conventional procedures, such as extraction, recrystallization, and/or chromatography.

[0141] For example, compounds of formula I can be prepared from commercially available starting materials and reagents using well-known procedures. In process (b), i.e. , the reaction between the reagents of formula I and II, the nucleophile can be represented by a primary or secondary amine, and the reaction can be performed under conventional amide coupling conditions. By way of illustration, this step involves combining about one equivalent of the amine compound of reagent compound of formula 2 with one or more equivalents of the carboxylic acid reagent compound of formula 1 , in the presence of one or more equivalents of an amine-carboxylic acid coupling reagent, and one or more equivalents of an organic base to form an intermediate I.

[0142] Compounds of formula I can be prepared by various procedures described herein or by procedures that are well-known to those skilled in the art. For example, the ester group of a reagent compound of formula 3 below, can be readily converted into the corresponding carboxylic acid using well- known reagents and procedures. By way of illustration, the carboxylic acid can be obtained under acid conditions using TFA or HCI. Generally, this reaction is conducted in an inert diluent, such as DCM or THF, at a temperature ranging from 25° C to 40° C until the reaction is substantially complete. The reaction product is then isolated using conventional procedures, such as extraction, recrystallization, and/or chromatography.

[0143] [Chem. 5] - reagent compound 3: [0144] Reagent compound of formula 3 in which b is an integer of 2 can be prepared by reduction of a reagent compound of formula 4:

[0145] [Chem. 6] - reagent compound 4:

[0146] By way of illustration, the alkene can be readily reduced to alkane using, for example, hydrogen metal catalyst, such as palladium on carbon, or platinum dioxide.

[0147] Reagent compound of formula 4 can be prepared by reacting a reagent compound of formula 5:

[0148] [Chem. 7] - Reagent compound 5: with an alkyne such as tert-butyl prop-2-ynoate in presence of a base.

[0149] Reagent compound of formula 5 can be prepared by reacting a reagent compound of formula 6 with a ketone in presence of a reducing agent:

[0150] [Chem. 8] - Reagent compound of formula 6: [0151 ] Referring to the reaction of a reagent compound of formula 6 with a ketone, any suitable reducing agent may be used in this reaction. For example, the reducing agent may be a metal hydride reagent, such as sodium triacetoxyborohydride or cyanoborohydride. Typically, this reduction reaction is conducted in an inert diluent and a protic solvent, such as methanol, at a temperature in the range of 0 °C to 100 °C until the reaction is substantially complete.

[0152] Reagent compound of formula 6 can be prepared by deprotecting a reagent compound of formula 7: wherein P2 represents an amino-protecting group, such as a Boc, Fmoc, tosyl or mesyl, and P3 represents a methyl group. Referring to process, i.e., a p- toluenesulfonyl group and methoxyl group can be simultaneously removed by treating the protected compound with one or more equivalents of 4-hydroxy benzoic acid and a HBr/AcOH solution. This reaction will generate the desired phenol reagent compound of formula 6.

[0153] Reagent compound of formula 7 can be prepared by reacting a reagent compound of formula 8:

[0154] [Chem. 10] - Reagent compound of formula 8: with a reagent compound of formula 9:

[0155] [Chem. 11] - Reagent compound of formula 9: wherein X1 represents a leaving group, and P2 represent a hydrogen atom or an amino-protecting group;

[0156] Reagent compound of formula 8 can be prepared by deprotecting a reagent compound of formula 10:

[0157] [Chem. 12] - Reagent compound of formula 10: wherein P4 represents an amino-protecting group, such as a Boc, Fmoc, tosyl or mesyl. Reagent compound of formula 8 can be prepared using the conditions described in method (a).

[0158] Reagent compound of formula 10 may be prepared by oxidizing the corresponding thioether reagent compound of formula 11 :

[0159] [Chem. 13] - Reagent compound of formula 11 :

[0160] Referring to process (e), i.e., a reagent compound of formula 11 is treated with a suitable oxidizing agent such as 3-chloroperbenzoic acid. This reaction is typically conducted in an inert diluent such as DCM, at a temperature in the range from about 0 °C to 25° C until the oxidation is substantially complete.

[0161 ] Reagent compound of formula 11 may be prepared by protection of reagent compound of formula 12:

[0162] [Chem. 14] - Reagent compound 12:

[0163] Referring to process (f), i.e., reagent compound of formula 12 is treated with one or more equivalents of di-tert-buty I dicarbonate, and a base such as triethylamine. The reaction is typically conducted in DCM, at a temperature in the range from about 0 °C to 25° C until the starting material is completely consumed.

[0164] Reagent compound of formula 12 can be prepared by removal of the te/Y-butanesulfinyl group present in reagent compound of formula 13:

[0165] [Chem. 15] - Reagent compound 13:

[0166] By way of illustration, the sulfinyl group can be readily removed by treating the protected compound with HCI/dioxane solution. This reaction will generate the desired amine reagent compound of formula 12.

[0167] Reagent compound of formula 13 can be prepared by reacting a reagent compound of formula 14:

[0168] [Chem. 16] - Reagent compound 14: with a Grignard reagent compound in anhydrous DCM. The Grignard reagent compound can be represented by the molecular formula R5MgBr wherein R5 represents the following groups (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3- 10C)cycloalkyl.

[0169] Reagents of formula XIV are generally known in the art or can be prepared from commercially available starting materials and reagents using well-known procedures. For example, reagent compound of formula 14 can be prepared by reacting a reagent compound of formula 15 with tert- butanesulfinamide:

[0170] [Chem. 17] - Reagent compound 15:

[0171 ] In process (g), i.e., the reaction of a reagent compound of formula

15 with te/Y-butanesulfinamide in the presence of a base such as potassium carbonate or cesium carbonate. The reaction is typically conducted in an inert diluent such as DCM, at a temperature in the range from about 0 °C to 25° C until the carbonyl compound is completely consumed.

[0172] Reagent compound of formula 2 is generally known in the art or can be prepared from commercially available starting materials and reagents using well-known procedures. For example, reagents of formula 2 can be prepared by deprotecting a reagent compound of formula 16:

[0173] [Chem. 18] - Reagent compound 16: wherein Nu represents a nucleophile, such as a primary or secondary amine, and P5 represents a hydroxyl-protecting group such as trimethylsilyl, tertbutyldimethylsilyl, or triisopropylsilyl.

[0174] Reagents of formula 16 can be prepared by protection of a reagent compound of formula 17:

[0175] [Chem. 19] - Reagent compound 17:

[0176] Reagents of formula 16 can be prepared using the conditions described in method (f).

[0177] Reagents of formula 17 in which c is an integer of 1 can be prepared by reacting of a reagent compound of formula 18:

[0178] [Chem. 20] - Reagent compound 18: pound of formula 19: m. 21 ] - Reagent compound 19:

[0180] Reagents of formula 17 can be prepared by reacting a reagent compound of formula 18 with an aldehyde in presence of a reducing agent using the conditions described in method (c). [0181 ] In another aspect of the invention, it is provided a general intermediate a:

[0182] [Chem. 4] - intermediate a: wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an aminoprotecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect.

[0183] In an embodiment, the intermediate is a compound selected from: compounds of examples 26, 32, 49, 56, 79, 94, 105, 114, 124, 130, 139, 146, 147, 162, 174, 175, 183, 184, 185, 186 or 188 included herein.

[0184] A reagent compound for the preparation of compounds of formula I is also provided, wherein the reagent compound is selected from:

[0185] [Chem. 2] - Reagent compound 1 : or [Chem. 3] - Reagent compound 2: wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an aminoprotecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect.

[0186] In an embodiment, the preferred reagent compound is selected from:

[0187] [Chem. 22] - Reagent compound 20:

[0188] [Chem. 23] - Reagent compound 21 :

; or

[0190] [Chem. 25] - Reagent compound 23:

[0191] The present invention is also directed to a pharmaceutical composition comprising at least one compounds of the general Formula I or any pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates thereof, defined in the first aspect, 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.

[0192] In the pharmaceutical composition of the current invention, it is considered a pharmaceutically acceptable vehicle any composition other than the compound of general Formula I, which has been intentionally added thereto to produce a pharmaceutical dosage form suitable 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.

[0193] 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. 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 inhalation, nasal, oral, parenteral, rectal, transmucosal, transdermal and topical. Preferably, the compositions are formulated for oral, by inhalation, topical, nasal, rectal, or injectable administration.

[0194] In one embodiment of the current invention, a compound of Formula I or a pharmaceutical composition containing a compound of Formula I is administered to a patient via inhalation or nasal administration.

[0195] Pharmaceutical compositions may be administered using an adequate device, such as dry powders inhalers, aerosol sprays from pumps, atomizers, nebulizers, or a pressurized container, with or without propellants. The pharmaceutical composition for inhaled administration may comprise excipients such as glucose, mannitol and lactose. Pharmaceutical composition for nasal administration may comprise a bioadhesive as an excipient, such as chitosan or cyclodextrin.

[0196] 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 thereof for the treatment of diseases, comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[0197] A compound of general formula I is intended for treating pathological conditions or diseases associated with beta-2 adrenergic receptor or muscarinic receptor, or a combination of both. Non-limiting examples of the use of the compounds of the invention for the treatment of human diseases include respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, rhinitis), pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders (such as urinary incontinence), and gastrointestinal disorders (e.g., irritable bowel syndrome, spastic colitis).

[0198] 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 seventy. The compounds of the present invention may be administered in therapeutically effective doses ranging from about 0.0001 mg to about 10,000 mg per day, more preferably 0.001 mg to about 3,000 mg per day. Effective doses may be extrapolated from dose-response 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.

[0199] 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 finished drug product, in particular, to manufacture a finished drug product for the treatment of human diseases. A finished drug product containing a compound of general formula I is useful for treating pathological conditions or diseases associated with beta-2 adrenergic receptor or muscarinic receptor, or a combination of both. Non-limiting examples of the use of the finished drug products of the invention for the treatment of human diseases include respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, rhinitis), pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders (such as urinary incontinence), and gastrointestinal disorders (e.g., irritable bowel syndrome, spastic colitis).

[0200] The present invention is also directed to provide a method of treating diseases, comprising the administration of a therapeutically effective amount of at least one compound of general Formula I to a patient in need. In some embodiments, the diseases are in humans. In other embodiments, the diseases are in animals. The present invention is also directed to method of treating respiratory diseases, such as asthma, COPD or rhinitis, 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 0.0001 mg to about 10,000 mg per day, more preferably 0.001 mg to about 3,000 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.

[0201] The present invention is also directed to a combination for simultaneous, separate or sequential use, which comprises: 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 agents selected from the list comprising a non-steroidal glucocorticoid receptor agonist; a PDE4 inhibitor; a modulator of chemokine receptor function; a corticosteroid; a histamine receptor modulator; an adrenergic agonist; and an inhibitor of p38 kinase function.

[0202] In one embodiment, the one or more agent is corticosteroid, optionally costicosteroid is selected from the group comprising budesonide, beclomethasone dipropionate, triamcinolone, mometasone furoate, ciclesonide, fluticasone propionate and fluticasone furoate and their pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates.

[0203] It is another aspect of the invention to provide a medicament comprising a compound of general Formula I for use in treating a disease, said disease comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[0204] In one embodiment, the medicament is for use in treating a respiratory disease, such as asthma, COPD or rhinitis.

[0205] In some embodiments, the disease is a human or veterinary disease.

[0206] In another embodiment, the medicament comprises the compound of general Formula I in an amount from of 0.0001 mg to 10,000 mg, optionally from 0.001 mg to 5,000 mg.

[0207] The following examples are illustrative and do not limit the scope of the present invention.

EXAMPLES

EXAMPLE 1 - Synthesis of examples of the invention Preparation of molecule example 1

Preparation of compound 2

(1 ) (2)

[0208] To a solution of compound 1 (25 g, 66.80 mmol, 1 eq) in CHCh (250 mL) were added TBSCI (20.14 g, 133.61 mmol, 16.37 mL, 2 eq) and Imidazole (22.74 g, 334.02 mmol, 5 eq) at 25 °C. Then the mixture was stirred at 60 °C for 12 hours. The reaction solution was poured into saturated NH4CI aqueous solution (300 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiC>2, PE:EA=10:1 to 2:1 ). Compound 2 (30.3 g, 60.29 mmol, 90.25% yield, 97.2% purity) was obtained as a white solid.

[0209] ¹H NMR (400 MHz, CDCh) 5 = 9.22 (br s, 1 H), 8.24 (d, J = 10.0 Hz, 1 H), 7.52 - 7.37 (m, 5H), 7.24 - 6.97 (m, 2H), 6.71 (d, J = 9.8 Hz, 1 H), 5.24 - 5.12 (m, 3H), 3.66 - 3.45 (m, 2H), 0.89 (s, 9H), 0.14 (s, 3H), -0.11 (s, 3H)

[0210] LCMS: Rt=1.207 min; [M+H]⁺=488.1

Preparation of compound 3

[0211 ] To a solution of compound 2 (10 g, 20.47 mmol, 1 eq), Nal (3.38 g, 22.52 mmol, 1.1 eq) in DMF (90 mL) and H2O (10 mL) was added NaNs (3.99 g, 61.41 mmol, 3 eq). The mixture was stirred at 90 °C for 12 hours. The reaction solution was adjusted to pH=10 with saturated Na2COs aqueous solution. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 x 2 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was used directly in the next step without further purification. Compound 3 (11 .9 g, crude) was obtained as a yellow solid.

[0212] LCMS: Rt=1.182 min; [M+H]⁺=451.2

Preparation of compound 4

(3) (4) [0213] To the solution of compound 3 (800 mg, 1 .78 mmol, 1 eq) in THF (15 mL) and H2O (2 mL) was added PPhs (931 .32 mg, 3.55 mmol, 2 eq) at 25 °C. Then the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mLx3). Then the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (basic condition). Compound 4 (500 mg, 1.14 mmol, 64.34% yield, 97% purity) was obtained as a yellow solid.

[0214] LCMS: Rt=0.853 min; [M+H]+=425.5

Preparation of compound 6

(4) (6)

[0215] The mixture of compound 4 (100 mg, 236 mmol, 1 eq) and compound 5 (35.6 mg, 236 mmol, 1 eq) in MeOH (3 mL), acetic acid (14.1 mg, 236 mmol, 1 eq) was stirred at 25 °C for 30 min, then NaBHsCN (14.8 mg, 236 mmol, 1 eq) was added, and stirred for 2 hours. The mixture was diluted with sodium bicarbonate (30 mL, sat.), extracted with ethyl acetate (30 mL), the organic phase was washed with brine (50 mL), dried over sodium sulfate, concentrated in vacuo to give a crude product (132 mg, crude) which was used in next step directly without purification.

[0216] LCMS: Rt = 0.898 min, [M+H]⁺= 560.3

Preparation of compound 7

(6) (7) [0217] To a mixture of compound 6 (130 mg, 232 mmol, 1 eq) in DCM (3 mL) was added BOC2O (76.0 mg, 348 mmol, 1 .5 eq), triethylamine (118 mg, 1.16 mmol, 5 eq) at 25 °C under nitrogen atmosphere. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo to give a crude product which was purified by silica gel chromatography (eluent: petroleum ether I ethyl acetate = 10 / 1 to 1 / 1 ) to give the product (154 mg) as a yellow oil.

Preparation of compound 8

(7) (8)

[0218] To a mixture of compound 7 (136 mg, 206 mmol, 1 eq) in THF (2 mL) was added A/,A/-diethylethanamine trihydrofluoride (1.98 g, 12.3 mmol, 2 mL, 60 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phase was separated, washed with sodium bicarbonate solution (20 mL, sat.), and brine (30 mL), dried over sodium sulfate, concentrated in vacuo to give a crude product 8 as a yellow oil (120 mg, crude) without purification.

[0219] LCMS: Rt = 0.952 min, [M+H]⁺= 546.4

Preparation of compound 9

[0220] To a mixture of compound 8 (100 mg, 183 mmol, 1 eq) in MeOH

(10 mL) was added Pd/C (30 mg, 10% w/w) at 25°C under hydrogen gas atmosphere. The mixture was stirred at 25°C for 5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product (80 mg, crude). The compound 9 is reserved for later use in the preparation of compound 26.

[0221 ] LCMS: Rt = 0.682 min, [M+H]⁺= 426.3

Preparation of compound 12

(10) (12)

[0222] To a solution of compound 10 (15 g, 106.99 mmol, 13.16 mL, 1 eq) and compound 11 (13.28 g, 106.99 mmol, 11 .25 mL, 1 eq) in DMF (150 mL) was added CS2CO3 (52.29 g, 160.48 mmol, 1.5 eq). The mixture was stirred at 50 °C for 2 hours. The reaction solution was poured into saturated NH4CI aqueous solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was used directly in the next step without further purification. Compound 12 (22.1 g, 90.28 mmol, 84.38% yield, 99.8% purity) was obtained as a yellow oil.

[0223] LCMS: Rt=0.930 min; [M+H]⁺=245.0

Preparation of compound 14

(12) (14)

[0224] To a solution of compound 12 (22.1 g, 90.46 mmol, 1 eq) in DCM (200 mL) was added CS2CO3 (29.47 g, 90.46 mmol, 1 eq) and compound 13 (16.45 g, 135.69 mmol, 1 .5 eq). The mixture was stirred at 50 °C for 2 hours. The reaction solution was poured into saturated NH4CI aqueous solution (200 mL) and extracted with ethyl acetate (100 mL x 3). 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 (SiC>2, PE:EA=40:1 to 10:1 ).

Compound 14 (29.4 g, 84.61 mmol, 93.53% yield) was obtained as a yellow oil.

[0225] ¹ H NMR (400 MHz, CDCh) 5 = 8.46 (s, 1 H), 7.67 (d, J = 8.4 Hz,

2H), 7.29 - 7.16 (m, 3H), 7.02 (d, J = 7.6 Hz, 1 H), 6.99 - 6.94 (m, 1 H), 6.86 (td, J = 1 .2, 8.3 Hz, 1 H), 3.74 (s, 3H), 1 .20 (s, 10H)

Preparation of compound 15

(14) (15)

[0226] To a solution of compound 14 (29.4 g, 84.61 mmol, 1 eq) in DCM (300 mL) was added MeMgBr (3 M, 84.61 mL, 3 eq) at -78 °C. The mixture was stirred at 0 °C for 6 hours. The reaction solution was poured into saturated NH4CI aqueous solution (500 mL) and extracted with ethyl acetate (300 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 (SiC>2, PE:EA=10:1 to 1 :1 ).

Compound 15 (22.5 g, 61.71 mmol, 72.93% yield, 99.7% purity) was obtained as a yellow oil.

[0227] ¹H NMR (400 MHz, CDCh) 5 = 7.35 - 7.27 (m, 4H), 7.23 (t, J = 8.0 Hz, 1 H), 6.94 (dd, J = 0.9, 7.7 Hz, 1 H), 6.90 - 6.87 (m, 1 H), 6.83 - 6.78 (m, 1 H), 4.57 (dd, J = 3.5, 6.6 Hz, 1 H), 3.78 (s, 3H), 3.34 (br d, J = 3.2 Hz, 1 H), 1 .54 (d, J = 6.7 Hz, 3H), 1 .21 (s, 9H)

[0228] LCMS: Rt=0.970 min; [M+H]⁺=364.1

Preparation of compound 16

(15) (16)

[0229] A solution of compound 15 (22.5 g, 61 .89 mmol, 1 eq) in HCI/dioxane (220 mL) was stirred at 25 °C for 1 hour. The reaction solution was concentrated under vacuum. The residue dissolved in ethyl acetate (300 mL) was stirred at 25 °C for 0.5 hour. And the mixture was filtered to obtain a solid. Compound 16 (18.6 g, crude, HCI) was obtained as a white solid.

[0230] LCMS: Rt=0.771 min; [M-NH₂]⁺=243.1

Preparation of compound 17

[0231 ] To a solution of compound 16 (29.6 g, 100.06 mmol, 1 eq, HCI) in DCM (300 mL) was added BOC2O (32.76 g, 150.09 mmol, 34.48 mL, 1.5 eq) and TEA (30.37 g, 300.18 mmol, 41.78 mL, 3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into saturated NH4CI aqueous (200 mL) and extracted with ethyl acetate (100 mL x 3). 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 used directly in the next step without further purification. Compound 17 (51 g, crude) was obtained as a yellow oil.

[0232] LCMS: Rt=1.002 min; [M-NH₂-Boc]⁺=243.1

Preparation of compound 18

(17) (18) [0233] To a solution of compound 17 (51 g, 99.31 mmol, 1 eq) in DCM (500 mL) was added m-CPBA (47.13 g, 218.48 mmol, 80% purity, 2.2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was poured into H2O (20 mL) and extracted with ethyl acetate (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. The crude product was used directly in the next step without further purification. Compound 18 (57 g, crude) was obtained as a white solid.

[0234] LCMS: Rt=0.915 min; [M+Na]⁺=414.1

Preparation of compound 19

[0235] A solution of compound 18 (57 g, 101.92 mmol, 1 eq) in HCI/dioxane (400 mL) was stirred at 25 °C for 0.5 hour. The reaction solution was concentrated under vacuum to give a residue. The residue dissolved in ethyl acetate (200 mL) was stirred at 25 °C for 0.5 hour, and the mixture was filtered. Compound 19 (28.3 g, 86.33 mmol, 84.70% yield, HCI) was obtained as a white solid.

[0236] ¹ H-NMR (400MHz, Methanol-^) 5 = 8.10 - 8.00 (m, 2H), 7.72 -

7.62 (m, 2H), 7.56 - 7.39 (m, 3H), 7.24 - 7.17 (m, 1 H), 4.55 (q, J = 6.9 Hz, 1 H), 3.85 (s, 3H), 1.63 (d, J = 7.0 Hz, 3H)

Preparation of compound 21

(19) (21 ) [0237] A solution of compound 19 (28.3 g, 86.33 mmol, 1 eq, HCI) and compound 20 (28.13 g, 94.96 mmol, 1.1 eq) in DIEA (55.79 g, 431 .63 mmol, 75.18 mL, 5 eq) was stirred at 120 °C for 12 hours. The reaction mixture was poured into saturated NH4CI aqueous solution (1000 mL) and extracted with ethyl acetate (1000 mL). The organic layers were washed with brine (500 mL), and dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid as crude product. The product was used directly in the next step without further purification. Compound 21 (45 g, crude) was obtained as a yellow solid.

[0238] LCMS: Rt=0.856 min; [M+H]⁺=515.2

Preparation of compound 21 ,^,L" ’ '

(21 ) (22)

[0239] To the mixture of compound 21 (40 g, 77.72 mmol, 1 eq) and 4- hydroxy benzoic acid (32.20 g, 233.17 mmol, 3 eq) was added HBr/AcOH 2:1 (400 mL). The mixture was stirred at 100 °C for 12 hours. The reaction solution was concentrated under vacuum. The residue was dissolved in DCM (200 mL) and adjusted to pH 9 with Na2COs aqueous solution. The organic layers were washed with brine (100 mL), and dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was used directly in the next step without further purification. Compound 22 (77 g, crude) was obtained as a yellow oil.

[0240] LCMS: Rt=0.545 min; [M+H]⁺=347.1

Preparation of compound Intermediate 1

(22) (Intermediate 1 ) [0241] To a solution of compound 22 (30 g, 78.35 mmol, 1 eq, HCI) and compound 23 (38.45 g, 391.74 mmol, 40.60 mL, 5 eq) in MeOH (400 mL) was added AcOH (2.35 g, 39.17 mmol, 2.24 mL, 0.5 eq), and the solution was stirred at 25 °C for 0.5 hour. Then NaBHsCN (14.77 g, 235.05 mmol, 3 eq) was added to the mixture at 0 °C, and the solution was stirred at 25 °C for 2 hours. The reaction solution was poured into H2O (500 mL) and extracted with ethyl acetate (500 mL x 2). 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 (SiC>2, DCM:MeOH=50:1 to 10:1 ). Compound Intermediate 1 (22.3 g, 50.47 mmol, 64.42% yield, 97% purity) was obtained as a yellow oil.

[0242] ¹H-NMR (400MHz, Methanol-^) 5 = 7.93 - 7.86 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 - 7.36 (m, 2H), 7.34 - 7.28 (m, 1 H), 7.06 - 6.98 (m, 1 H), 3.60 (q, J = 6.8 Hz, 1 H), 3.21 - 2.34 (m, 9H), 2.11 - 1 .98 (m, 2H), 1.95 - 1 .82 (m, 2H), 1.68 (br d, J = 12.0 Hz, 1 H), 1.43 - 1.10 (m, 9H)

[0243] LCMS: Rt=0.796 min; [M+H] ⁺=429.2

Preparation of Compound 24

(Intermediate 1 ) (24)

[0244] A mixture of the compound Intermediate 1 (1 .2 g, 2.80 mmol, 1 eq), tert-butyl prop-2-ynoate (1 .41 g, 11 .20 mmol, 1 .54 mL, 4 eq) and TEA (1.13 g, 11.20 mmol, 1.56 mL, 4 eq) in THF (50 mL) was stirred at 20 °C for 1 hour. The reaction mixture was poured into saturated NH4CI aqueous solution (100 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The yellow residue was purified by column chromatography (SiC>2, PE: EA=10:1-EA: MeOH=10:1 ). Compound 24 (1.2 g, 82% purity) was obtained as a yellow oil.

[0245] LCMS: Rt=0.882 min, [M+H]⁺=555.4 Preparation of Compound 25

[0246] To a solution of compound 24 (1 .1 g, 1 .98 mmol, 1 eq) in EtOH (20 mL) was added PtCh (450.27 mg, 1.98 mmol, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 3 times. The reaction mixture was stirred under H2 (15 psi) at 20 °C for 10 min. The reaction mixture was filtered. The filtrate was concentrated. The crude product was used for next step without further purification. Compound 25 (1 g, crude) was obtained as a yellow oil.

[0247] LCMS: Rt=0.881 min, [M+H]⁺=557.4

Preparation of Compound Intermediate 2

(25) (Intermediate 2)

[0248] To a solution of Compound 25 (1 g, 1.80 mmol, 1 eq) in DCM (20 mL) was added TFA (7.70 g, 5 mL). The reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25x10um; mobile phase: [water(0.1 %TFA)-ACN];B%: 10%- 40%,10min). Compound Intermediate 2 (0.1 g, 128.52 mmol, 7.16% yield, 79% purity, TFA) was obtained as a white solid.

[0249] LCMS: Rt=0.774 min, [M+H]⁺=501 .3

Preparation of compound 26

(9) (26)

[0250] To a mixture of compound 9 (50 mg, 81 .3 pmol, 1 eq, TFA salt) and compound Intermediate 2 (41.5 mg, 97.6 pmol, 1.2 eq) in pyridine (1 mL) was added EDC (31 .2 mg, 163 pmol, 2.0 eq) at 25°C under nitrogen atmosphere. The mixture was stirred at 25°C for 3 hours. The mixture was concentrated in vacuo to give a crude product which was purified by prep- HPLC (column: Phenomenex Synergi C18 150x25x1 Oum; mobile phase: [water(0.225%FA)-ACN];B%: 35%-65%,9min) to give the desired product 26 (35 mg, formic acid salt, 45% yield) as a white solid.

Preparation of Molecule 1

[0251 ] To a mixture of compound 26 (20 mg, 21 pmol, 1 eq) in DCM (1 mL) was added TFA (308 mg, 2.70 mmol, 0.2 mL, 129 eq) at 25°C. The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated in vacuo, and the crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25x1 Oum; mobile phase: [water(0.1 %TFA)- ACN];B%: 11 %-38%, 10min) to give the desired product Molecule 1 (23 mg, TFA salt, 95% yield) as a white solid.

[0252] ¹ H-NMR (400MHz, Methanol-^) 5 = 8.26 (d, J = 9.9 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 2H), 7.70 (br d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.56 - 7.44 (m, 5H), 7.28 (d, J = 8.3 Hz, 1 H), 7.24 (br d, J = 7.7 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 6.66 (d, J = 9.8 Hz, 1 H), 5.41 (br t, J = 6.7 Hz, 1 H), 4.41 (t, J = 5.9 Hz, 2H), 4.29 (s, 2H), 3.70 (q, J = 6.5 Hz, 1 H), 3.50 (br d, J = 1 .2 Hz, 1 H), 3.39 - 3.34 (m, 2H), 3.32 - 3.28 (m, 1 H), 3.23 (br d, J = 6.7 Hz, 3H), 3.19 - 3.04 (m, 2H), 2.91 (br t, J = 5.9 Hz, 2H), 2.78 - 2.76 (m, 1 H), 2.49 (br s, 1 H), 2.11 (br d, J = 8.8 Hz, 2H), 1.93 (br d, J = 10.6 Hz, 2H), 1.71 (br d, J = 12.3 Hz, 1 H), 1.51 - 1.30 (m, 7H), 1.29 - 1.11 (m, 1 H).

[0253] LCMS: Rt = 0.779 min, [M+H]⁺= 808.4

[0254] SFC: Rt = 1 .820 min, ee% > 99%.

PREPARATION OF MOLECULE EXAMPLE 2

Preparation of compound 28

OTBS^ ⁰ B .. .. ..I H

(27) (28)

[0255] A solution of compound 27 (76.88 mg, 1 .02 mmol, 78.93 mL, 5 eq), compound 2 (100 mg, 204.71 pmol, 1 eq), Nal (613.71 pg, 4.09 mmol, 0.02 eq) and NaHCOs (51.59 mg, 614.14 pmol, 23.89 mL, 3 eq) in DMSO (1 mL) was stirred at 100 °C for 1 hour. The reaction mixture was poured into saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate. Then the mixture was filtered and concentrated. The crude product was used for next step directly. Compound 28 (100 mg, crude) was obtained as a yellow oil.

[0256] LCMS: Rt=0.868 min; [M+H]⁺=483.3

Preparation of compound 29

(28) (29) [0257] A solution of compound 28 (100 mg, 207.17 pmol, 1 eq), TEA (41.93 mg, 414.35 pmol, 2 eq) and BOC2O (54.26 mg, 248.61 pmol, 1.2 eq) in DCM (1 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by prep-TLC (SiC>2, PE:EA= 10:1 ). Compound 29 (100 mg, 149.28 mmol, 72.05% yield, 87% purity) was obtained as a yellow oil.

[0258] LCMS: Rt=1.031 min; [M+H]⁺=583.3

Preparation of compound 30

(29) (30)

[0259] A mixture of compound 29 (100 mg, 171.59 pmol, 1 eq), TEMPO (5.40 mg, 34.32 pmol, 0.2 eq) and Phl(OAc)₂ (138.17 mg, 428.96 pmol, 2.5 eq) in DCM (1 mL) and H2O (0.5 mL) was stirred at 25 °C for 1 hour. The reaction was concentrated under vacuum, and residue was purified by prep- HPLC (column: Waters Xbridge 150x25mmx5um; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B%: 26%-56%, 10min). Compound 30 (70 mg, 85.63 mmol, 49.90% yield, 73% purity) was obtained as a yellow oil.

[0260] LCMS: Rt= 1 .013 min; [M+H]⁺=597.2

Preparation of compound 31

(30) (31 )

[0261 ] Under H2 (15 psi) atmosphere, a suspension of compound 30 (70 mg, 117.30 pmol, 1 eq) and Pd/C (10 mg, 10% w/w) in MeOH (1 mL) was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was used without further purification. Compound 31 (35 mg, 69.08 pmol, 58.89% yield) was obtained as a yellow oil.

[0262] LCMS: Rt=0.967 min; [M+H]⁺=507.2

Preparation of compound 32

(31 ) (32)

[0263] A solution of compound 31 (35 mg, 69.08 pmol, 1 eq), compound 37 (the synthesis of compound 37 is described further below) (34.52 mg, 64.38 pmol, 9.32e-1 eq, HCI), EDCI (19.86 mg, 103.62 pmol, 1 .5 eq), HOBt (14.00 mg, 103.62 pmol, 1.5 eq) and DIEA (17.86 mg, 138.16 pmol, 24.06 pL, 2 eq) in DCM (1 mL) was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate. Then the mixture was filtered, and the filtrate was concentrated. The crude product was used in the next step without further purification. Compound 32 (60 mg, crude) was obtained as a yellow oil.

[0264] LCMS: Rt=0.945 min; [1/2M+H]⁺=444.9

Preparation of Molecule 2

[0265] A solution of compound 32 (60 mg, 60.71 pmol, 1 eq) in HCI/dioxane (2 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25x1 Oum; mobile phase: [water (0.1%TFA)-ACN]; B%: 18%-38%, 10min). Molecule 2 (12.48 mg, 13.35 pmol, 21 .99% yield, 95% purity, TFA) was obtained as a white solid. [0266] ¹H-NMR (400MHz, Methanol-cU) 6 = 8.37 (d, J=9.9 Hz, 1 H), 7.94 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.53 - 7.44 (m, 3H), 7.30 (d, J=8.3 Hz, 1 H), 7.18 (td, J=2.5, 6.5 Hz, 1 H), 7.03 (d, J=8.2 Hz, 1 H), 6.67 (d, J=9.8 Hz, 1 H), 5.42 (dd, J=4.2, 9.0 Hz, 1 H), 4.06 (t, J=6.2 Hz, 2H), 3.72 - 3.60 (m, 1 H), 3.51 - 3.34 (m, 6H), 3.29 - 3.23 (m, 3H), 3.17 - 3.07 (m, 2H), 2.89 (br d, J=10.8 Hz, 1 H), 2.70 (t, J=6.5 Hz, 2H), 2.50 - 2.21 (m, 2H), 2.09 (br d, J=8.9 Hz, 2H), 1.92 (br d, J=12.6 Hz, 2H), 1.87 - 1.78 (m, 2H), 1.75 - 1.65 (m, 3H), 1.47 - 1.29 (m, 8H), 1.27 - 1.13 (m, 1 H)

[0267] LCMS: Rt=0.753 min; [M+H]⁺=774.3

Synthesis of compound 37

Preparation of compound 34 kil l BOC₂O, TEA HO^\^\/^{N H2} - ► _Ho^\^\^^NHB

DCM

(33) (34)

[0268] A solution of compound 33 (500 mg, 5.61 mmol, 520.83 mL, 1 eq), TEA (1.14 g, 11.22 mmol, 1.56 mL, 2 eq) and BOC2O (1.22 g, 5.61 mmol, 1 .29 mL, 1 eq) in DCM (20 mL) was stirred at 25 °C for 2 hours. The reaction solution was concentrated under vacuum. The residue was purified by column chromatography (SiC>2, PE:EA=10:1-1 :1 ). Compound 34 (900 mg, 4.76 mmol, 84.78% yield) was obtained as a yellow oil.

[0269] ¹H NMR (400MHz, CDCI3) 5 = 4.62 (br s, 1 H), 3.68 (br s, 2H), 3.16 (br d, J=5.7 Hz, 2H), 1.72 - 1.54 (m, 5H), 1.45 (s, 9H).

Preparation of compound 35

TsCI, TEA

DCM

(34) (35)

[0270] A solution of compound 34 (200 mg, 1 .06 mmol, 1 eq), TEA (320.81 mg, 3.17 mmol, 441 .28 mL, 3 eq) and p-TsCI (402.95 mg, 2.11 mmol, 2 eq) in DCM (2 mL) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by prep- TLC (SiC>2, PE:EA=3:1 ). Compound 35 (350 mg, 1.02 mmol, 96.43% yield, N/A purity) was obtained as a yellow oil.

[0271 ] LCMS: Rt=0.955 min; [M-Boc]⁺=244.1

Preparation of compound 36

(Intermediate 1 ) (36)

[0272] A solution of compound 35 (80.13 mg, 233.33 pmol, 1 eq), compound Intermediate 1 (the synthesis of intermediate Intermediate 1 is described in the procedure for synthesis of Molecule 1 ) (100 mg, 233.33 pmol, 1 eq) and CS2CO3 (228.07 mg, 699.98 pmol, 3 eq) in MeCN (1 mL) was stirred at 80 °C for 1 hour. The reaction mixture was poured into saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate. Then the mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1 ). Compound 36 (110 mg, 163.22 pmol, 69.95% yield, 89% purity) was obtained as a yellow oil.

[0273] LCMS: Rt=0.798 min; [M+H]⁺=600.3

Preparation of compound 37

(36) (37)

[0274] A solution of compound 36 (110 mg, 183.39 pmol, 1 eq) in HCI/dioxane (2 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was used in the next step without further purification. Compound 37 (100 mg, crude, HCI) was obtained as a white solid. [0275] LCMS: Rt=0.588 min; [M+H]⁺=500.3

PREPARATION OF MOLECULE EXAMPLE 3

Preparation of compound 39

(Intermediate 1 ) (39)

[0276] To a solution of compound Intermediate 1 (the synthesis of intermediate Intermediate 1 is described in the procedure for synthesis of compound Example 1 ) (7 g, 16.33 mmol, 1 eq) in MeCN (70 mL) was added K2CO3 (6.77 g, 49.00 mmol, 3 eq) and compound 38 (4.89 g, 21 .23 mmol, 1 .3 eq). The mixture was stirred at 80 °C for 4 hours. The reaction solution was poured into saturated NH4CI aqueous (200 mL) and extracted with ethyl acetate (200 mL x 2). 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 (SiC>2, DCM:MeOH=30:1 to 10:1 ). Compound 39 (7.2 g, 12.03 mmol, 73.64% yield, 81 .3% purity) was obtained as a yellow solid.

[0277] LCMS: Rt=0.807 min; [M+H] ⁺=487.3

Preparation of compound 40

(39) (40)

[0278] To a solution of compound 39 (7.2 g, 14.79 mmol, 1 eq) in acetone (150 mL) was added sulfuric acid trioxochromium (0.26 M, 56.90 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hours. After quenched the excess oxidant with i-PrOH (10 mL), the mixture was filtered and the solid washed with acetone (200 mL x 2). The pH was adjusted to 7 with saturated Na2COs aqueous solution and concentrated under vacuum. DCM (300 mL) and water (300 mL) were added to the residue, and two layers were separated. The aqueous phase was extracted with DCM (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The crude product was purified by reversephase HPLC (0.1 % HCI condition). Compound 44 (2.77 g, 4.44 mmol, 30.01 % yield, 86.1 % purity, HCI was obtained as a yellow solid and reserved for later use in the preparation of compound 49.

[0279] ¹H-NMR (400MHz, Methanol-d₄) 5 = 8.04 (d, J = 8.4 Hz, 2H), 7.76 (br d, J = 8.3 Hz, 2H), 7.59 - 7.43 (m, 3H), 7.22 (ddd, J = 1 .0, 2.4, 8.1 Hz, 1 H), 4.39 - 4.18 (m, 3H), 3.84 - 3.61 (m, 2H), 3.58 - 3.44 (m, 2H), 3.28 - 2.72 (m, 6H), 2.18 - 2.07 (m, 2H), 1.93 (br d, J = 12.8 Hz, 2H), 1.74 - 1.58 (m, 4H), 1.52 - 1.30 (m, 4H), 1.27 - 1.11 (m, 1 H)

[0280] LCMS: Rt=0.804 min; [M+H] ⁺=501 .2

Preparation of compound 42

(41) (42)

[0281] To a solution of compound 41 (1 g, 5.12 mmol, 1 eq) in MeOH (20 mL) was added NaBH₄ (1 .36 g, 35.87 mmol, 7 eq) in small portions. The mixture was stirred at 25 °C for 12 hours. TLC indicated compound 41 was consumed completely, and two new spots were formed. The reaction solution was poured into water (40 mL), and then extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with NH₄CI aqueous solution (40 mL) and brine (40 mL), dried over Na2SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, PE:EA=10:1 to 5:1). Compound 42 (460 mg, 2.75 mmol, 53.71 % yield) was obtained as a yellow solid.

[0282] ¹H NMR (400 MHz, CDCh) 5 = 8.10 (dd, J = 2.3, 8.5 Hz, 1 H), 8.06 (d, J = 2.0 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 4.82 (d, J = 5.0 Hz, 2H), 2.42 (s, 3H), 1.81 (t, J = 5.4 Hz, 1 H) Preparation of compound 43

(42) (43)

[0283] To a solution of compound 42 (460 mg, 2.75 mmol, 1 eq) in DCM (10 mL) was added Dess-Martin reagent compound (1 .75 g, 4.13 mmol, 1 .28 mL, 1.5 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, PE:EA=10:1 to 5:1 ). Compound 43 (430 mg, 2.60 mmol, 94.62% yield) was obtained as a yellow solid and reserved for later use in the preparation of compound 45.

[0284] ¹H NMR (400 MHz, CDCI3) 5 = 10.31 (s, 3H), 8.11 (dd, J = 2.0, 8.0 Hz, 1 H), 8.07 (d, J = 2.0 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 2.72 (s, 3H)

Preparation of compound 44

(3) (44)

[0285] To a solution of compound 3 (previously prepared in the synthesis of molecule Example 1 ) (11 .9 g, 26.41 mmol, 1 eq) in THF (500 mL) was added Pd/C (4 g, 10% w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 hours. LCMS showed compound 3 was consumed completely and the desired mass was detected. The reaction solution was filtered and the filtrate was concentrated under vacuum to give a residue. The crude product was used directly in the next step without further purification. Compound 44 (7.7 g, crude) was obtained as a yellow solid.

[0286] LCMS: Rt=0.802 min; [M+H]⁺=335.1 Preparation of compound 45

(43) (45)

[0287] A solution of compound 44 (100 mg, 230.21 pmol, 1 eq), compound 43 (38.02 mg, 230.21 pmol, 1 eq) and AcOH (6.91 mg, 115.10 pmol, 6.58 mL, 0.5 eq) in MeOH (1 .5 mL) was stirred at 25 °C for 0.5 hour. Then NaBHsCN (28.93 mg, 460.41 mmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into H2O (40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 45 (141 mg, crude) was obtained as a yellow solid.

[0288] LCMS: Rt=0.874 min; [M+H] ⁺=484.2

Preparation of compound 46

[0289] To a solution of compound 45 (140 mg, 220.00 pmol, 1 eq) in

DCM (1.5 mL) was added TEA (66.79 mg, 660.01 pmol, 91 .87 pL, 3 eq) and BOC2O (52.82 mg, 242.00 pmol, 55.60 pL, 1.1 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into H2O (40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 46 (176 mg, crude) was obtained as a yellow oil.

[0290] LCMS: Rt=1.288 min; [M+H] ⁺=684.2

Preparation of compound 47

[0291] To a solution of compound 46 (196 mg, 335.76 pmol, 1 eq) in THF

(2 mL) was added N,N-diethylethanamine trihydrofluoride (989.00 mg, 6.13 mmol, 1 mL, 18.27 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was adjusted to pH=7 with saturated Na2COs aqueous solution. Ethyl acetate (40 mL) and water (40 mL) were added to the residue, and two layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, DCM:MeOH=10:1 ). Compound 47 (130 mg, 258.07 pmol, 76.86% yield, 93.2% purity) was obtained as a yellow solid.

[0292] LCMS: Rt=0.920 min; [M+H] ⁺=470.2

Preparation of compound 48

[0293] To a solution of compound 47 (130 mg, 276.90 pmol, 1 eq) in

MeOH (4 mL) was added Pd/C (40 mg, 10% w/w) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification.

Compound 48 (101 mg, crude) was obtained as a yellow solid.

[0294] LCMS: Rt=0.739 min; [M+H] ⁺=440.3

Preparation of compound 49

[0295] To a solution of compound 48 (40 mg, 91.01 pmol, 1 eq) and compound 40 (45.56 mg, 91.01 pmol, 1 eq) in Py (0.5 mL) was added EDCI (22.68 mg, 118.32 mmol, 1.3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into H2O (20 mL) and extracted with ethyl acetate (10 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-TLC (SiC>2, DCM:MeOH=8:1). Compound 49 (65 mg, 62.73 pmol, 68.93% yield, 89.0% purity) was obtained as a yellow solid.

[0296] LCMS: Rt=0.886 min; [M+H] ⁺=922.5

Preparation of Molecule 3

[0297] A solution of compound 49 (65 mg, 70.49 pmol, 1 eq) in formic acid (0.8 mL) was stirred at 25 °C for 3 hours. The reaction solution was adjusted to pH=7 with saturated Na2C0s aqueous solution, and then the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30mmx3um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 7 min). Molecule 3 (28.9 mg, 32.79 pmol, 46.52% yield, 98.5% purity, formic acid salt) was obtained as a yellow solid.

[0298] ¹H NMR (400MHz, Methanol-d₄) 5 = 8.51 (s, 2H), 8.29 (d, J = 9.9 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 7.63 - 7.42 (m, 7H),7.37 (d, J = 8.1 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 7.24 - 7.19 (m, 1 H), 7.02 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 9.8 Hz, 1 H), 5.39 (t, J = 6.7 Hz, 1 H), 4.39 (t, J = 5.9 Hz, 2H), 4.23 (s, 2H), 3.59 (q, J = 6.6 Hz, 1 H), 3.26 - 3.02 (m, 6H), 3.01 - 2.50 (m, 7H), 2.41 (s, 3H), 2.12 - 1 .98 (m, 2H), 1.96 - 1 .81 (m, 2H), 1 .68 (br d, J = 11 .9 Hz, 1 H), 1 .44 - 1.27 (m, 7H), 1 .25 - 1.09 (m, 1 H)

[0299] LCMS: Rt=0.787 min; [M+H] ⁺=822.4

PREPARATION OF MOLECULE EXAMPLE 4

Preparation of compound 51

(50) (51)

[0300] To a solution of compound 50 (800 mg, 6.72 mmol, 1 eq) in THF (20 mL) was added LiAIH₄ (509.78 mg, 13.43 mmol, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 .5 hours. The reaction solution was quenched by addition saturated Na2SO₄ aqueous (0.5 mL) at 0 °C. Then the mixture was filtered, and the filter cake was washed with THF (10 mL). The filtrate was poured into H2O (100 mL) and extracted with ethyl acetate (50 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 (SiC>2, DCM:MeOH=50:1 to 20:1 ).

Compound 51 (440 mg, 3.60 mmol, 53.65% yield) was obtained as a yellow solid. [0301] ¹H NMR (400MHz, Methanol-cU) 6 = 9.68 (s, 1 H), 8.41 (d, J = 1.7

Hz, 1 H), 7.86 (dd, J = 2.3, 8.8 Hz, 1 H), 6.61 (d, J = 8.8 Hz, 1 H)

Preparation of compound 52

(44) (52)

[0302] A solution of compound 44 (the synthesis of compound 44 is described in the procedure for synthesis of Example 3) (200 mg, 597.94 pmol, 1 eq), compound 51 (73.02 mg, 597.94 pmol, 1 eq) and AcOH (17.95 mg, 298.97 pmol, 17.10 mL, 0.5 eq) in MeOH (2 mL) was stirred at 25 °C for 0.5 hour. Then NaBHsCN (112.72 mg, 1 .79 mmol, 3 eq) was added to the mixture and the mixture was stirred at 25 °C for 0.5 hour. The reaction solution was poured into H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 52 (320 mg, crude) was obtained as a yellow solid.

[0303] LCMS: Rt=0.780 min; [M+1 ]⁺=441.2

Preparation of compound 53

(52) (53)

[0304] To a solution of compound 52 (320 mg, 508.39 pmol, 1 eq) in

DCM (4 mL) was added TEA (154.33 mg, 1.53 mmol, 212.28 pL, 3 eq) and tert-butoxycarbonyl tert-butyl carbonate (122.05 mg, 559.23 pmol, 128.47 mL, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into H2O (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 53 (393 mg, crude) was obtained as a yellow oil.

[0305] LCMS: Rt=0.993 min; [M+1 ]⁺=641.3

Preparation of compound 54

(53) (54)

[0306] To a solution of compound 53 (390 mg, 426.00 pmol, 1 eq) in THF (4 mL) and MeOH (4 mL) was added a solution of LiOH (30.61 mg, 1 .28 mmol, 3 eq) in H2O (0.3 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH=7 with 1 N HCI aqueous solution, and then the mixture was concentrated under vacuum to give a residue. Ethyl acetate (30 mL) and H2O (30 mL) were added to the residue, and two layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, DCM:MeOH=50:1 to 8:1 ). Compound 54 (214 mg, 359.35 pmol, 84.35% yield, 90.8% purity) was obtained as a yellow solid.

[0307] LCMS: Rt=0.912 min; [M+1]⁺=541.2

Preparation of compound 55

[0308] To a solution of compound 54 (200 mg, 369.87 pmol, 1 eq) in THF (4 mL) was added N,N-diethylethanamine trihydrofluoride (1.98 g, 12.27 mmol, 2 mL, 33.17 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was adjusted to pH=7 with saturated Na2COs aqueous solution. Then the mixture was lyophilized to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30 mmx3 urn; mobile phase: [water (0.225% FA)-ACN]; B%: 3%-33%, 7 min). Compound 55 (86 mg, 198.43 pmol, 53.65% yield, 98.4% purity) was obtained as a yellow solid.

[0309] ¹H N MR (400 MHz, DMSO-de) 5 = 10.33 (br s, 1 H), 8.29 - 8.16 (m, 1 H), 8.14 (s, 1 H), 7.73 (br d, J = 9.4 Hz, 1 H), 7.22 (dd, J = 2.4, 8.5 Hz, 1 H), 7.16 - 6.99 (m, 1 H), 6.97 - 6.89 (m, 1 H), 6.56 - 6.43 (m, 1 H), 6.39 (d, J = 8.4 Hz, 1 H), 5.84 (br s, 2H), 5.68 - 5.46 (m, 1 H), 5.31 - 5.01 (m, 1 H), 4.23 (br s, 1 H), 4.20 - 4.04 (m, 1 H), 3.34 - 3.23 (m, 1 H), 3.17 (br dd, J = 7.0, 13.6 Hz, 1 H), 1.50 - 1.13 (m, 9H)

[0310] LCMS: Rt=0.691 min; [M+H]⁺=427.3

Preparation of compound 56

(Intermediate 2)

[0311 ] To a solution of compound 55 (40 mg, 84.66 pmol, 1 eq, FA) and compound Intermediate 2 (the synthesis of intermediate Intermediate 2 is described in the procedure for synthesis of example Example 1 ) (52.87 mg, 84.66 pmol, 1 eq, HCI) in Py (0.5 mL) was added EDCI (21 .10 mg, 110.06 pmol, 1 .3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, DCM:MeOH=6:1 ). Compound 56 (53 mg, 45.88 pmol, 54.20% yield, 78.7% purity) was obtained as a yellow solid.

[0312] LCMS: Rt=0.844 min; [M+H]⁺=909.4

Preparation of Molecule 4

(56) (Molecule 4)

[0313] A solution of compound 56 (50 mg, 55.00 pmol, 1 eq) in formic acid (0.5 mL) was stirred at 25 °C for 10 hours. The reaction solution was adjusted to pH=7 with saturated Na2COs aqueous, and then the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25x10 urn; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 8 min). Molecule 4 (12.9 mg, 14.91 pmol, 27.10% yield, 98.8% purity, FA) was obtained as a white solid.

[0314] ¹H NMR (400 MHz, Methanol-d₄) 5 = 8.53 (s, 1 H), 8.36 - 8.25 (m, 2H), 8.09 (br d, J = 8.5 Hz, 1 H), 7.92 (d, J = 8.3 Hz, 2H), 7.78 (dd, J = 1 .8, 8.6 Hz, 1 H), 7.59 - 7.43 (m, 5H), 7.22 (br d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 9.9 Hz, 1 H), 5.27 (dd, J = 4.0, 8.6 Hz, 1 H), 4.39 (t, J = 5.8 Hz, 2H), 3.95 (s, 2H), 3.55 (q, J = 6.5 Hz, 1 H), 3.11 - 2.86 (m, 8H), 2.83 - 2.43 (m, 5H), 2.00 (br s, 2H), 1.85 (br s, 2H), 1.66 (br d, J = 12.1 Hz, 1 H), 1.41 - 1.24 (m, 7H), 1.22 - 1.04 (m, 1 H)

[0315] LCMS: Rt=0.797 min; [M+H]⁺=809.4

PREPARATION OF MOLECULE EXAMPLE 5

Preparation of compound 59

(57) (59)

[0316] To a solution of compound 57 (6.5 g, 46.36 mmol, 5.70 mL, 1 eq) and compound 58 (9.27 g, 46.36 mmol, 1 eq) in DMF (70 mL) was added CS2CO3 (45.32 g, 139.08 mmol, 3 eq). The mixture was stirred at 80 °C for 1 hour. The reaction solution was poured into saturated NH4CI aqueous solution (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL x 3) and dried over Na2SO4. Then the mixture was filtered and the filtrate was concentrated under vacuum. The crude product was used directly in the next step without further purification. Compound 59 (13.8 g, crude) was obtained as a yellow solid.

[0317] ¹H NMR (400 MHz, CDCI3) 5 = 8.95 (d, J = 1 .8 Hz, 1 H), 7.99 (dd, J = 2.4, 8.4 Hz, 1 H), 7.43 - 7.36 (m, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.18 - 7.13 (m, 1 H), 7.03 (td, J = 1.2, 8.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 3.83 (s, 3H), 2.57 (s, 3H).

Preparation of compound 60

[0318] To a solution of compound 59 (10 g, 38.56 mmol, 1 eq) in MeOH (100 mL) was added NaBH4 (2.05 g, 54.05 mmol, 1 .40 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by addition 1 N HCI (100 mL) at 0 °C, then diluted with water (100 mL) and remove MeOH under vacuum. Then extracted with ethyl acetate (200 mL x 2), 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 to 2/1 ). Compound 60 (9.8 g, 35.62 mmol, 92.38% yield, 95% purity) was obtained as a yellow solid.

[0319] ¹H NMR (400 MHz, CDCh) 5 = 8.42 (d, J = 2.0 Hz, 1 H), 7.54 (dd, J = 2.0, 8.4 Hz, 1 H), 7.38 - 7.31 (m, 1 H), 7.17 (d, J = 7.6 Hz, 1 H), 7.15 - 7.10 (m, 1 H), 7.00 - 6.91 (m, 2H), 4.96 - 4.88 (m, 2H), 3.82 (s, 3H), 1 .50 (d, J = 6.4 Hz, 3H).

Preparation of compound 61

[0320] To a solution of compound 60 (8.8 g, 33.67 mmol, 1 eq) in MeCN (25 mL) was added a solution of NaICU (15.12 g, 70.71 mmol, 3.92 mL, 2.1 eq) and RuCh (698.47 mg, 3.37 mmol, 224.59 mL, 0.1 eq) in CCI4 (25 mL) and H2O (5 mL) at 0 °C. Then the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by addition saturated Na2SOs aq. (50 mL) at 0 °C, then diluted with water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). Combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether/Ethyl acetate=100/1 to 1/1 ). Compound 61 (9.8 g, 33.07 mmol, 98.22% yield, 99% purity) was obtained as a yellow solid.

[0321 ] ¹H NMR (400 MHz, CDCh) 5 = 8.66 (d, J = 2.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.95 (dd, J = 2.0, 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.59 - 7.54 (m, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.13 (dd, J = 2.0, 8.4 Hz, 1 H), 5.03 (q, J = 6.4 Hz, 1 H), 3.87 (s, 3H), 2.33 - 2.06 (m, 1 H), 1 .52 (d, J = 6.4 Hz, 3H).

Preparation of compound 62

(61 ) (62)

[0322] To a solution of compound 61 (8.8 g, 30.00 mmol, 1 eq) and TEA (9.11 g, 90.00 mmol, 12.53 mL, 3 eq) in DCM (90 mL) was added MsCI (8.02 g, 70.01 mmol, 5.42 mL, 2.33 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 62 (13.5 g, crude) was obtained as a yellow solid.

[0323] LCMS: Rt=0.823 min; [M+H]⁺=371 .9

Preparation of compound 64

(62) (64)

[0324] To a solution of compound 62 (13.5 g, 36.35 mmol, 1 eq) in ACN (150 mL) was added TMP (7.70 g, 54.52 mmol, 9.26 mL, 1.5 eq) and tertbutyl piperazine-1 -carboxylate (63) (8.80 g, 47.25 mmol, 1.3 eq). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under vacuum to give a residue. Then, ethyl acetate (200 mL) and water (200 mL) were added, and layers were separated. The aqueous phase was extracted with ethyl acetate (200 mL x 2). Combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether/Ethyl acetate=10/1 to 1/1 ). Compound 64 (10.6 g, 22.74 mmol, 62.55% yield, 99% purity) was obtained as a yellow oil.

[0325] ¹H NMR (400 MHz, CDCh) 5 = 8.63 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.89 (dd, J = 2.0, 8.0 Hz, 1 H), 7.64 (td, J = 1.2, 8.0 Hz, 1 H), 7.61 - 7.57 (m, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.14 (ddd, J = 0.8, 2.8, 8.2 Hz, 1 H), 3.87 (s, 3H), 3.51 (q, J = 6.8 Hz, 1 H), 3.39 (d, J = 3.6 Hz, 4H), 2.43 (br s, 2H), 2.35 - 2.22 (m, 2H), 1.53 - 1 .39 (m, 9H), 1 .34 (d, J = 6.8 Hz, 3H).

Preparation of compound 65

[0326] A mixture of compound 64 (10.2 g, 22.10 mmol, 1 eq) and HCI/dioxane (100 mL) and MeOH (30 mL) was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under vacuum to give the crude product. The crude product was used directly in the next step without further purification. Compound 65 (10.6 g, crude, HCI) was obtained as a yellow solid.

[0327] LCMS: Rt=0.698 min; [M+H]⁺=362.0

Preparation of compound 67

(65) (67)

[0328] A mixture of compound 65 (9.6 g, 26.56 mmol, 1 eq), DIEA (5.15 g, 39.84 mmol, 6.94 mL, 1.5 eq) and cycloheptanone (66) (11.92 g, 106.24 mmol, 12.53 mL, 4 eq) in MeOH (100 mL) was stirred at 25 °C for 0.5 hour. Then NaBHsCN (3.34 g, 53.12 mmol, 2 eq) was added at 25 °C and the mixture was stirred for 12 hours. The reaction mixture was poured into H2O (200 mL) and MeOH was removed under reduced pressure. Then, the residue was extracted with ethyl acetate (200 mL x 3). 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 (SiC>2, Petroleum ether/Ethyl acetate=10/1 to 1/10). Compound 67 (8.8 g, 18.27 mmol, 68.78% yield, 95% purity) was obtained as a yellow solid.

[0329] ¹ H NMR (400 MHz, Methanol-d₄) 5 = 8.64 (d, J = 2.0 Hz, 1 H), 8.19

(d, J = 8.0 Hz, 1 H), 8.07 (dd, J = 2.0, 8.0 Hz, 1 H), 7.61 - 7.45 (m, 3H), 7.23 (ddd, J = 0.8, 2.4, 8.0 Hz, 1 H), 3.86 (s, 3H), 3.67 (q, J = 6.8 Hz, 1 H), 2.93 - 2.37 (m, 9H), 1.97 - 1.86 (m, 2H), 1.74 (tdd, J = 3.6, 6.8, 9.6 Hz, 2H), 1.64 - 1.32 (m, 13H).

Preparation of compound 68

(67) (68) (68b)

[0330] Compound 67 (2 g, 4.37 mmol, 1 eq) was purified by chiral SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um);mobile phase: [0.1 %NH₃H₂O MEOH];B%: 45%-45%,6.1min ; 105 min). Compound 68

(890 mg, 1.85 mmol, 42.28% yield, 95% purity) was obtained as a yellow solid. Compound 68b (940 mg, 1.85 mmol, 42.30% yield, 90% purity) was obtained as a yellow solid.

[0331] Compound 68

[0332] ¹ H NMR (400 MHz, Methanol-d₄) 5 = 8.62 (d, J = 2.0 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 8.05 (dd, J = 2.0, 8.0 Hz, 1 H), 7.60 - 7.46 (m, 3H), 7.26 - 7.19 (m, 1 H), 3.86 (s, 3H), 3.60 (q, J = 6.8 Hz, 1 H), 2.66 - 2.27 (m, 9H), 1.87 - 1 .77 (m, 2H), 1.69 (dt, J = 4.0, 6.8 Hz, 2H), 1.61 - 1 .32 (m, 11 H).

Preparation of compound 69

[0333] To a solution of compound 68b (395 mg, 863.15 pmol, 1 eq) in DCM (50 mL) was added BBrs (1 .30 g, 5.18 mmol, 499.01 pL, 6 eq) at 0 °C. Then the mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with NHs/MeOH (0.5M, 40 mL) and the mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, DCM/MeOH=50/1 to 10/1 ). Compound 69 (435 mg, 1 .73 mmol, 99.98% yield, 88% purity) was obtained as a yellow solid.

[0334] ¹H NMR (400 MHz, Methanol-d₄) 5 = 8.67 (d, J = 1 .6 Hz, 1 H), 8.22 - 8.15 (m, 1 H), 8.12 - 8.06 (m, 1 H), 7.49 - 7.32 (m, 3H), 7.10 - 7.01 (m, 1 H), 3.78 (q, J = 6.8 Hz, 1 H), 3.28 - 3.10 (m, 5H), 2.93 - 2.37 (m, 3H), 2.12 - 2.01 (m, 2H), 1.86 - 1.47 (m, 12H), 1.41 (d, J = 6.8 Hz, 3H).

Preparation of compound 70

(69) (70)

[0335] To a solution of 3-hydroxypropyl 4-methylbenzenesulfonate (467.67 mg, 2.03 mmol, 1 .3 eq) in MeCN (1 mL) was added K2CO3 (647.74 mg, 4.69 mmol, 3 eq) and compound 69 (770 mg, 1.56 mmol, 90% purity, 1 eq). The mixture was stirred at 80 °C for 4 hours. The reaction mixture was poured into saturated NH4CI aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 2). 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: Phenomenex luna C18 150x40mmx 15um; mobile phase: [water(FA)-ACN];B%: 10%- 40%,10min). Compound 70 (560 mg, 1.06 mmol, 67.88% yield, 95% purity) was obtained as a yellow solid. [0336] ¹H NMR (400 MHz, Methanol-cU) 6 = 8.67 (d, J = 2.0 Hz, 1 H), 8.49 (s, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.08 (dd, J = 2.0, 8.0 Hz, 1 H), 7.61 - 7.52 (m, 2H), 7.52 - 7.43 (m, 1 H), 7.24 (ddd, J = 0.8, 2.4, 8.0 Hz, 1 H), 4.15 (t, J = 6.4 Hz, 2H), 3.79 - 3.70 (m, 3H), 3.27 - 3.05 (m, 5H), 2.94 - 2.27 (m, 3H), 2.06 - 1.97 (m, 4H), 1.85 - 1.45 (m, 10H), 1.40 (d, J = 6.8 Hz, 3H).

Preparation of compound 71

(70) (71 )

[0337] To a solution of compound 70 (200 mg, 365.16 pmol, 1 eq, FA) in acetone (10 mL) was added sulfuric acid trioxochromium (2.7 M, 676.2 pL, 5 eq) at 0 °C. The mixture was stirred at 25 °C for 3 hours. After quenching the excess oxidant with i-PrOH (5 mL), the mixture was adjusted to pH-7 with saturated Na2COs aqueous solution, and diluted with DCM/MeOH (30 mL, 5:1 ). The mixture of filtered by celite and concentrated under vacuum. DCM (20 mL) and water (20 mL) were added, and layers were separated. The aqueous phase was extracted with DCM (20 mL x 2). Combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The crude product was used directly in the next step without further purification. Compound 71 (120 mg, crude) was obtained as a yellow solid and reserved for later use in the preparation of compound 79 and 130.

[0338] LCMS: Rt=0.771 min; [M+H]⁺=516.1

Preparation of compound 73

(72) (73)

[0339] To a solution of compound 72 (1 .1 g, 3.72 mmol, 1 eq) in THF (16 mL) was added MeLi (1.6 M, 3.25 mL, 1 .4 eq) slowly at -78 °C under N2 atmosphere, and the mixture was stirred for 0.1 h Then s-BuLi (1 .3 M, 4.00 mL, 1.4 eq) was added slowly at -78 °C and stirred for 0.1 h Then N,N- dimethylformamide (1.90 g, 26.01 mmol, 2.00 mL, 7 eq) was added at - 78 °C. The mixture was warmed up to 20 °C and stirred for 1 h The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (20 mL x 4). 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 (SiC>2, Petroleum ether/Ethyl acetate=20/1 to 5/1 ). Compound 73 (310 mg, 1.25 mmol, 33.55% yield, 98.6% purity) was obtained as a yellow solid, which was confirmed by HNMR and LCMS.

[0340] 1 H NMR (400 MHz, CHLOROFORM-d)

5 = 10.56 (s, 1 H), 7.99 (br s, 1 H), 7.37 (s, 2H), 2.64 (s, 6H)

[0341] LCMS: Rt=0.851 min; [M+H]⁺=246.1

Preparation of compound 74

(44) (74)

[0342] A solution of 44 (250 mg, 747.42 pmol, 1 eq), compound 73 (183.27 mg, 747.42 pmol, 1 eq) and AcOH (22.44 mg, 373.71 pmol, 21 ,37pL, 0.5 eq) in MeOH (3 mL) was stirred at 25 °C for 0.5 h Then NaBHsCN (93.94 mg, 1 .49 mmol, 2 eq) was added to the mixture and the mixture was stirred at 25 °C for 1 h The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 74 (540 mg, crude) was obtained as a yellow solid.

[0343] LCMS: Rt=0.848 min; [M+H]⁺=564.2 Preparation of compound 75

[0344] To a solution of compound 74 (540 mg, 766.39 pmol, 80% purity, 1 eq) in DCM (6 mL) and H2O (6 mL) was added NaHCOs (416.78 mg, 4.96 mmol, 192.96 pL, 6.47 eq) and tert-butoxycarbonyl tert-butyl carbonate (200.71 mg, 919.67 pmol, 211 .28 pL, 1 .2 eq). The mixture was stirred at 25 °C for 12 h The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 75 (500 mg, crude) was obtained as a yellow solid.

[0345] LCMS: Rt=1.228 min; [M+H]⁺=764.2

Preparation of compound 76

[0346] To a solution of compound 75 (500 mg, 654.52 pmol, 1 eq) in THF (5 mL) and MeOH (5 mL) was added a solution of LiOH (47.03 mg, 1 .96 mmol, 3 eq) in H2O (0.5 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h The reaction mixture was adjusted to pH-8 with 1 N HCI aqueous solution, then the mixture was concentrated under vacuum to give a residue. Ethyl acetate (20 mL) and saturated H2O (20 mL) were added, and layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). Combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The crude product was used directly in the next step without further purification. Compound 76 (490 mg, crude) was obtained as a yellow solid.

[0347] LCMS: Rt=1 .138 min; [M+H]⁺=664.1

Preparation of compound 77

[0348] To a solution of compound 76 (490 mg, 738.18 pmol, 1 eq) in MeOH (5 mL) and H2O (0.5 mL) was added K2CO3 (306.06 mg, 2.21 mmol, 3 eq). The mixture was stirred at 50 °C for 2 h The reaction mixture was adjusted to pH-8 with 1 N HCI aqueous solution, then the mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 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 (SiC>2, Petroleum ether/Ethyl acetate=3/1 to 0/1 ). Compound 77 (260 mg, 447.38 pmol, 60.61 % yield, 97.7% purity) was obtained as a white solid.

[0349] LCMS: Rt=0.942 min; [M+H]⁺=568.2

Preparation of compound 78

[0350] To a solution of compound 77 (260 mg, 457.92 pmol, 1 eq) in THF (2.5 mL) was added N,N-Diethylethanamine trihydrofluoride (989.00 mg, 6.13 mmol, 1 mL, 13.40 eq). The mixture was stirred at 25 °C for 12 h The reaction mixture was adjusted to pH-8 with saturated NaHCOs aqueous solution. Ethyl acetate (10 mL) and water (10 mL) were added, and layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 2). Combined extracts were washed dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, DCM: MeOH = 10:1 ). Compound 78 (83 mg, 152.63 pmol, 33.33% yield, 83.4% purity) was obtained as a yellow solid.

[0351 ] LCMS: Rt=0.748 min; [M+H]⁺=454.2

Preparation of compound 79

[0352] To a solution of compound 71 (80 mg, 131.87 pmol, 85% purity, 1 eq) and 78 (59.81 mg, 131 .87 pmol, 1 eq) in Py (1 mL) was added EDCI (37.92 mg, 197.80 pmol, 1.5 eq). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 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: Phenomenex luna C18 150x40mmx15um; mobile phase: [water(FA)-ACN];B%: 22%-52%,7 min). Compound 79 (66 mg, 65.52 pmol, 49.69% yield, 99% purity, FA) was obtained as a yellow solid. [0353] ¹H NMR (400 MHz, Methanol-cU) 5 = 8.62 (s, 1 H), 8.53 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 2H), 7.62 - 7.55 (m, 2H), 7.53 - 7.45 (m, 1 H), 7.31 - 7.20 (m, 3H), 7.19 - 7.04 (m, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.52 (d, J = 10.0 Hz, 1 H), 5.26 - 5.15 (m, 1 H), 4.65 - 4.57 (m, 3H), 4.39 (t, J = 6.0 Hz, 2H), 3.67 (q, J = 7.2 Hz, 1 H), 3.26 - 2.39 (m, 14H), 2.27 (s, 6H), 2.00 - 1.87 (m, 2H), 1.73 (d, J = 5.6 Hz, 2H), 1.63 - 1.42 (m, 18H), 1.37 (d, J = 6.8 Hz, 3H)

[0354] LCMS: Rt=0.861 min; [M+H]⁺=951.1

Preparation of Molecule 5

[0355] A mixture of compound 79 (66 mg, 66.19 pmol, 1 eq, FA) in formic acid (1 .22 g, 26.50 mmol, 1 mL, 400.46 eq) was stirred at 25 °C for 3 hours. The reaction mixture was adjusted to pH-7 with saturated Na2COs aqueous solution, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75x30mmx3um; mobile phase: [water(FA)-ACN];B%: 8%-38%,7min).

Molecule 5 (38.31 mg, 41.10 mmol, 62.10% yield, 96.24% purity, FA) was obtained as a white solid.

[0356] ¹H NMR (400 MHz, Methanol-d₄) 5 = 8.64 (d, J = 1 .6 Hz, 1 H), 8.53 (s, 1 H), 8.34 (d, J = 10.0 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 8.05 (dd, J = 2.0, 8.0 Hz, 1 H), 7.61 - 7.55 (m, 2H), 7.53 - 7.46 (m, 1 H), 7.32 (s, 2H), 7.29 - 7.22 (m, 2H), 7.01 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 10.0 Hz, 1 H), 5.42 - 5.34 (m, 1 H), 4.39 (t, J = 6.0 Hz, 2H), 4.22 - 4.01 (m, 2H), 3.68 (q, J = 6.8 Hz, 1 H), 3.17 - 3.07 (m, 2H), 3.02 - 2.82 (m, 7H), 2.81 - 2.46 (m, 4H), 2.40 (s, 6H), 2.01 - 1.88 (m, 2H), 1.81 - 1.67 (m, 2H), 1.66 - 1.27 (m, 11 H).

[0357] LCMS: Rt=0.753 min; [M+H]⁺=851 .1

PREPARATION OF MOLECULE EXAMPLE 6

Preparation of compound 82

(80) (82)

[0358] To a solution of compound 80 (9 g, 64.19 mmol, 7.89 mL, 1 eq) and compound 81 (8.87 g, 64.19 mmol, 7.78 mL, 1 eq) in DMF (90 mL) was added CS2CO3 (41.83 g, 128.39 mmol, 2 eq). The mixture was stirred at 80 °C for 0.5 hour. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over Na2SO4. Then the mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 10/1 ). Compound 82 (16.2 g, 60.75 mmol, 94.64% yield, 96.88% purity) was obtained as a yellow oil.

[0359] LCMS: Rt=0.908 min; [M+H]⁺=259.1

Preparation of compound 83

[0360] To a solution of compound 82 (15.2 g, 58.84 mmol, 1 eq) in EtOH (150 mL) was added NaBH4 (3.65 g, 96.48 mmol, 1.64 eq). The mixture was stirred at 25 °C for 1 h The reaction mixture was quenched by addition of saturated NH4CI (50 mL) at 0 °C, then diluted with water (10 mL), concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with ethyl acetate (100 mL x 3), the combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate=100/1 to 3/1 ). Compound 83 (16.4 g, 60.66 mmol, 51.55% yield, 96.3% purity) was obtained as a yellow oil.

[0361 ] ¹H NMR (400 MHz, CDCI3) 5 = 7.39 - 7.35 (m, 2H), 7.35 - 7.32 (m, 2H), 7.22 (t, J = 8.0 Hz, 1 H), 6.92 - 6.88 (m, 1 H), 6.87 (t, J = 2.0 Hz, 1 H), 6.79 (td, J = 1 .2, 8.3 Hz, 1 H), 4.95 - 4.85 (m, 1 H), 3.77 (s, 3H), 1 .80 (br s, 1 H), 1.50 (d, J = 6.4 Hz, 3H).

Preparation of compound 84

(83) (84)

[0362] To a solution of compound 83 (15.4 g, 59.15 mmol, 1 eq) in DCM (154 mL) was added m-CPBA (24.02 g, 118.30 mmol, 85% purity, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by addition saturated Na2SOs aqueous (100 mL) at 0 °C, then diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated NaHCOs aqueous solution (100 mL x 3) and brine (100 mL x 3), 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=10/1 to 1/1 ). Compound 84 (15 g, 49.77 mmol, 84.14% yield, 97% purity) was obtained as a white solid.

[0363] LCMS: Rt=0.745 min; [M+H]⁺=293.1

Preparation of compound 85

(84) (85)

[0364] To a solution of compound 84 (14 g, 47.89 mmol, 1 eq) and TEA (14.54 g, 143.66 mmol, 20.00 mL, 3 eq) in DCM (140 mL) was added methylsulfonyl methanesulfonate (12.51 g, 71.83 mmol, 1.5 eq). The mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 85 (17 g, crude) was obtained as a yellow oil.

[0365] LCMS: Rt=0.794 min.

Preparation of compound 87

Boc >

(85) (87)

[0366] To a solution of compound 85 (17 g, 45.89 mmol, 1 eq) in ACN (150 mL) was added TMP (7.78 g, 55.07 mmol, 9.35 mL, 1.2 eq) and 86 (9.40 g, 50.48 mmol, 1.1 eq). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether/Ethyl acetate=10/1 to 1/1 ). Compound 87 (20 g, 39.64 mmol, 86.38% yield, 91.29% purity) was obtained as a yellow oil.

[0367] ¹H NMR (400 MHz, CDCI3) 5 = 7.88 (d, J = 8.4 Hz, 2H), 7.54 - 7.51 (m, 1 H), 7.49 - 7.45 (m, 3H), 7.41 (t, J = 8.0 Hz, 1 H), 7.09 (ddd, J = 0.8, 2.6, 8.3 Hz, 1 H), 3.85 (s, 3H), 3.43 - 3.35 (m, 5H), 2.45 - 2.23 (m, 4H), 1 .43 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Preparation of compound 88

(87) (88)

[0368] A mixture of compound 87 (20 g, 43.42 mmol, 1 eq) in dioxane (20 mL) was added HCI/dioxane (4 M, 108.56 mL, 10 eq) was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under vacuum to give the crude product. The crude product was used in the next step without further purification. Compound 88 (20.3 g, crude) was obtained as a white solid.

[0369] LCMS: Rt=0.757 min; [M+H]⁺=361 .2

Preparation of compound 90

(88) (90)

[0370] A mixture of compound 88 (20.3 g, 56.32 mmol, 1 eq) and 89 (63.17 g, 563.15 mmol, 66.42 mL, 10 eq) in MeOH (200 mL) was stirred at 25 °C for 0.5 hour. Then NaBHsCN (17.69 g, 281 .58 mmol, 5 eq) was added at 25 °C and the mixture was stirred for 30 hours. The reaction mixture was poured into H2O (100 mL) and MeOH was removed under reduce pressure. Then the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 3), 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 to 10/1 ). Compound 90 (16.5 g, 33.25 mmol, 59.05% yield, 92.03% purity) was obtained as a yellow oil. [0371 ] ¹H NMR (400 MHz, CDCh) 6 = 7.89 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 7.9 Hz, 1 H), 7.49 - 7.39 (m, 4H), 7.10 (dd, J = 2.0, 7.9 Hz, 1 H), 3.86 (s, 3H), 3.51 - 3.48 (m, 1 H), 3.03 - 2.87 (m, 5H), 2.74 - 2.52 (m, 3H), 2.07 - 1 .86 (m, 3H), 1 .76 (br d, J = 7.2 Hz, 2H), 1 .60 - 1 .50 (m, 8H), 1 .32 (d, J = 6.8 Hz, 3H).

Preparation of compound 91

[0372] To a solution of compound 90 (2.00 g, 4.38 mmol, 1 eq) in DCM (50 mL) was added BBrs (5.49 g, 21 .90 mmol, 2.11 mL, 5 eq) at 0 °C. Then the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with NHs/MeOH (0.5 M, 30 mL), and partitioned between water (20 mL), and ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM: MeOH =100/1 to 10/1 ). Compound 91 (5.8 g, 12.38 mmol, 70.66% yield, 94.47% purity) was obtained as a white solid.

[0373] LCMS: Rt=0.457 min; [M+H]⁺=443.2

Preparation of compound 92

[0374] Compound 91 (5.8 g, 12.38 mmol, 1 eq) was purified by chiral

SFC (column: Phenomenex-Cellulose-2 (250mm x 50mm, 10um); mobile phase: [MeOH-ACN];B%: 60%-60%,4.3min). Compound 92 (2 g, 4.51 mmol, 39.94% yield, 99.85% purity) was obtained as a white solid. [0375] Compound 92

[0376] ¹H NMR (400 MHz, CDCh) 5 = 7.80 (d, J = 8.4 Hz, 2H), 7.42 - 7.34 (m, 3H), 7.33 - 7.27 (m, 2H), 6.96 (dd, J = 1 .6, 8.0 Hz, 1 H), 3.48 (s, 1 H), 3.35 (q, J = 6.8 Hz, 1 H), 2.60 - 2.33 (m, 8H), 1.88 - 1 .76 (m, 2H), 1 .73 - 1 .60 (m, 2H), 1.56 - 1 .32 (m, 8H), 1 .28 (d, J = 6.8 Hz, 3H)

Preparation of compound 93

(92) (93)

[0377] To a solution of compound 92 (1 .60 g, 3.61 mmol, 1 eq) in MeCN (16 mL) was added K2CO3 (1.50 g, 10.82 mmol, 3 eq) and 3-hydroxypropyl 4-methylbenzenesulfonate (1.08 g, 4.69 mmol, 1.3 eq). The mixture was stirred at 80 °C for 5 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x40mmx 15um; mobile phase: [water(FA)-ACN];B%: 15%-45%,10min). Compound 93 (1.1 g, 2.20 mmol, 60.89% yield, 99.99% purity) was obtained as a white solid.

[0378] LCMS: Rt=0.810 min; [M+H]⁺=501 .3

Preparation of compound Intermediate 3

(93) (Intermediate 3)

[0379] To a solution of compound 93 (1 g, 2.00 mmol, 1 eq) in acetone (10 mL) was added sulfuric acid trioxochromium (2.7 M, 739.72 pL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. After quenching the excess oxidant with i-PrOH (2 mL), the solid was wash with DCM (20 mL) and acetone (20 mL). The pH was adjusted to 7 with saturated Na2COs aqueous solution, the mixture was filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: YMC Triart C18 150x25mmx5um; mobile phase: [water (HCI)-ACN]; B%: 20%-50%,10min). Compound Intermediate 3 (410 mg, 796.54 pmol, 39.88% yield, 99.99% purity) was obtained as a white solid.

[0380] LCMS: Rt=0.483 min; [M+H]⁺=515.3

Preparation of compound 94

[0381] To a solution of Intermediate 3 (80 mg, 155.44 pmol, 1 eq) and compound 9 (the synthesis of compound 9 is described in the procedure for synthesis of Example 1 ) (72.75 mg, 170.98 pmol, 1.1 eq) in pyridine (1 mL) was added EDCI (59.60 mg, 310.88 pmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 150x25mmx10um; mobile phase: [water(FA)-ACN]; B%: 16%-46%,10min). Compound 94 (59 mg, 63.98 pmol, 41 .16% yield, 99.99% purity) was obtained as a yellow solid.

[0382] LCMS: Rt=0.864 min; [M+H]⁺=922.3 Preparation of Molecule 6

[0383] To a solution of compound 94 (50 mg, 54.22 pmol, 1 eq) in formic acid (0.5 mL) was stirred at 25 °C for 1.5 hours. The reaction mixture was adjusted to pH=7 with saturated Na2COs aqueous solution, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75x30mmx3um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 7 min). Molecule 6 (39.53 mg, 47.88 pmol, 88.31 % yield, 99.57% purity) was obtained as a yellow solid.

[0384] ¹ H NMR (400 MHz, Methanol-d₄) 5 = 8.52 (s, 1 H), 8.23 (d, J = 1 .0

Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52 - 7.45 (m, 3H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 - 7.19 (m, 2H), 7.00 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 1.0 Hz, 1 H), 5.32 (dd, J = 5.2, 8.2 Hz, 1 H), 4.38 (t, J = 5.6 Hz, 2H), 4.11 (s, 2H), 3.58 (q, J = 6.8 Hz, 1 H), 3.14 - 2.98 (m, 7H), 2.87 (t, J = 6.0 Hz, 2H), 2.83 - 2.38 (m, 4H), 2.03 - 1 .90 (m, 2H), 1 .76 (br d, J = 6.4 Hz, 2H), 1 .68 - 1 .44 (m, 8H), 1 .35 (d, J = 6.8 Hz, 3H).

[0385] LCMS: Rt=0.802 min; [M+H]⁺ = 822.3

PREPARATION OF MOLECULE EXAMPLE 7

Preparation of Compound 97

(95) (96) (97) [0386] To the solution of Compound 95 and Compound 96 (2.66 g, 21.40 mmol, 2.25 mL, 1 eq) in DMF (100 mL) was added CS2CO3 (13.94 g, 42.80 mmol, 2 eq). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered. The filtrate was diluted with ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL x 4), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiC>2, PE: EA=25:1-10:1 ). Compound 97 (3.7 g, 14.69 mmol, 68.65% yield, 97% purity) was obtained as a yellow solid.

Preparation of Compound 98

[0387] To the solution of Compound 97 (3.7 g, 15.14 mmol, 1 eq) in THF (100 mL) was added MeMgBr (3 M, 6.06 mL, 1.2 eq) dropwise in 0.5 hour at -78 °C under N2, with the temperature rising to 25 °C. The reaction mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was poured into H2O (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was used in the next step without further purification. Compound 98 (3.5 g, 12.50 mmol, 82.55% yield, 93% purity) was obtained as a yellow oil.

Preparation of Compound 99

[0388] To the solution of Compound 98 (3.50 g, 13.44 mmol, 1 eq) in DCM (100 mL) was added m-CPBA (6.82 g, 33.61 mmol, 85% purity, 2.5 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into saturated Na2SOs solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was suspended in ethyl acetate (20 mL), and the solids were collected after filtering. Compound 99 (3.6 g, 9.24 mmol, 68.70% yield, 75% purity) was obtained as a white solid.

[0389] LCMS: Rt=0.839 min, [M-OH]⁺=274.9

Preparation of Compound 100

[0390] To the solution of compound 99 (3.60 g, 12.31 mmol, 1 eq) in DCM (100 mL) were added TEA (3.74 g, 36.94 mmol, 5.14 mL, 3 eq) and MsCI (2.93 g, 25.58 mmol, 1 .98 mL, 2.08 eq) under N2 to get a yellow solution. After stirring at rt for 1 hour, the reaction mixture was poured into H2O (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was used for next step directly. Compound 100 (4 g, crude) was obtained as a yellow oil.

[0391 ] LCMS: Rt=0.888 min, [M+Na]⁺=392.8

Preparation of Compound 101

(100) (101 )

[0392] To the solution of Compound 100 (2.8 g, 7.56 mmol, 1 eq) and 1- cyclohexylpiperazine (1.53 g, 9.07 mmol, 77.85 pL, 1.2 eq) in MeCN (25 mL) was added K2CO3 (2.61 g, 18.90 mmol, 2.5 eq). The reaction mixture was stirred at 80 °C for 1 hour, and then filtered. The filtrate was concentrated. The crude product was used in next step directly. Compound 101 (3.2 g, crude) was obtained as a yellow solid. [0393] LCMS: Rt=0.814 min, [M+H]⁺=443.1

Preparation of Intermediate 4

[0394] To a solution of Compound 101 (1 .5 g, 3.39 mmol, 1 eq) in DCM (50 mL) was added BBrs (1 .70 g, 6.78 mmol, 653.08 pL, 2 eq) portion wise with the temperature was kept at -20 °C under N2, with the temperature rising to 25 °C. The reaction mixture was kept under N2 at 25°C for 0.5 hour. The reaction mixture was quenched with MeOH (50 mL) and concentrated under vacuum. The crude product was used in the next step without further purification. Compound Intermediate 4 (3 g, crude) was obtained as a yellow solid.

[0395] LCMS: Rt=0.909 min, [M+H]⁺=429.3

Preparation of Compound 102

(Intermediate 4) (102)

[0396] To the solution of Intermediate 4 (0.2 g, 466.65 pmol, 1 eq) and 6- bromohexan-1 -ol (84.50 mg, 466.65 pmol, 61.23 pL, 1 eq) in MeCN (2 mL) was added CS2CO3 (456.13 mg, 1.40 mmol, 3 eq). The reaction mixture was stirred at 80°C for 2 hours. The filtrate was concentrated. The crude product was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water(0.04%NH3H20+10mM NH4HCO3)- ACN];B%: 55%-85%,10min). Compound 102 (80 mg, 151.30 pmol, 32.42% yield, 100% purity) was obtained as yellow oil.

[0397] LCMS: Rt=0.846 min, [M+H]⁺=529.5

Preparation of Compound 103

(102) (103)

[0398] To a solution of Compound 102 (70 mg, 132.39 pmol, 1 eq) in DCM (1 mL) was added Dess-Martin reagent compound (112.30 mg, 264.78 pmol, 81 ,97pL, 2 eq). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into saturated Na2SOs aqueous solution (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was used for the next step directly.

Compound 103 (80 mg, crude) was obtained as a yellow oil.

[0399] LCMS: Rt=0.835 min, [M+H]⁺=527.1

Preparation of Compound 104

(103) (104)

[0400] To a solution of Compound 103 and compound 4 (the synthesis of compound 4 is described in the procedure for synthesis of Example 1 ) (64.49 mg, 151.88 pmol, 1 eq) in EtOH (1 mL) and DCM (1 mL) was added acetic acid (9.12 mg, 151.88 pmol, 8.69 pL, 1 eq). The reaction mixture was stirred at 20 °C for 0.5 hour. NaBHsCN (14.32 mg, 227.82 pmol, 1.5 eq) was added and the reaction mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was poured into saturated NaHCOs aqueous solution (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. Compound 104 (150 mg, crude) was obtained as a yellow oil.

[0401] LCMS: Rt=0.900 min, [M+H]⁺=935.3 Preparation of Compound 105

(104) (105)

[0402] To the solution of Compound 104 (150 mg, 160.37 pmol, 1 eq) in THF (2 mL) was added N,N-diethylethanamine trihydrofluoride (206.83 mg, 1.28 mmol, 209.13 pL, 8 eq). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into saturated NaHCOs aqueous solution (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. Compound 105 (0.1 g, crude) was obtained as colorless oil.

[0403] LCMS: Rt=0.801 min, [M+H]⁺=821.5

Preparation of Molecule 7

(105) (Molecule 7)

[0404] To the solution of compound 105 (100.00 mg, 121.79 pmol, 1 eq) in DCM (1 mL) was added BCh (1 M, 608.96 pL, 5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was poured into MeOH (5 ml) at 0 °C. The solution was concentrated under vacuum and purified by prep-HPLC (column: Boston pH-lex 150*25 10um; mobile phase: [water(0.1%TFA)-ACN];B%: 20%-47%,9min). The crude product was dissolved in saturated NaHCOs aqueous solution (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified again by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water(0.225%FA)-ACN];B%: 15%- 45%,10min). Molecule 7 (2 mg, 2.49 pmol, 2.05% yield, 96.9% purity, FA) was obtained as a white solid.

¹H NMR (400MHz, Methanol-d4)

5 8.53 (s, 2H), 8.38 (d, J=9.8 Hz, 1 H), 7.92 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.51 - 7.43 (m, 3H), 7.28 (d, J=8.2 Hz, 1 H), 7.21 - 7.14 (m, 1 H), 7.03 (d, J=8.2 Hz, 1 H), 6.68 (d, J=9.8 Hz, 1 H), 5.40 (t, J=6.4 Hz, 1 H), 4.05 (t, J=6.1 Hz, 2H), 3.58 (q, J=6.5 Hz, 1 H), 3.22 (d, J=6.5 Hz, 2H), 3.15 - 3.01 (m, 5H), 2.93 - 2.44 (m, 4H), 2.04 (s, 2H), 1.97 - 1 .63 (m, 8H), 1 .59 - 1 .46 (m, 4H), 1 .36 (d, J=6.7 Hz, 8H)

[0405] LCMS: Rt=0.779 min, [M+H]⁺=731 .3

PREPARATION OF MOLECULE EXAMPLE 8

Preparation of compound 106

(2) (106)

[0406] To a solution of compound 2 (the synthesis of compound 2 is described in the procedure for synthesis of Example 1 ) (90 mg, 184.24 pmol, 1 eq) in NMP (1 mL) was added BnNH2 (59.23 mg, 552.73 pmol, 60.25 pL, 3 eq). The mixture was stirred at 90°C for 12 hours. The combined reaction mixture was poured into saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. Compound 106 (440 mg, crude) was obtained as a yellow oil and used for nest step directly.

[0407] LCMS: Rt=0.910 min, [M+H]⁺=515.1

Preparation of compound 108

(106) (108)

[0408] To a solution of compound 106 (440 mg, 170.97 pmol, 1 eq) and compound 107 (52.30 mg, 341.93 pmol, 32.29 pL, 2 eq) in CHCh (2 mL) was added TEA (51 .90 mg, 512.89 pmol, 71.39 pL, 3 eq). The mixture was stirred at 60°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by prep-TLC (SiC>2, PE:EA = 1 :1 ). Compound 108 (53 mg, 68.64 pmol, 45.30% yield, 76% purity) was obtained as a yellow oil.

[0409] ¹H NMR (400 MHz, Methanol-d4)

[0410] 5 = 7.52 (br d, J = 7.1 Hz, 2H), 7.46 - 7.28 (m, 5H), 7.22 - 7.07 (m,

6H), 6.49 - 6.39 (m, 1 H), 5.49 (s, 2H), 5.38 - 5.29 (m, 2H), 5.04 (br t, J = 6.1 Hz, 1 H), 3.68 - 3.65 (m, 3H), 3.50 (d, J = 5.1 Hz, 1 H), 3.00 - 2.89 (m, 1 H), 2.87 - 2.75 (m, 1 H), 3.02 - 2.74 (m, 1 H), 0.94 - 0.75 (m, 9H), 0.12 - -0.01 (m, 2H), -0.15 - -0.32 (m, 3H)

[0411 ] LCMS: Rt= 1.062 min, [M+H]⁺=587.3

Preparation of compound 109

(108) (109)

[0412] Under H2 (15 psi) atmosphere, to a solution of compound 108 (52 mg, 88.62 pmol, 1 eq) in MeOH (0.5 mL) was added Pd/C (50 mg, 88.62 pmol, 10% purity, 1 eq) at 25°C and the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Compound 109 (62 mg, crude) was obtained as a yellow oil and used in the next step directly.

[0413] LCMS: Rt=0.983 min, [M+H]⁺=407.1

Preparation of compound 110

(109) (110)

[0414] To a solution of compound 109 (62 mg, 124.83 pmol, 1 eq) in H2O (1 mL) and THF (1 mL) was added LiOH monohydrate (10.48 mg, 249.66 pmol, 2 eq). The mixture was stirred at 25°C for 0.5 hour. The reaction mixture was concentrated under vacuum. The residue was purified by prep- HPLC (column: Luna C18 150x25 5u; mobile phase: [water (0.075%TFA)- ACN]; B%: 15%-45%, 2min). Compound 110 (18 mg, 45.86 pmol, 36.74% yield, 100% purity, TFA) was obtained as a white solid and reserved for later use in the preparation of compound 114.

[0415] LCMS: Rt=0.794 min, [M+H]⁺=393.1

Preparation of compound 112

(Intermediate 1 ) (112)

[0416] To a solution of Intermediate 1 (the synthesis of intermediate Intermediate 1 is described in the procedure for synthesis of Example 1 ) (100 mg, 233.33 pmol, 1 eq) and compound 111 (70.60 mg, 279.99 pmol, 57.40 pL, 1.2 eq) in DMF (1 mL) was added CS2CO3 (152.04 mg, 466.65 pmol, 2 eq). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (S iO 2 , PE: EA= 2: 1 ). Compound 112 (113 mg, 182.74 pmol, 78.32% yield, 97% purity) was obtained as a colorless oil. [0417] ¹H NMR (400 MHz, Methanol-d4)

[0418] 5 = 7.91 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.50 - 7.48

(m, 1H), 7.52-7.43 (m, 2H), 7.19 (dd, J = 1.7, 2.6 Hz, 1H), 7.17 (dd, J = 1.7, 2.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 3.52-3.44 (m, 1H), 3.10 (t, J = 6.9 Hz, 2H), 2.61 (brs, 4H), 2.45-2.29 (m, 2H), 2.28- 2.15 (m, 1H), 2.02 (s, 2H), 1.96- 1.88 (m, 2H), 1.85 - 1.75 (m, 4H), 1.65 (quin, J = 7.1 Hz, 3H), 1.44 (s, 9H), 1.36 (d, J = 6.7 Hz, 3H), 1.33- 1.17 (m, 1H), 1.20- 1.14 (m, 1H), 1.31 - 1.06 (m, 5H), 1.12-1.06 (m, 1H)

[0419] LCMS: Rt=0.881 min, [M+H]⁺=600.2

Preparation of compound 113

(112) (113)

[0420] To a solution of HCI/dioxane (2 mL) was added compound 112 (113 mg, 188.39 pmol, 1 eq). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. Compound 113 (79 mg, crude, HCI) was obtained as a white solid.

[0421] LCMS: Rt=0.745 min, [M+H]⁺=500.2

Preparation of compound 114

[0422] To a solution of compound 110 (18 mg, 35.53 pmol, 1 eq, TFA), compound 113 (22.86 mg, 42.64 pmol, 1.2 eq, HCI), DIEA (13.78 mg, 106.60 pmol, 18.57 pL, 3 eq) and HOBt (7.20 mg, 53.30 pmol, 1.5 eq) in DCM (0.5 mL) was added EDCI (10.22 mg, 53.30 pmol, 1.5 eq) under N2. The mixture was stirred at 25°C for 4 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh , DCM: MeOH = 10:1). Compound 114 (20 mg, 11 .90 pmol, 33.48% yield, 52% purity) was obtained as a white solid.

[0423] LCMS: Rt=0.829 min, [M+H]⁺=874.4

Preparation of Molecule 8

(114) (Molecule 8)

[0424] The solution of compound 114 (20 mg, 11 .44 pmol, 1 eq) in HCI/dioxane (2 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150x25x1 Oum; mobile phase: [water (0.1 %TFA)-ACN]; B%: 10%-40%, 10min). Molecule 8 (8.65 mg, 9.55 pmol, 83.50% yield, 96.5% purity, TFA) was obtained as a yellow solid.

[0425] 1 H NMR (400 MHz, Methanol-d4)

[0426] 5 = 8.37 (d, J = 9.8 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7.58 (d, J =

8.4 Hz, 2H), 7.51 - 7.40 (m, 3H), 7.29 (d, J = 8.2 Hz, 1 H), 7.16 (td, J = 2.2, 7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 6.67 (d, J = 9.9 Hz, 1 H), 5.45 (dd, J = 4.5, 9.0 Hz, 1 H), 4.11 - 4.02 (m, 2H), 3.95 - 3.84 (m, 2H), 3.65 (q, J = 6.5 Hz, 1 H), 3.48 (br dd, J = 1 .5, 3.3 Hz, 2H), 3.34 (br s, 2H), 3.21 - 2.95 (m, 4H), 2.95 - 2.74 (m, 1 H), 2.59 - 2.20 (m, 2H), 2.09 (br d, J = 8.9 Hz, 2H), 1.92 (br d, J = 11.6 Hz, 2H), 1.87 - 1 .79 (m, 2H), 1.77 - 1 .66 (m, 3H), 1 .48 - 1 .27 (m, 9H), 1.26 - 1.12 (m, 2H) [0427] LCMS: Rt=0.762 min, [M+H]+=760.3

PREPARATION OF MOLECULE EXAMPLE 9

Preparation of compound 116

(115) (116)

[0428] To a solution of compound 115 (200 mg, 1.24 mmol, 192.31 pL, 1 eq) in Py (4 mL) was added TsCI (473.07 mg, 2.48 mmol, 2 eq) at 0 °C.

After addition, the mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (25 mLx3). The combined organic layers were dried over sodium sulfate. Then the mixture was filtered and the filtrate was concentrated. Compound 116 (394 mg, crude) was obtained as a yellow oil and used for next step directly.

[0429] LCMS: Rt=0.919 min, [M-Boc]+=216.0

Preparation of compound 117

(Intermediate 1 ) (117)

[0430] To a solution of compound Intermediate 1 (the synthesis of intermediate Intermediate 1 is described in the procedure for synthesis of Example 1 ) (100 mg, 233.33 pmol, 1 eq) and compound 116 (147.17 mg, 466.65 pmol, 2 eq) in MeCN (2 mL) was added Cs2CO3 (152.04 mg, 466.65 pmol, 2 eq). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mLx3). The combined organic layers were dried over sodium sulfate. Then the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1 ).

Compound 117 (103 mg, 171.14 pmol, 73.35% yield, 95% purity) was obtained as a yellow oil. [0431] LCMS: Rt=0.848 min, [M+H]+=572.3

Preparation of compound 118

(117) (118)

[0432] A solution of compound 117 (103 mg, 180.14 pmol, 1 eq) in HCI/dioxane (2 mL) was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under vacuum to give a residue. Compound 118 (98 mg, crude, HCI) was obtained as a yellow solid and reserved for later use in the preparation of compound 124.

[0433] LCMS: Rt=0.714 min, [M+H]+=472.2

Preparation of compound 120

OTBS^ ⁰

B . .

(119) (120)

[0434] To a mixture of compound 2 (the synthesis of intermediate 2 is described in the procedure for synthesis of Example 1 ) (100 mg, 204.71 pmol, 1 eq) and compound 119 (36.49 mg, 409.43 pmol, 38.02 pL, 2 eq) in DMSO (1 mL) was added Nal (3.07 mg, 20.47 pmol, 0.1 eq), NaHCO3 (34.39 mg, 409.43 pmol, 15.92 pL, 2 eq) at 10 °C under N2. The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with brine (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic layers were dried over sodium sulfate, filtered and concentrated. Compound 120 (101 mg, 203.34 pmol, 99.33% yield) was obtained as a yellow oil.

[0435] LCMS: Rt=0.864 min, [M+H]+=497.6

Preparation of compound 121

(120) (121 )

[0436] To a mixture of compound 120 (101 mg, 203.34 pmol, 1 eq) in DCM (1 mL) was added Boc2O (66.57 mg, 305.01 pmol, 70.07 pL, 1.5 eq), TEA (30.86 mg, 305.01 pmol, 42.45 pL, 1 .5 eq) at 10 °C under N2. The mixture was stirred at 25 °C for 10 hours. The mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (20 mL) and dried over sodium sulfate. Then the solution was concentrated under vacuum to give compound 121 (130 mg, crude) as a yellow oil.

[0437] LCMS: Rt=1.125 min, [M+H]+=597.4

Preparation of compound 122

(121) (122)

[0438] To a solution of compound 121 (60 mg, 100.53 pmol, 1 eq) and TEMPO (3.16 mg, 20.11 pmol, 0.2 eq) in DCM (1 mL) and H2O (0.5 mL) was added Phl(OAc)2 (80.95 mg, 251.33 pmol, 2.5 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 32%-62%, 10min). Compound 122 (18 mg, 29.47 pmol, 29.31 % yield, 100% purity) was obtained as a yellow solid.

[0439] LCMS: Rt=1.110 min, [M+H]+=611.3

Preparation of compound 123 (122) (123)

[0440] To a solution of compound 122 (18 mg, 29.47 pmol, 1 eq) in MeOH (0.5 mL) was added Pd/C (10 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 for 3 times. The reaction mixture was stirred under H2 (15 psi) at 25°C for 0.5 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. Compound 123 (19 mg, crude) was obtained as a white solid.

[0441] LCMS: Rt=0.980 min, [M+H]+=521.2

Preparation of compound 124

[0442] To a solution of compound 123 (19 mg, 36.49 pmol, 1 eq) and compound 118 (20.40 mg, 40.14 pmol, 1.1 eq, HCI) in DCM (0.5 mL) was added HATU (27.75 mg, 72.98 pmol, 2 eq) and DIEA (18.86 mg, 145.96 pmol, 25.42 pL, 4 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, EA: MeOH = 10:1 ). Compound 124 (10 mg, 8.83 pmol, 24.19% yield, 86% purity) was obtained as a yellow oil.

[0443] LCMS: Rt=0.953 min, [M+H]+=974.5

Preparation of Molecule 9

(124) (Molecule 9) [0444] A mixture of compound 124 (10 mg, 10.26 pmol, 1 eq) in HCI/dioxane (2 mL) was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.1 %TFA)-ACN]; B%: 12%-42%, 10min). Molecule 9 (8.37 mg, 9.39 pmol, 91.44% yield, 98% purity, TFA) was obtained as a white solid.

[0445] 1 H NMR (400 MHz, Methanol-d4)

[0446] 5 = 8.37 (d, J = 9.9 Hz, 1 H), 7.99 - 7.86 (m, 2H), 7.65 - 7.54 (m,

2H), 7.52 - 7.44 (m, 3H), 7.29 (d, J = 8.2 Hz, 1 H), 7.24 - 7.16 (m, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 6.65 (dd, J = 1.5, 9.8 Hz, 1 H), 5.47 - 5.37 (m, 1 H), 4.18 - 4.09 (m, 2H), 3.81 - 3.70 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.59 (t, J = 5.3 Hz, 1 H), 3.32 (br s, 4H), 3.29 - 3.21 (m, 3H), 3.14 (br t, J = 7.1 Hz, 4H), 3.00 - 2.62 (m, 2H), 2.43 (t, J = 6.7 Hz, 2H), 2.09 (br d, J = 8.8 Hz, 2H), 2.04 - 1 .96 (m, 2H), 1 .95 - 1 .87 (m, 2H), 1 .70 (br d, J = 11 .5 Hz, 1 H), 1 .49 - 1 .30 (m, 7H), 1.25 - 1.12 (m, 1 H)

[0447] LCMS: Rt=0.735 min, [M+H]+=760.4

PREPARATION OF MOLECULE EXAMPLE 10

Preparation of compound 126

(125) (126)

[0448] To a solution of compound 125 (200 mg, 1 .20 mmol, 1 eq) in MeCN (6 mL) was added IBX (1 .01 g, 3.59 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EA=15:1 -5:1 ). Compound 126 (92 mg, 557.08 pmol, 46.56% yield) was obtained as a red solid.

[0449] 1 H NMR (400 MHz, CHLOROFORM-d) [0450] 5 = 9.83 (t, J = 1 .7 Hz, 1 H), 8.25 (d, J = 8.6 Hz, 2H), 7.41 (d, J =

8.7 Hz, 2H), 3.88 (d, J = 1.3 Hz, 2H)

Preparation of compound 127

(126) (127)

[0451 ] To a solution of compound 44 (previously prepared in the synthesis of molecule Example 3) (80.22 mg, 188.92 pmol, 1.2 eq) and compound 126 (26 mg, 157.44 pmol, 1 eq) in MeOH (1 mL) was added AcOH (47.27 mg, 787.18 pmol, 45.02 pL, 5 eq). The mixture was stirred at 25 °C for 0.5 hour, and then NaBH3CN (29.68 mg, 472.31 pmol, 3 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 .5 hours. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 15:1 ).

Compound 127 (71 mg, 117.56 pmol, 74.67% yield, 95% purity) was obtained as a yellow solid.

[0452] LCMS: Rt=0.933 min, [M+H]+=574.2

Preparation of compound 128

[0453] To a solution of compound 127 (71 mg, 123.75 pmol, 1 eq) and Boc2O (32.41 mg, 148.50 pmol, 34.11 pL, 1 .2 eq) in DCM (1 mL) was added TEA (37.57 mg, 371.24 pmol, 51.67 pL, 3 eq). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE: EA=20: 1-1 :1). Compound 128 (81 mg, 114.19 pmol, 92.28% yield, 95% purity) was obtained as a yellow oil.

[0454] LCMS: Rt=1.224 min, [M+H]+=674.3

Preparation of compound 129

[0455] To the solution of compound 128 (81 mg, 120.20 pmol, 1 eq) in MeOH (1 mL) was added Pd/C (50 mg, 194.40 pmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 for three times. The reaction mixture was stirred under H2 (15 psi) at 25 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. Compound 129 (44 mg, crude) was obtained as a yellow solid.

[0456] LCMS: Rt=0.888 min, [M+H]+=554.3

Preparation of compound 130

(71 ) (130)

[0457] To a solution of compound 71 (113.15 mg, 225.57 pmol, 1.1 eq, the synthesis of which was described in Example of Molecule 5) in Py (2.2 mL) was added EDCI (117.93 mg, 615.19 pmol, 3 eq) and compound 129. The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into water (10 mL), and then extracted with ethyl acetate (30 mLx2). The combined organic layers were washed with brine (2x15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH=10:1 ). Compound 130 (87 mg, 84.93 pmol, 41.42% yield, 99.9% purity) was obtained as a yellow solid.

[0458] LCMS: Rt=0.977 min; [M+H] +=1023.5

Preparation of Molecule 10

(130) (Molecule 10)

[0459] A solution of compound 130 (87 mg, 85.01 pmol, 1 eq) in formic acid (1 mL) was stirred at 25 °C for 4 hours. The reaction solution 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 (0.1 % TFA)-ACN]; B%: 20%-30%, 7 min).

Molecule 10 (40 mg, 48.85 pmol, 57.46% yield, 98.8% purity) was obtained as a white solid.

[0460] LCMS: Rt=0.755 min; [M+H] +=809.5

[0461 ] 1 H NMR (400 MHz, Methanol-d4)

[0462] 5 = 8.66 (d, J = 1 .8 Hz, 1 H), 8.25 (d, J = 9.9 Hz, 1 H), 8.19 (d, J =

8.4 Hz, 1 H), 8.08 (dd, J = 2.1 , 8.1 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 2H), 7.61 - 7.54 (m, 2H), 7.52 - 7.44 (m, 3H), 7.30 - 7.24 (m, 2H), 7.02 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 9.9 Hz, 1 H), 5.39 (t, J = 6.7 Hz, 1 H), 4.40 (t, J = 5.9 Hz, 2H), 4.27 (s, 2H), 3.77 (q, J = 6.8 Hz, 1 H), 3.56 - 3.45 (m, 1 H), 3.44 - 3.34 (m, 1 H), 3.21 (d, J = 6.8 Hz, 3H), 3.17 - 2.98 (m, 3H), 2.90 (t, J = 5.9 Hz, 3H), 2.51 - 2.32 (m, 2H), 2.10 (br d, J = 9.3 Hz, 2H), 1.92 (br d, J = 12.6 Hz, 2H), 1.70 (br d, J = 13.6 Hz, 1 H), 1.40 (br d, J = 6.8 Hz, 6H), 1.35 - 1.28 (m, 1 H), 1.25 - 1.13 (m, 1 H)

PREPARATION OF MOLECULE EXAMPLE 11

Preparation of compound 132

(131) (132)

[0463] To a solution of compound 131 (500 mg, 2.32 mmol, 1 eq) in MeOH (10 mL) was added NaBH4 (438.68 mg, 11 .60 mmol, 5 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction solution was quenched by addition 1 N HCI (20 mL) at 0 °C and extracted with ethyl acetate (50 mL x 2). 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, PE: EA=15:1 to 3:1). Compound 132 (400 mg, 2.13 mmol, 91 .95% yield) was obtained as a yellow solid.

[0464] 1 H NMR (400 MHz, CHLOROFORM-d)

[0465] 5 = 8.17 (d, J = 2.3 Hz, 1 H), 8.11 (dd, J = 2.2, 8.6 Hz, 1 H), 7.71 (d,

J = 8.4 Hz, 1 H), 4.82 (s, 2H), 1.59 - 1.42 (m, 1 H)

Preparation of compound 133

(132) (133)

[0466] To a solution of compound 132 (400 mg, 2.13 mmol, 1 eq) in DCM (8 mL) was added Dess-Martin reagent compound (1.36 g, 3.20 mmol, 990.27 pL, 1 .5 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=30:1 ). Compound 133 (279.1 mg, 1.50 mmol, 70.53% yield) was obtained as a yellow solid.

Preparation of compound 134

(133) (134)

[0467] To a solution of compound 133 (85.44 mg, 460.41 pmol, 1 eq) and compound 44 (the synthesis of compound 44 is described in the procedure for synthesis of example 3) (200 mg, 460.41 pmol, 1 eq) in MeOH (3 mL) was added AcOH (13.82 mg, 230.21 pmol, 13.17pL, 0.5 eq), and the mixture was stirred for 30 minutes. Then NaBH3CN (57.87 mg, 920.82 pmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25 °C for another 0.5 hour. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used for next step directly. Compound 134 (253 mg, crude) was obtained as a yellow solid.

[0468] LCMS: Rt=0.864 min; [M+H]⁺=504.2

Preparation of compound 135

(134) (135)

[0469] To a solution of compound 134 (253 mg, 386.49 pmol, 1 eq) in DCM (6 mL) was added TEA (117.33 mg, 1.16 mmol, 161 .38 pL, 3 eq) and Boc2O (88.57 mg, 405.81 pmol, 93.23 pL, 1.05 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into water (20 mL) and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used for next step directly. Compound 135 (298 mg, crude) was obtained as a yellow oil.

[0470] LCMS: Rt=1.270 min; [M+H]+=704.4

Preparation of compound 136

[0471] To a solution of compound 135 (298 mg, 423.13 pmol, 1 eq) in

THF (3 mL) and MeOH (3 mL) was added a solution of LiOH (30.40 mg, 1 .27 mmol, 3 eq) in H2O (0.2 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH=8 with 1 N HCI aqueous solution, and then the mixture was concentrated under vacuum to give a residue. Then the residue was dissolved in ethyl acetate (30 mL) and saturated NH4CI aqueous solution (30 mL), and two layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=5:1 to 0:1 ). Compound 136 (103 mg, 170.48 pmol, 40.29% yield) was obtained as a yellow solid.

[0472] LCMS: Rt=1.191 min; [M+H]+=604.3

Preparation of compound 137

[0473] To a solution of compound 136 (100 mg, 165.52 pmol, 1 eq) in THF (1 mL) was added N,N-diethylethanamine trihydrofluoride (494.50 mg, 3.07 mmol, 0.5 mL, 18.53 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was adjusted to pH=7 with saturated Na2CO3 aqueous solution and poured into ethyl acetate (40 mL) and water (40 mL). Then two layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The crude product was used directly for next step without further purification. Compound 137 (77 mg, 157.17 pmol, 94.96% yield) was obtained as a yellow solid.

[0474] LCMS: Rt=0.937 min; [M+H]+=490.1

Preparation of compound 138

[0475] To a solution of compound 137 (65 mg, 132.68 pmol, 1 eq) and LiCI (5.62 mg, 132.68 pmol, 2.72pL, 1 eq) in MeOH (2 mL) was added Pd/C (30 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 138 (68 mg, crude) was obtained as a yellow solid.

[0476] LCMS: Rt=0.812 min; [M+H]+=460.1

Preparation of compound 139

(Intermediate 2) (139)

[0477] To a solution of compound 138 (55 mg, 96.86 pmol, 1 eq) and compound Intermediate 2 (the synthesis of intermediate 2 is described in the procedure for synthesis of Example 1 ) (60.50 mg, 96.86 pmol, 1 eq, HCI) in Py (0.6 mL) was added EDCI (24.14 mg, 125.92 pmol, 1.3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction solution was poured into H2O (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH=8:1 ). Compound 139 (53 mg, 51.79 pmol, 53.46% yield, 92.1 % purity) was obtained as a yellow solid.

[0478] LCMS: Rt=0.879 min; [M+H]+=942.5

Preparation of Molecule 11

(139) (Molecule 11 )

[0479] To compound 139 (50 mg, 53.05 pmol, 1 eq) was added formic acid (1 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH=7 with saturated Na2CO3 aqueous solution, and then the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 9%-39%, 10 min). Molecule 11 (18 mg, 19.98 pmol, 37.66% yield, 98.6% purity, FA) was obtained as a white solid.

[0480] LCMS: Rt=0.805 min; [M+H]+=842.4

[0481 ] 1 H NMR (400 MHz, Methanol-d4)

[0482] 5 = 8.50 (s, 2H), 8.27 (d, J = 9.9 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2H),

7.84 (d, J = 2.0 Hz, 1 H), 7.57 - 7.39 (m, 7H), 7.22 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1 H), 6.62 (d, J = 9.8 Hz, 1 H), 5.28 (dd, J = 4.5, 8.3 Hz, 1 H), 4.38 (t, J = 5.9 Hz, 2H), 4.09 (s, 2H), 3.59 (q, J = 6.6 Hz, 1 H), 3.18 - 2.97 (m, 6H), 2.97 - 2.76 (m, 4H), 2.74 - 2.47 (m, 3H), 2.04 (br s, 2H), 1 .88 (br d, J = 6.0 Hz, 2H), 1.68 (br d, J = 12.3 Hz, 1 H), 1.36 (br d, J = 6.7 Hz, 7H), 1.23 - 1.11 (m, 1 H) PREPARATION OF MOLECULE EXAMPLE 12

Preparation of compound 141

(140) (141 )

[0483] To a solution of compound 140 (500 mg, 3.53 mmol, 1 eq) in dioxane (10 mL) was added DDQ (1 .68 g, 7.42 mmol, 2.1 eq) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, and the filtrate was then diluted with brine (10 mL) and extracted with ethyl acetate (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. The residue was purified by column chromatography (SiO2, PE:EA=10:1 to 5:1 ). Compound 141 (0.302 g, 1.94 mmol, 54.97% yield) was obtained as a yellow solid.

Preparation of compound 142

(141) (142)

[0484] To a solution of compound 141 (71.63 mg, 460.41 pmol, 1 eq) and compound 44 (the synthesis of compound 44 is described in the procedure for synthesis of Example 3) (200 mg, 460.41 pmol, 1 eq) in MeOH (3 mL) was added AcOH (13.82 mg, 230.21 pmol, 13.17 pL, 0.5 eq), and the solution was stirred for 30 minutes. Then NaBH3CN (57.87 mg, 920.82 pmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 hour. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 142 (244 mg, crude) was obtained as a yellow solid.

[0485] LCMS: 0.846 min; [M+H]+=474.3

Preparation of compound 143

[0486] To a solution of compound 142 (244 mg, 339.70 pmol, 1 eq) in

DCM (6 mL) was added TEA (103.12 mg, 1.02 mmol, 141.85 pL, 3 eq) and Boc2O (77.84 mg, 356.68 pmol, 81.94 pL, 1.05 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into water (20 mL) and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used for next step directly. Compound 143 (254 mg, crude) was obtained as a yellow oil.

[0487] LCMS: Rt=1.209 min; [M+H]+=676.4

Preparation of compound 144

[0488] To a solution of compound 143 (254 mg, 376.69 pmol, 1 eq) in THF (3 mL) and MeOH (3 mL) was added a solution of LiOH (27.06 mg, 1.13 mmol, 3 eq) in H2O (0.2 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH=8 with 1 N HCI aqueous solution, and then mixture was concentrated under vacuum to give a residue. The residue was dissolved in ethyl acetate (30 mL) and saturated NH4CI aqueous solution (30 mL), and the two layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH=10:1 ). Compound 144 (180 mg, 235.12 pmol, 62.42% yield, 75% purity) was obtained as a yellow solid.

[0489] LCMS: Rt=1 .132 min; [M+H]+=574.3

Preparation of compound 145

[0490] To a solution of compound 144 (180 mg, 235.12 pmol, 1 eq) in THF (2 mL) was added N,N-Diethylethanamine trihydrofluoride (989.00 mg, 6.13 mmol, 1 mL, 26.09 eq). The mixture was stirred at 25 °C for 12 hours. The reaction solution was adjusted to pH=7 with saturated Na2COs aqueous solution and poured into a solution of ethyl acetate (40 mL) and water (40 mL). Two layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, DCM:MeOH=10:1 ). Compound 145 (88 mg, 170.29 pmol, 72.43% yield, 89% purity) was obtained as a yellow solid.

[0491 ] LCMS: Rt=0.860 min; [M+H]+=460.2

Preparation of compound 146

(Intermediate 2) (146)

[0492] To a solution of compound 145 (78 mg, 150.94 pmol, 1 eq) and Intermediate 2 (the synthesis of intermediate 2 is described in the procedure for synthesis of Example 1 ) (83.12 mg, 166.03 pmol, 1.1 eq) in Py (1.5 mL) was added EDCI (86.81 mg, 452.82 pmol, 3 eq). The mixture was stirred at 25 °C for 0.5 hour. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mLx2). The combined organic layers were washed with brine (2x15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, DCM: MeOH=10:1). Compound 146 (51 mg, 54.11 pmol, 35.85% yield) was obtained as a yellow solid.

[0493] LCMS: Rt=0.887 min; [M+H]+=942.5

Preparation of Molecule 12

(146) (Molecule 12)

[0494] To compound 146 (51 mg, 54.11 pmol, 1 eq) was added formic acid (1 .5 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH=7 with saturated Na2CO3 aqueous solution, and then the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.225%FA)-ACN]; B%: 13%-33%, 8min). Molecule 12 (18 mg, 19.96 pmol, 36.88% yield, 98.5% purity, FA) was obtained as a white solid.

[0495] LCMS: Rt=0.787 min; [M+H]+=842.4 [0496] 1 H NMR (400 MHz, Methanol-d4)

[0497] 6 = 8.51 (s, 2H), 8.27 (d, J = 9.8 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2H),

7.81 (br d, J = 8.3 Hz, 1 H), 7.59 - 7.46 (m, 6H), 7.35 (dd, J = 1 .7, 8.3 Hz, 1 H), 7.23 (br d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1 H), 6.63 (d, J = 9.8 Hz, 1 H), 5.30 (dd, J = 4.3, 8.3 Hz, 1 H), 4.40 (t, J = 5.7 Hz, 2H), 4.03 (s, 2H), 3.58 (q, J = 6.5 Hz, 1 H), 3.05 - 3.00 (m, 2H), 3.09 (br s, 2H), 2.89 (br d, J = 3.3 Hz, 1 H), 2.99 - 2.75 (m, 3H), 2.75 - 2.51 (m, 3H), 2.03 (br s, 2H), 1 .88 (br s, 2H), 1.67 (br d, J = 12.7 Hz, 1 H), 1.42 - 1.27 (m, 7H), 1.22 - 1.12 (m, 1 H)

PREPARATION OF MOLECULE EXAMPLE 13

Preparation of compound 147

(78) (147)

[0498] To a solution of compound 78 (the synthesis of compound 78 is described in the procedure for synthesis of Example 5) (60 mg, 132.30 pmol, 1 eq) and Intermediate 2 (the synthesis of intermediate 2 is described in the procedure for synthesis of Example 1 ) (66.23 mg, 132.30 pmol, 1 eq) in Py (0.9 mL) was added EDCI (32.97 mg, 171 .98 pmol, 1 .3 eq). The mixture was stirred at 25 °C for 2 h The reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 7:1 ). Compound 147 (80 mg, 80.07 pmol, 60.52% yield, 93.7% purity) was obtained as a yellow solid.

[0499] LCMS: Rt=0.799 min; [M+H]+=936.6

Preparation of Molecule 13 (147) (Molecule 13)

[0500] A mixture of compound 147 (80 mg, 85.46 pmol, 1 eq) and formic acid (0.8 mL) was stirred at 25 °C for 4 h The reaction mixture was adjusted to pH-7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep- HPLC (column: Shim-pack C18 150*25*1 Oum; mobile phase: [water(0.225%FA)-ACN];B%: 13%-33%,10min). Molecule 13 (21 mg, 24.54 pmol, 28.72% yield, 97.7% purity) was obtained as a yellow solid.

[0501 ] 1 H NMR (400 MHz, Methanol-d4)

[0502] 5 = 8.52 (s, 1 H), 8.34 (d, J = 9.9 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2H),

7.60 - 7.43 (m, 5H), 7.33 (s, 2H), 7.26 (d, J = 8.3 Hz, 1 H), 7.24 - 7.18 (m, 1 H), 7.02 (d, J = 8.3 Hz, 1 H), 6.65 (d, J = 9.8 Hz, 1 H), 5.38 (dd, J = 5.1 , 8.2 Hz, 1 H), 4.38 (t, J = 5.9 Hz, 2H), 4.25 - 4.06 (m, 2H), 3.56 (q, J = 6.7 Hz, 1 H), 3.22 - 3.09 (m, 2H), 3.07 - 2.91 (m, 4H), 2.86 (t, J = 5.9 Hz, 2H), 2.82 - 2.45 (m, 5H), 2.41 (s, 6H), 2.01 (br s, 2H), 1.86 (br d, J = 3.0 Hz, 2H), 1.67 (br d, J = 12.1 Hz, 1 H), 1.39 - 1.26 (m, 7H), 1.22 - 1.05 (m, 1 H)

[0503] LCMS: Rt=0.790 min; [M+H]+=836.0

PREPARATION OF MOLECULE EXAMPLE 14

Preparation of compound 150

(148) (150)

[0504] To a solution of compound 148 (14 g, 99.86 mmol, 12.28 mL, 1 eq) and compound 149 (16.96 g, 119.83 mmol, 1 .2 eq) in DMF (140 mL) was added Cs2CO3 (97.60 g, 299.57 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h The reaction solution was poured into saturated NH4CI aqueous solution (200 mL) and extracted with ethyl acetate (200 mLx2). The combined organic layers were washed with brine (200 mLx3) and dried over Na2SO4. Then the mixture was filtered, and the filtrate was concentrated under vacuum to give a crude product. Compound 150 (23.8 g, 96.06 mmol, 96.19% yield, 99% purity) was obtained as a yellow oil.

Preparation of compound 151

[0505] To a solution of compound 150 (20 g, 81.53 mmol, 1 eq) in THF (200 mL) was added EtMgBr/Et20 (3 M, 54.36 mL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h The reaction mixture was quenched by addition saturated NH4CI (100 mL) at 0°C, then diluted with water (100 mL) and extracted with ethyl acetate (200 mLx2), 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 to 2/1 ). Compound 151 (21 g, 76.19 mmol, 93.44% yield, 99.9% purity) was obtained as a yellow solid.

Preparation of compound 152

[0506] To a solution of compound 151 (16 g, 58.10 mmol, 1 eq) in DCM

(150 mL) was added m-CPBA (22.41 g, 110.40 mmol, 85% purity, 1.9 eq) at

0 °C. The mixture was stirred at 20 °C for 1 h The reaction mixture was quenched by addition saturated Na2SO3 aqueous (100 mL) at 0 °C, then diluted with water (100 mL) and extracted with ethyl acetate (200 mLx2), 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 2/1 ). Compound 152 (21.9 g) was obtained as a yellow oil.

[0507] To a solution of compound 152 (17.9 g, 58.24 mmol, 1 eq) and TEA (17.68 g, 174.71 mmol, 24.32 mL, 3 eq) in DCM (180 mL) was added MsCI (19.22 g, 167.80 mmol, 12.99 mL, 2.88 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h The reaction mixture was poured into H2O (300 mL) and extracted with ethyl acetate (300 mLx2). The combined organic layers were washed with brine (300 mLx3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 153 (26.1 g, crude) was obtained as a yellow oil.

[0508] LCMS: Rt=0.851 min; [M+H]⁺=385.9

Preparation of compound 155

(153) (155)

[0509] To a solution of compound 153 (26.1 g, 67.71 mmol, 1 eq) in MeCN (260 mL) was added TMP (11.48 g, 81 .25 mmol, 13.79 mL, 1.2 eq) and tert-butyl piperazine-1 -carboxylate (154) (13.87 g, 74.48 mmol, 1.1 eq). The mixture was stirred at 80 °C for 12 h The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether/Ethyl acetate=10/1 to 1/1 ). Compound 155 (14.03 g, 29.20 mmol, 43.13% yield, 99% purity) was obtained as a yellow oil.

Preparation of compound 156

[0510] A mixture of compound 155 (14 g, 29.44 mmol, 1 eq) and HCI/dioxane (200 mL) and MeOH (140 mL) was stirred at 25 °C for 12 h The reaction mixture was concentrated under vacuum to give the crude product.

The crude product was used directly in the next step without further purification. Compound 156 (14.1 g, crude, HCI) was obtained as a yellow solid.

[0511] LCMS: Rt=0.741 min; [M+H]⁺=376.0

Preparation of compound 157

[0512] A mixture of compound 156 (14.1 g, 34.23 mmol, 1 eq, HCI) and cyclohexanone (33.59 g, 342.28 mmol, 35.47 mL, 10 eq) in MeOH (150 mL) was stirred at 25 °C for 0.5 h Then NaBHsCN (10.75 g, 171 .14 mmol, 5 eq) was added at 25 °C and the mixture was stirred for 2 h The reaction mixture was poured into H2O (200 mL) and removed MeOH under reduce pressure. The residue was extracted with ethyl acetate (200 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 (SiCh, Petroleum ether/Ethyl acetate=10/1 to 1/10). Compound 157 (12.3 g, 25.53 mmol, 74.60% yield, 95% purity) was obtained as a yellow solid.

Preparation of compound 158

(157) (158) (158b)

[0513] Compound 157 (5 g, 10.93 mmol, 1 eq) was purified by chiral SFC (column: DAICEL CHIRALPAK AD-H(250mm*30mm,5um); mobile phase: [0.1 %NH₃H₂O EtOH];B%: 35%-35%,8min;840 min). Compound 158 (2.3 g, 4.98 mmol, 45.54% yield, 99% purity) was obtained as a yellow solid.

Compound 158b (2.6 g, 5.62 mmol, 51.48% yield, 99% purity) was obtained as a yellow solid.

Preparation of compound 159

[0514] To a solution of compound 158b (500 mg, 1 .09 mmol, 1 eq) in DCM (25 mL) was added BBrs (1 .92 g, 7.65 mmol, 736.93 pL, 7 eq) at 0 °C. Then the mixture was stirred at 20 °C for 2 h The reaction mixture was quenched by NHs/MeOH (0.5M, 30 mL) and the mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiC>2, Ethyl acetate/MeOH=50/1 to 10/1). Compound 159 (430 mg, 2.78 mmol, 84.94% yield, 95% purity) was obtained as a yellow solid.

Preparation of compound 160

[0515] To a solution of compound 159 (1 .3 g, 2.64 mmol, 90% purity, 1 eq) in MeCN (13 mL) was added K2CO3 (1 .09 g, 7.91 mmol, 3 eq) and 3- hydroxypropyl 4-methylbenzenesulfonate (789.58 mg, 3.43 mmol, 1.3 eq).

The mixture was stirred at 80 °C for 4 h The reaction mixture was poured into saturated NH4CI aqueous (50 mL) and extracted with ethyl acetate (50 mLx2). 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 (SiC>2, DCM/MeOH=30/1 to 10/1 ).

Compound 160 (1.1 g, 1.75 mmol, 66.44% yield, 80% purity) was obtained as a yellow solid.

Preparation of compound 161

(160) (161 )

[0516] To a solution of compound 160 (1 .1 g, 1 .75 mmol, 80% purity, 1 eq) in acetone (30 mL) was added trioxochromium sulfuric acid (2.7 M, 649.67 pL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h After quenching the excess oxidant with i-PrOH (0.2 mL), the mixture was filtered and the solid was wash with acetone (10 mLx2). The filtrate was adjusted to pH-7 with aqueous saturated Na2COs, and concentrated under vacuum. DCM (40 mL) and water (40 mL) were added and layers were separated.

The aqueous phase was extracted with DCM (30 mLx2). Combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (HCI)-ACN]; B%: 20%-40%,7min). Compound 161 (430 mg, 700.93 pmol, 39.96% yield, 90% purity, HCI) was obtained as a yellow solid.

Preparation of compound 162

(161) (162) [0517] To a solution of compound 161 (90 mg, 174.53 pmol, 1 eq) and compound 78 (the synthesis of compound 78 is described in the procedure for synthesis of Example 5) (79.16 mg, 174.53 pmol, 1 eq) in Py (1 mL) was added EDCI (43.50 mg, 226.89 pmol, 1 .3 eq). The mixture was stirred at 25 °C for 2 h The reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (10 mLx3). 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: Phenomenex Synergi Polar-RP 100*25mm*4um; mobile phase: [water(TFA)-ACN];B%: 42%-62%,7min). Compound 162 (73 mg, 72.91 pmol, 41 .77% yield, 95% purity) was obtained as a yellow solid.

[0518] LCMS: Rt=0.871 min; [M+H]⁺=951 .1

Preparation of Molecule 14

(162) (Molecule 14)

[0519] A mixture of compound 162 (70 mg, 73.59 pmol, 1 eq) in formic acid (3.39 mg, 73.59 pmol, 2.78 pL, 1 eq) was stirred at 25 °C for 3 h The reaction mixture was adjusted to pH-7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN];B%: 6%-36%,10min). Molecule 14 (28 mg, 31.45 pmol, 42.74% yield, 95.6% purity) was obtained as a yellow solid.

[0520] 1 H NMR (400 MHz, Methanol-d4)

[0521] 5 = 8.58 (d, J = 1.6 Hz, 1 H), 8.52 (s, 1 H), 8.34 (d, J = 10.0 Hz,

1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.00 (dd, J = 2.0, 8.0 Hz, 1 H), 7.64 - 7.56 (m, 2H), 7.54 - 7.47 (m, 1 H), 7.34 (s, 2H), 7.30 - 7.20 (m, 2H), 7.02 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 10.0 Hz, 1 H), 5.39 (dd, J = 5.2, 8.4 Hz, 1 H), 4.40 (t, J = 6.0 Hz, 2H), 4.26 - 4.05 (m, 2H), 3.53 (dd, J = 5.6, 8.8 Hz, 1 H), 3.18 - 3.10 (m, 2H), 3.03 - 2.82 (m, 6H), 2.77 - 2.44 (m, 5H), 2.41 (s, 6H), 2.06 - 1.92 (m, 3H), 1.90 - 1.74 (m, 3H), 1.71 - 1.60 (m, 1 H), 1.34 - 1.23 (m, 4H), 1.17 - 1.08 (m, 1 H), 0.76 (t, J = 7.2 Hz, 3H).

[0522] LCMS: Rt=0.767 min; [M+H]+=851.0

PREPARATION OF MOLECULE EXAMPLE 15

Preparation of compound 164 8.77 mmol, 1 eq), diphenylmethanimine (5.10 g, 28.16 mmol, 4.72 mL, 1 .5 eq), Pd2(dba)3 (859.45 mg, 938.55 pmol, 0.05 eq), BINAP (1.17 g, 1.88 mmol, 0.1 eq) and Cs2CO3 (15.29 g, 46.93 mmol, 2.5 eq) in toluene (80 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 12 h under N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The crude product was used directly in the next step without further purification. Compound 164 (10.5 g, crude) was obtained as a yellow oil.

[0524] LCMS: Rt=1.034 min; [M+H]+=314.2

Preparation of compound 165

(164) (165)

[0525] A mixture of compound 164 (10.5 g, 33.50 mmol, 1 eq), HCI (1 M, 70 mL, 2.09 eq) and THF (70 mL) was stirred at 25 °C for 0.15 h The reaction mixture was adjusted to pH-8 with saturated Na2CO3 aqueous solution, then the mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mLx3). 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=50/1 to 10/1 ). Compound 165 (3.2 g, crude) was obtained as a yellow solid.

[0526] LCMS: Rt=0.336 min; [M+H]+=150.2

Preparation of compound 166

(165) (166)

[0527] To a solution of compound 165 (2 g, 8.04 mmol, 60% purity, 1 eq) in DCM (20 mL) was added Br2 (1.29 g, 8.04 mmol, 414.59pL, 1 eq) in DCM (20 mL) dropwise at -78 °C. Then the mixture was stirred at -78 °C for 1 .5 h The reaction mixture was adjusted to pH-8 with saturated Na2CO3 aqueous solution, then the mixture was poured into H2O (50 mL) and extracted with DCM (50 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, PE/EA=50/1 to 7/1). Compound 166 (700 mg, 3.07 mmol, 38.16% yield) was obtained as a yellow solid.

Preparation of compound 167

(166) (167)

[0528] To a solution of compound 166 (810 mg, 3.55 mmol, 1 eq) in DCM (8 mL) was added TEA (1 .08 g, 10.65 mmol, 1 .48 mL, 3 eq) and (2,2,2- trifluoroacetyl) 2,2,2-trifluoroacetate (1.12 g, 5.33 mmol, 740.87 pL, 1.5 eq). The reaction mixture was poured into H2O (30 mL) and extracted with ethyl acetate (30 mLx3). 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=100/1 to 10/1 ). Compound 167 (1.1 g, 3.39 mmol, 95.58% yield) was obtained as a yellow solid.

Preparation of compound 168

[0529] To a solution of compound 167 (1 .45 g, 4.47 mmol, 1 eq) in DMF (70 mL) was added TEA (1.36 g, 13.42 mmol, 1 .87 mL, 3 eq), Et3SiH (1 .04 g, 8.95 mmol, 1.43 mL, 2 eq) and Pd(dppf)CI2 (654.69 mg, 894.74 pmol, 0.2 eq) under N2. The suspension was degassed under vacuum and purged with CO several times. Then the mixture was stirred under CO (45 psi) at 80 °C for 20 h The reaction mixture was cooled to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, and layers were separated. The aqueous phase was extracted with DCM (50 mL x 2). Combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 5/1 ). Compound 168 (930 mg, 3.40 mmol, 76.08% yield) was obtained as a yellow solid.

Preparation of compound 169

(44) (169)

[0530] A solution of 44 (the synthesis of compound 44 is described in the procedure for synthesis of Example 3) (250 mg, 747.42 pmol, 1 eq), compound 168 (204.22 mg, 747.42 pmol, 1 eq) and AcOH (22.44 mg, 373.71 pmol, 21 .37 pL, 0.5 eq) in MeOH (3 mL) was stirred at 25 °C for 0.5 h Then NaBH3CN (93.94 mg, 1 .49 mmol, 2 eq) was added to the mixture and the mixture was stirred at 25 °C for 1 h The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 169 (470 mg, crude) was obtained as a yellow solid.

[0531 ] LCMS: Rt=0.777 min; [M+H]+=592.3

Preparation of compound 170

(169) (170)

[0532] To a solution of compound 169 (470 mg, 794.30 pmol, 1 eq) in DCM (5 mL) and H2O (5 mL) was added NaHCO3 (431.96 mg, 5.14 mmol, 199.98 pL, 6.47 eq) and tert-butoxycarbonyl tert-butyl carbonate (208.02 mg, 953.16 pmol, 218.97 pL, 1 .2 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated. And the residue was poured into H2O (20 mL) and extracted with ethyl acetate (20 mLx2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 170 (610 mg, crude) was obtained as a yellow solid.

[0533] LCMS: Rt=1 .128 min; [M+H]+=792.4

Preparation of compound 171

(170) (171 ) [0534] To a solution of compound 170 (610 mg, 770.25 pmol, 1 eq) in THF (6 mL) and MeOH (6 mL) was added a solution of LiOH (55.34 mg, 2.31 mmol, 3 eq) in H2O (0.6 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH-8 with 1 N HCI aqueous solution, then mixture was concentrated under vacuum to give a residue. Ethyl acetate (10 mL) and H2O (10 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 2). Combined extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 1/1 ). Compound 171 (240 mg, 317.77 pmol, 41 .25% yield, 91 .6% purity) was obtained as a yellow solid.

[0535] LCMS: Rt=1.035 min; [M+H]+=692.4

Preparation of compound 172

[0536] To a solution of compound 171 (240 mg, 346.91 pmol, 1 eq) in MeOH (3 mL) and H2O (1 mL) was added K2CO3 (958.92 mg, 6.94 mmol, 20 eq). The mixture was stirred at 60 °C for 6 h The reaction mixture was adjusted to pH-8 with 1 N HCI aqueous solution, then the mixture was poured into H2O (20 mL) and extracted with ethyl acetate (10 mLx3). 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, DCM/MeOH=100/1 to 20/1 ). Compound 172 (190 mg, 284.45 pmol, 82.00% yield, 89.2% purity) was obtained as a yellow solid.

[0537] LCMS: Rt=2.631 min; [M+H]+=596.4

Preparation of compound 173

[0538] To a solution of compound 172 (190 mg, 318.89 pmol, 1 eq) in

THF (2 mL) was added N,N-Diethylethanamine trihydrofluoride (989.00 mg, 6.13 mmol, 1 mL, 19.24 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was adjusted to pH-8 with saturated Na2CO3 aqueous solution. Ethyl acetate (10 mL) and water (10 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 2). Combined extracts were washed dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 10:1 ). Compound 173 (110 mg, 214.26 pmol, 67.19% yield, 93.8% purity) was obtained as a yellow solid.

[0539] LCMS: Rt=0.745 min; [M+H]+=482.3

Preparation of compound 174

[0540] To a solution of compound 173 (110mg, 228.42 pmol, 1 eq) and Intermediate 2 (the synthesis of Intermediate 2 is described in the procedure for synthesis of Example 1 ) (122.69 mg, 228.42 pmol, 1 eq, HCI) in Py (1.5 mL) was added EDCI (56.93 mg, 296.95 pmol, 1.3 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (10 mLx3). 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 prep-TLC (SiO2, DCM: MeOH = 8:1 ). Compound 174 (120 mg, 69.45 pmol, 30.40% yield, 55.8% purity) was obtained as a yellow solid.

[0541 ] LCMS: Rt=0.762 min; [M+H]+=964.2

Preparation of Molecule 15

(174) (Molecule 15)

[0542] A mixture of compound 174 (120 mg, 74.67 pmol, 60% purity, 1 eq) and formic acid (1 mL) was stirred at 25 °C for 4 h. The reaction mixture was adjusted to pH-7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(0.225%FA)-ACN];B%: 6%-36%,10min). Molecule 15 (37.1 mg, 39.91 pmol, 53.44% yield, 97.9% purity, FA) was obtained as a white solid.

[0543] 1 H NMR (400 MHz, Methanol-d4)

[0544] 5 = 8.51 (s, 1 H), 8.18 (d, J = 9.9 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2H),

7.74 - 7.69 (m, 1 H), 7.68 - 7.62 (m, 1 H), 7.58 - 7.42 (m, 7H), 7.27 (br d, J =

7.8 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 6.58 (d, J =

9.8 Hz, 1 H), 5.31 (dd, J = 4.5, 8.6 Hz, 1 H), 4.52 - 4.37 (m, 4H), 3.61 - 3.53 (m, 1 H), 3.21 - 2.94 (m, 8H), 2.91 - 2.31 (m, 5H), 2.02 (br d, J = 11 .7 Hz, 2H), 1.92 - 1.77 (m, 2H), 1.67 (br d, J = 12.1 Hz, 1 H), 1 .42 - 1 .23 (m, 7H), 1.22 - 1.05 (m, 1 H)

[0545] LCMS: Rt=0.686 min; [M+H]+=864.5

PREPARATION OF MOLECULE EXAMPLE 16

Preparation of compound 175 (161) (175)

[0546] To a solution of 173 (the synthesis of compound 173 is described in the procedure for synthesis of Example 15) (69.78 mg, 144.89 pmol, 1 eq) and compound 161 (the synthesis of compound 161 is described in the procedure for synthesis of Example 14) (80 mg, 144.89 pmol, 1 eq, HCI) in Py (1 mL) was added EDCI (41 .66 mg, 217.34 pmol, 1 .5 eq). The mixture was stirred at 25 °C for 3 h The reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (10 mLx2). The organic phase was dried over Na2SO4 and filter, then concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN];B%: 19%- 49%,10min). Compound 175 (66 mg, 63.73 pmol, 43.98% yield, 99% purity, FA) was obtained as a yellow solid.

[0547] 1 H NMR (400 MHz, Methanol-d4)

[0548] 5 = 8.55 (d, J = 1 .6 Hz, 1 H), 8.52 (s, 1 H), 8.30 (d, J = 10.0 Hz,

1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.02 - 7.91 (m, 1 H), 7.71 - 7.57 (m, 3H), 7.56 - 7.40 (m, 2H), 7.37 - 7.28 (m, 2H), 7.23 - 7.05 (m, 2H), 6.95 (d, J = 7.6 Hz, 1 H), 6.56 (d, J = 8.8 Hz, 1 H), 5.45 - 5.24 (m, 1 H), 4.59 (br s, 4H), 4.48 - 4.40 (m, 2H), 3.54 - 3.38 (m, 3H), 3.07 - 2.24 (m, 10H), 2.08 - 1.85 (m, 3H), 1 .84 - 1 .69 (m, 3H), 1 .68 - 1.57 (m, 1 H), 1.54 - 1.37 (m, 9H), 1.32 - 1.01 (m, 5H), 0.74 (t, J = 7.2 Hz, 3H).

[0549] LCMS: Rt=0.847 min; [M+H]+=979.0

Preparation of Molecule 16

(175) (Molecule 16)

[0550] A mixture of compound 175 (65 mg, 63.40 pmol, 1 eq, FA) in formic acid (1 .22 g, 26.50 mmol, 1 mL, 418.05 eq) was stirred at 25 °C for 3 h. The reaction mixture was adjusted to pH-7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN];B%: 4%- 34%,10min). Molecule 16 (34.50 mg, 36.38 pmol, 57.37% yield, 97.54% purity, FA) was obtained as a white solid.

[0551 ] 1 H NMR (400 MHz, Methanol-d4)

[0552] 5 = 8.57 (d, J = 1.6 Hz, 1 H), 8.51 (s, 1 H), 8.28 - 8.15 (m, 2H), 7.99

(dd, J = 2.0, 8.0 Hz, 1 H), 7.74 - 7.69 (m, 1 H), 7.67 - 7.57 (m, 3H), 7.56 - 7.45 (m, 3H), 7.32 (dd, J = 2.0, 8.0 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 10.0 Hz, 1 H), 5.32 (dd, J = 4.8, 8.4 Hz, 1 H), 4.52 - 4.39 (m, 4H), 3.53 (dd, J = 5.6, 8.4 Hz, 1 H), 3.21 - 2.92 (m, 7H), 2.88 - 2.32 (m, 5H), 2.06 - 1.90 (m, 3H), 1.89 - 1.70 (m, 3H), 1.65 (d, J = 12.0 Hz, 1 H), 1 .35 - 1 .20 (m, 4H), 1 .19 - 1 .02 (m, 1 H), 0.75 (t, J = 7.2 Hz, 3H).

[0553] LCMS: Rt=0.771 min; [M+H]+=879.0

PREPARATION OF MOLECULE EXAMPLE 17

Preparation of compound 97

(95) (96) (97)

[0554] To a solution of compound 95 (3 g, 21 .40 mmol, 2.63 mL, 1 eq) and compound 96 (2.66 g, 21.40 mmol, 2.25 mL, 1 eq) in DMF (30 mL) was added Cs2CO3 (10.46 g, 32.10 mmol, 1 .5 eq). The mixture was stirred at 50 °C for 0.5 h The reaction solution was poured into water (40 mL) and extracted with ethyl acetate (50 mLx 2). The combined organic layers were washed with brine (50 mLx 3) and dried over Na2SO4. Then the mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 10/1 ). Compound 97 (6.3 g, 24.63 mmol, 57.56% yield, 95.52% purity) was obtained as a yellow oil.

Preparation of compound 98

[0555] To a solution of compound 97 (5.3 g, 21 .69 mmol, 1 eq) in THF (60 mL) was added EtMgBr (3 M, 8.68 mL, 1.2 eq). The reaction flask was degassed and purged with N2 for 3 times at 0°C, and then the mixture was stirred at 0 °C for 0.5 hunder N2 atmosphere. The reaction mixture was quenched by addition saturated NH4CI (40 mL) at 0°C, then diluted with water (10 mL) and extracted with ethyl acetate (50 mLx 3). The combined organic layers were washed with brine (50 mLx 3), 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 to 3/1). Compound 98 (6.3 g, 22.96 mmol, 52.92% yield) was obtained as a yellow oil.

Preparation of compound 99

(98) (99)

[0556] To a solution of compound 98 (5.3 g, 19.32 mmol, 1 eq) in DCM (106 mL) was added m-CPBA (10.00 g, 40.56 mmol, 70% purity, 2.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h The reaction mixture was quenched by addition saturated Na2SO3 aqueous (30 mL) at 0 °C, then diluted with water (100 mL) and extracted with DCM (50 mLx 3). The combined organic layers were washed with saturated NaHCO3 aqueous (50 mLx 3), brine (50 mLx 3), 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 to 3/1 ). Compound 99 (5.7 g, 18.60 mmol, 96.31% yield, 100%)

Preparation of compound 100

(99) (100)

[0557] To a solution of compound 99 (4.58 g, 14.95 mmol, 1 eq) and TEA (4.54 g, 44.85 mmol, 6.24 mL, 3 eq) in DCM (47 mL) was added methylsulfonyl methanesulfonate (3.91 g, 22.42 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h The reaction mixture was poured into H2O (30 mL) and extracted with DCM (30 mLx 3). The combined organic layers were washed with brine (30 mLx 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step without further purification. Compound 100 (6 g, crude) was obtained as a yellow oil.

Preparation of compound 176

[0558] To a solution of compound 100 (6 g, 15.61 mmol, 1 eq) in MeCN (60 mL) was added TMP (2.65 g, 18.73 mmol, 3.18 mL, 1.2 eq) and tertbutyl piperazine-1 -carboxylate (3.20 g, 17.17 mmol, 1.1 eq). The mixture was stirred at 80 °C for 16 h The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether/Ethyl acetate=100/1 to 2/1 ). Compound 176 (5.3 g, 9.89 mmol, 63.38% yield, 88.57% purity) was obtained as a white solid.

[0559] LCMS: Rt=0.606 min; [M+H]⁺=475.2

Preparation of compound 177

[0560] A mixture of compound 176 (4.3 g, 9.06 mmol, 1 eq) and HCI/dioxane (4 M, 22.65 mL, 10 eq) and dioxane (3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum to give the crude product. The crude product was used directly in the next step without further purification. Compound 177 (4.3 g, crude) was obtained as a yellow oil.

[0561] LCMS: Rt=0.473 min; [M+H]⁺=375.1

Preparation of compound 178

[0562] A mixture of compound 177 (4.3 g, 11 .48 mmol, 1 eq) and cyclohexanone (12.88 g, 114.82 mmol, 13.54 mL, 10 eq) in MeOH (150 mL) was stirred at 25 °C for 0.5 h Then NaBHsCN (3.61 g, 57.41 mmol, 5 eq) was added at 25 °C and the mixture was stirred for 0.5 h The reaction mixture was poured into H2O (50 mL) and removed MeOH under reduce pressure. The resulting mixture was extracted with ethyl acetate (50 mLx 3). The combined organic layers were washed with brine (50 mLx 3), 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 to 10/1 ). Compound 178 (4.1 g, 8.54 mmol, 74.35% yield, 98% purity) was obtained as a yellow oil. Preparation of compound 179

[0563] Compound 178 (5 g, 10.10 mmol 1 eq) was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10pm); mobile phase: [0.1 %NH₃H₂O MeOH]; B%: 50%-50%,8.4 min). Compound 179 (2.1 g, 4.20 mmol, 39.53% yield, 94.13% purity) was obtained as a yellow oil.

Preparation of compound 180

[0564] To a solution of compound 179 (500 mg, 1 .06 mmol, 1 eq) in DCM (10 mL) was added BBrs (1 .33 g, 5.31 mmol, 511 .80 pL, 5 eq) at 0 °C. Then the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by NHs/MeOH (0.5M, 30 mL) and the mixture was concentrated under vacuum to give a residue. The reaction mixture was water (20 mL), extracted with ethyl acetate (20 mLx 3). The combined organic layers were washed with brine (20 mLx 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM/MeOH =100/1 to 10/1 ). Compound 180 (880 mg, 1.91 mmol, 89.71 % yield, 98.9% purity) was obtained as a white solid.

[0565] LCMS: Rt=0.821 min; [M+H]⁺=457.3

Preparation of compound 181

(180) (181 )

[0566] To a solution of compound 180 (780.00 mg, 1.71 mmol, 1 eq) in MeCN (8 mL) was added K2CO3 (708.22 mg, 5.12 mmol, 3 eq) and 3- hydroxypropyl 4-methylbenzenesulfonate (472.02 mg, 2.05 mmol, 1.2 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was water (15 mL), extracted with ethyl acetate (15 mLx 3). The combined organic layers were washed with brine (15 mLx 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water(FA)-ACN];B%: 20%-50%,10min). Compound 181 (580 mg, 1.12 mmol, 65.85% yield, 99.82% purity) was obtained as a yellow gum.

Preparation of compound 182

(181 ) (182)

[0567] To a solution of compound 181 (200 mg, 388.56 pmol, 1 eq) in acetone (30 mL) was added Trioxochromium sulfuric acid (2.7 M, 287.82 pL, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h After quenching the excess oxidant with i-PrOH (2 mL) and the solid was wash with DCM (20 mL) and acetone (20 mL). The filtrate was adjusted to pH=7 with saturated Na2COs aqueous, the mixture was filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: YMC Triart C18 150*25mm*5um; mobile phase: [water (HCI)-ACN]; B%: 7%-37%,10min). Compound 182 (80 mg, 149.12 pmol, 38.38% yield, 98.55% purity) was obtained as a white solid.

[0568] LCMS: Rt=0.504 min; [M+H]⁺=529.3

Preparation of compound 183

(182) (183)

[0569] To a solution of compound 182 (80 mg, 151.31 pmol, 1 eq) and compound 78 (the synthesis of compound 78 is described in the procedure for synthesis of Example 5) (68.63 mg, 151.31 pmol, 1 eq) in pyridine (1 mL) was added EDCI (43.51 mg, 226.97 pmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (5 mLx 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 22%-52%,7min). Compound 183 (70 mg, 70.06 pmol, 46.30% yield, 96.51% purity) was obtained as a yellow solid.

[0570] LCMS: Rt=0.905 min; [M+H]⁺=964.4

Preparation of Molecule 17

(183) (Molecule 17)

[0571] A mixture of compound 183 (60 mg, 62.23 pmol, 1 eq) in formic acid (1 mL) was stirred at 25 °C for 2 h The reaction mixture was adjusted to pH=7 with saturated Na2COs aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water (FA)-ACN]; B%: 8%-38%,9min). Molecule 17 (24.38 mg, 28.21 pmol, 45.34% yield, 99.99% purity) was obtained as a yellow solid.

[0572] 1 H NMR (400 MHz, CD3OD) [0573] 5 = 8.51 (s, 2H), 8.35 (d, J = 10.0 Hz, 1 H), 7.95 (d, J = 8.4 Hz,

2H), 7.54 - 7.46 (m, 5H), 7.36 (s, 2H), 7.28 (d, J = 8.4 Hz, 1 H), 7.25 - 7.20 (m, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.66 (d, J = 10.0 Hz, 1 H), 5.43 (dd, J = 4.0, 9.3 Hz, 1 H), 4.39 (t, J = 6.0 Hz, 2H), 4.33 - 4.18 (m, 2H), 3.49 - 3.43 (m, 1 H), 3.24 - 2.93 (m, 8H), 2.87 (t, J = 6.0 Hz, 2H), 2.59 (br s, 3H), 2.43 (s, 6H), 1.96 (br dd, J = 6.8, 12.9 Hz, 3H), 1.82 - 1.72 (m, 3H), 1.68 (br s, 8H), 0.74 (t, J = 7.2 Hz, 3H)

[0574] LCMS: Rt=0.814 min; [M+H]+=864.3

PREPARATION OF MOLECULE EXAMPLE 18

Preparation of compound 184

(Intermediate s) (184)

[0575] To a solution of Intermediate 3 (previously described in the procedure for the synthesis of Molecule example 6) (60 mg, 116.58 pmol, 1 eq) and compound 78 (the synthesis of compound 78 is described in the procedure for synthesis of Example 5) (52.87 mg, 116.58 pmol, 1 eq) in pyridine (1 mL) was added EDCI (44.70 mg, 233.16 pmol, 2 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (5 mLx 3). The combined organic layers were washed with brine (5 mLx 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm; mobile phase: [water(FA)-ACN];B%: 27%-57%,7min). Compound 184 (50 mg, 49.01 pmol, 42.04% yield, 93.14% purity) was obtained as a yellow solid.

[0576] LCMS: Rt=0.903 min; [M+H]+=950.4

Preparation of Molecule 18

(184) (Molecule 18)

[0577] A mixture of compound 184 (40 mg, 42.10 pmol, 1 eq) in formic acid (0.5 mL) was stirred at 25 °C for 2 hrs. The reaction mixture was adjusted to pH=7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: llnisil 3-100 C18 Ultra 150*50mm*3 pm; mobile phase: [water(FA)-ACN];B%: 8%-38%,7min). Molecule 18 (22.04 mg, 25.40 pmol, 60.34% yield, 97.97% purity) was obtained as a yellow solid.

[0578] 1 H NMR (400 MHz, Methanol-d4)

[0579] 5 = 8.51 (s, 2H), 8.34 (d, J = 10.0 Hz, 1 H), 7.93 (d, J = 8.4 Hz,

2H), 7.56 (d, J = 8.4 Hz, 2H), 7.53 - 7.45 (m, 3H), 7.35 (s, 2H), 7.27 (d, J = 8.0 Hz, 1 H), 7.25 - 7.20 (m, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.66 (d, J = 10.0 Hz, 1 H), 5.41 (dd, J = 4.4, 9.1 Hz, 1 H), 4.38 (t, J = 6.0 Hz, 2H), 4.30 - 4.13 (m, 2H), 3.59 (d, J = 6.8 Hz, 1 H), 3.26 - 2.99 (m, 8H), 2.86 (t, J = 5.8 Hz, 2H), 2.80 - 2.47 (m, 4H), 2.42 (s, 6H), 2.02 - 1 .93 (m, 2H), 1.81 - 1 .72 (m, 2H), 1.69 - 1.47 (m, 8H), 1.37 (d, J = 6.8 Hz, 3H).

[0580] LCMS: Rt=0.804 min; [M+H]+=850.3

PREPARATION OF MOLECULE EXAMPLE 19

Preparation of compound 185

(173) (185)

[0581 ] To a solution of Intermediate 3 (the synthesis of Intermediate 3 is described in the procedure for synthesis of Example 6) (70 mg, 136.01 pmol, 1 eq) in Py (0.1 mL) was added EDCI (52.15 mg, 272.02 pmol, 2 eq) and 173 (the synthesis of compound 173 is described in the procedure for synthesis of Example 15) (72.05 mg, 149.61 pmol, 1.1 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 ml_x2). The combined organic layers were washed with brine (20 ml_x3) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75x30mmx3um; mobile phase: [water(FA)-ACN];B%: 22%-52%,7min). Compound 185 (64 mg, 64.70 pmol, 47.57% yield, 98.89% purity) was obtained as a white solid.

Preparation of Molecule 19

(185) (Molecule 19)

[0582] A mixture of compound 185 (54 mg, 55.20 pmol, 1 eq) in formic acid (1 mL) was stirred at 25 °C for 1 h The reaction mixture was adjusted to pH=7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 8%-38%,5min). Molecule 19 (33.00 mg, 37.48 pmol, 67.90% yield, 99.74% purity) was obtained as an off-white solid.

[0583] 1 H NMR (400 MHz, Methanol-d4)

[0584] 5 = 8.52 (s, 1 H), 8.18 (d, J = 10.0 Hz, 1 H), 7.92 (d, J = 8.4 Hz,

2H), 7.70 - 7.66 (m, 1 H), 7.63 (d, J = 5.6 Hz, 1 H), 7.54 (dd, J = 3.6, 4.8 Hz, 4H), 7.49 (d, J = 8.0 Hz, 1 H), 7.47 - 7.41 (m, 2H), 7.27 (br d, J = 7.6 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 1 H), 6.57 (d, J = 10.0 Hz, 1 H), 5.28 (dd, J = 4.4, 8.4 Hz, 1 H), 4.43 (br t, J = 6.0 Hz, 2H), 4.38 (s, 2H), 3.57 (q, J = 6.8 Hz, 1 H), 3.14 - 2.94 (m, 9H), 2.90 - 2.47 (m, 4H), 1.98 - 1.87 (m, 2H), 1.80 - 1.68 (m, 2H), 1.64 - 1.42 (m, 8H), 1.35 (d, J = 6.8 Hz, 3H).

[0585] LCMS: Rt=0.800 min; [M+H]+=878.2

PREPARATION OF MOLECULE EXAMPLE 20

Preparation of compound 186

(71 ) (186)

[0586] To a solution of compound 71 (the procedure to obtain compound 71 is described in Example 5) (70 mg, 135.75 pmol, 1 eq) and compound 173 (the synthesis of compound 173 is described in the procedure for synthesis of Example 15) (65.37 mg, 135.75 pmol, 1 eq) in pyridine (0.5 mL) was added EDCI (52.05 mg, 271.49 pmol, 2 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (5 mL) and extracted with ethyl acetate (5 mLx 3). The combined organic layer was washed with brine (5 mLx 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 20%-50%,7min). Compound 186 (60 mg, 61.27 pmol, 45.13% yield, 99.99% purity) was obtained as a white solid.

[0587] LCMS: Rt=0.881 min; [M+H]+=979.3

Preparation of Molecule 20

(186) (Molecule 20)

[0588] A mixture of compound 186 (50 mg, 51 .06 pmol, 1 eq) in formic acid (0.5 mL) was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH=7 with saturated Na2CO3 aqueous, then the mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 5%-35%,7min). Molecule 20 (20.66 mg, 23.37 pmol, 45.78% yield, 99.46% purity, formic acid) was obtained as a yellow solid.

[0589] 1 H NMR (400 MHz, Methanol-d4) [0590] 5 = 8.63 (d, J = 1 .6 Hz, 1 H), 8.52 (s, 1 H), 8.22 - 8.14 (m, 2H), 8.04

(dd, J = 2.0, 8.1 Hz, 1 H), 7.70 - 7.66 (m, 1 H), 7.65 - 7.57 (m, 3H), 7.53 - 7.43 (m, 3H), 7.31 (br dd, J = 2.0, 8.3 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.57 (d, J = 9.8 Hz, 1 H), 5.30 (br dd, J = 4.4, 8.6 Hz, 1 H), 4.47 - 4.39 (m, 4H), 3.68 (q, J = 6.8 Hz, 1 H), 3.13 - 2.96 (m, 9H), 2.79 - 2.45 (m, 4H), 1 .98 - 1 .89 (m, 2H), 1 .73 (br d, J = 5.6 Hz, 2H), 1 .63 - 1 .44 (m, 8H), 1.36 (d, J = 6.8 Hz, 3H).

[0591 ] LCMS: Rt=0.788 min; [M+H]+=879.2

PREPARATION OF MOLECULE EXAMPLE 21

Preparation of compound 187

(Intermediate 2) (187)

[0592] To a solution of Intermediate 2 (the synthesis of Intermediate 2 is described in the procedure for synthesis of Example 1 ) (1 g, 2.00 mmol, 1 eq) and 4-hydroxybenzaldehyde (243.93 mg, 2.00 mmol, 1 eq) in DCM (10 mL) was added DCC (824.24 mg, 3.99 mmol, 808.08 pL, 2 eq) and DMAP (24.40 mg, 199.74 pmol, 0.1 eq). The reaction mixture was stirred at 25 °C for 12 h, then filtered and concentrated under reduced pressure to give compound 187 (1.3 g, crude) as a yellow solid.

[0593] LCMS: Rt=0.486 min; [M+H]⁺=605.4

Preparation of compound 188

(187) (188)

[0594] To a solution of 187 (1.3 g, 2.15 mmol, 1 eq) and 44 (the synthesis of compound 44 is described in the procedure for synthesis of Example 3) (1 .08 g, 3.22 mmol, 1 .5 eq) in THF (5 mL) was stirred at 25 °C for 0.5 h NaBH(OAc)3 (1.37 g, 6.45 mmol, 3 eq) was added and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (10 mLx 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: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water(FA)- ACN];gradient:15%-45% B over 15 min) to obtain compound 188 (270 mg, 224.02 pmol, 10.42% yield, 76.6% purity) as a white solid.

[0595] LCMS: Rt= 1.217 min; [M+H]+=923.4

Preparation of Molecule 21

(188) (Molecule 21 )

[0596] To a solution of compound 188 (270 mg, 224.02 pmol, 1 eq) in THF (1 mL) was added N,N-Diethylethanamine trihydrofluoride (180.57 mg, 1.12 mmol, 182.57 pL, 5 eq). The reaction mixture was stirred at 25 °C for 2 h and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN];gradient:12%-42% B over 7 min) to obtain compound Molecule 21 (67.36 mg, 78.78 pmol, 35.17% yield, 99.99% purity, FA) as a white solid.

[0597] LCMS: Rt=0.431 min; [M+H]+=809.5

[0598] 1 H NMR (400 MHz, CD3OD)

[0599] 5 = 8.53 (s, 1 H), 8.26 (d, J = 9.6 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2H),

7.58 - 7.45 (m, 7H), 7.28 - 7.21 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1 H), 6.63 (d, J = 9.6 Hz, 1 H), 5.38 - 5.30 (m, 1 H), 4.41 (t, J = 5.6 Hz, 2H), 4.13 (s, 2H), 3.61 - 3.52 (m, 1 H), 3.15 - 2.96 (m, 9H), 2.88 - 2.47 (m, 5H), 2.01 (br s, 2H), 1.87 (br s, 2H), 1 .66 (br d, J = 12.0 Hz, 1 H), 1.39 - 1 .28 (m, 7H), 1.22 - 1.10 (m, 1 H)

[0600] Using the methods described above and the appropriate reagents, the following compounds were prepared. [0601] [Table 1], Preferred compounds according to the present invention

Example 2 - Pharmacological testing

[0602] The practice of the instant invention for the treatment of diseases by modulation of muscarinic receptor M3 and/ or the adrenergic receptor beta-2 can be evidenced by the activity in at least one of the protocols described herein.

In vitro human beta-2 adrenergic receptor (hp2) agonism assay [0603] To determine agonist potencies for human [32-adrenergic receptors, cAMP accumulation in recombinant cell lines expressing human [32-adrenergic receptors was measured following incubation with the test compounds. Cells (1 .5x103 cells/ well) were transferred to plates and then was spined at 1 ,000 rpm for 1 minute. Test compounds were added to the assay plate from a DMSO stock solution in a 10-point 3-fold serial dilution with 1 - 100 pM as the maximum concentration. Plates were incubated for 60 minutes at room temperature in Hanks Buffer Saline Solution (HBSS, 1x) with HEPES (1 M), BSA Stabilizer (0.1 %) and IBMX (0.5mmol/L). cAMP Detection Kit from Cisbio (Cat. # 62AM4PEJ) was employed according to the manufacturer’s instructions. Detection reagent was added, and the plates were incubated for 60 minutes at room temperature. Plates were read on EnVision (PerkinElmer). Half maximal effective concentration (EC50) was calculated using GraphPad Prism 5 (GraphPad Software Inc., USA). Experiments performed in duplicate.

In vitro human muscarinic M3 receptor (hM3) binding assay [0604] Affinity for the human muscarinic M3 receptor was determined by measuring ability of the test compounds to displace the binding of N-methyl- [3H] scopolamine ([3H]-NMS) to cell membrane preparations expressing the receptor. Test compounds were added to the assay plate from a DMSO stock solution in a 10-point 3-fold serial dilution with 100 nM - 100 pM as the maximum concentration. Membrane (1.25 pg/ well) and [3H]-NMS (0.6 nM) were added to the assay plate. Buffer was HEPES (10 mM, pH7.4) supplemented with MgCI2 (1 mM). Atropine (1 pM/ well) was included into specific wells to account for nonspecific binding and DMSO for total binding. Plates were sealed and shaken at 300 rpm at room temperature for 2 h and 24 h (incubation time). Unifilter-96 GF/B filter plates were washed to remove the excess free ligand from the bound receptor-ligand complex using Perkin Elmer Filtermate Harvester. Plates were dried for 1 hour at 50°C. Microscint 20 cocktail (PerkinElmer, Cat. # 6013329) was added and remaining radioligand was evaluated using TopCount NXT HTS Reader (PerkinElmer). Half maximal inhibitory concentrations (IC50) were calculated using GraphPad Prism 5 (GraphPad Software Inc., USA). The inhibition constants (Ki) were calculated using the Cheng-Prusoff equation. Experiments performed in duplicate.

In vitro human muscarinic M3 receptor (hM3) functional assays [0605] Agonism and antagonism of human muscarinic M3 receptor was assessed using stable CHO-K1 cell lines expressing the hM3 receptor. Cells (2x104/ well) were added to the plates and incubated overnight at 37 oC and 5% CO2. Fluo-4 DirectTM (Life Technologies, Cat. # F10471 ), a fluorescent Ca2+ indicator, was added at the final concentration of 4 pM. For the agonist activity, test compounds were added, plates were incubated for 50 minutes at 37 °C and 5% CO2 and then for 10 minutes at room temperature. Compounds were pre-incubated with cells for 15 minutes or 1 hour as follows. For the 15-minute condition, plates were incubated for 45 min at 37 °C and 5% CO2 after dye loading, then test compound was added and the plate was incubated for additional 15 minutes at room temperature. For the 1-hour condition, test compounds were added to the plates, incubated for 50 minutes at 37 °C and 5% CO2 and then for 10 min at room temperature. Afterwards, plates were transferred to FLIPR Tetra System (Molecular Device) and acetylcholine (ACh) was added at its EC80. EC80 value was determined previously to the antagonist activity assay using the same batch of cells. Plates for the either agonist or antagonist activity were mixed for 2 strokes and the fluorescence signal was read. Emission at 516 nm and measured fluorescence at 494 nm. Test compounds were tested in a 10- point 3-fold serial dilution with 100 nM - 100 pM as the maximum concentration. Half maximal effective concentrations (EC50) and apparent dissociation constant (KB) were calculated using GraphPad Prism 5 (GraphPad Software Inc., USA). Experiments performed in duplicate.

[0606] [Table 2], In vitro pharmacology at human beta-2 adrenergic and muscarinic M3 receptors (binding affinity, functional agonism and antagonism)

Data is shown as mean of N=1 replicate (marked with #) or mean ± S.D. of N=2 replicates. KB - apparent dissociation constant. EC50 - half-maximal effective concentration. Ki - inhibition constant. Experiments were performed in duplicates. NT - not tested. For the hM3 antagonism, compounds were pre-incubated with cells for 15 minutes or 1 hour. For the hM3 binding, compounds were incubated with cell membranes for 2 or 24 hours.

Ex vivo relaxation of isolated guinea pig trachea

[0607] Guinea pig isolated trachea was employed to evaluate airway smooth muscle relaxation mediated by muscarinic antagonism and/or beta-2 adrenergic agonism. Male Dunkin-Hartley albino guinea pigs (Cavia porcellus), 250 - 300 g, were used for the study. Animals were euthanized by CO2 inhalation and then exsanguinated. Trachea was carefully excised, cleaned of surrounding connective tissue and cut into 2.5 mm long rings. The preparations were then mounted in 5-mL organ baths filled with Krebs’s solution maintained at 37.0 ± 0.5°C and gassed with a mixture of 95% 02 and 5% CO2. Krebs’s solution was made up as follows (mM): NaCI: 95.01 KCI: 5.0 / CaCI2: 2.6 / MgSO4 (7H2O): 1 .2 / NaHCO3: 24.9 / KH2PO4: 1.2 / glucose: 10.0. Indomethacin (10 pM) and guanethidine (3 pM) were added to the Krebs’s solution to avoid the influence of cyclooxygenase products and to block postganglionic sympathetic nerve transmission, respectively. Propranolol (10 pM) was used for specific groups to inhibit beta-2 adrenergic receptor-mediated relaxation. The preparations were allowed to equilibrate for 60 minutes at an optimal resting tension of 1 g. Contractile tensions were measured using an isometric force transducer and signals are analyzed using a specialized software (IOX, EMKA Technologies, Paris, France). Tissue viability was verified using three challenges of carbachol (0.3 - 1 .0 pM). Relaxation through the muscarinic antagonism was assessed in tissues precontracted with carbachol in the presence of propranolol. The dual relaxation via muscarinic M3 antagonism and adrenergic beta-2 agonism was evaluated in in tissues precontracted with carbachol in the absence of propranolol. The test substances were evaluated for potency determination and duration of action.

[0608] The first phase was potency determination. After tissue viability evaluation, the preparations were pre-contracted with carbachol (1 pM) for at least 20 minutes or more, if needed, until a stable tonic contraction was reached. The baseline values were measured just before carbachol addition. Six cumulative concentrations of test substances with log increases (0.1 , 1 , 10, 100, 1000 and 10000 nM) were then added into the bath and relaxations were recorded to plot a concentration-response curve. Each concentration was incubated until a relaxation steady-state was reached (for at least 30 minutes, or for a longer time if the steady-state was not reached within this period). Preparations with a pre-contraction below 1 .5 g were be excluded. The time required to reach the steady-state was estimated for each concentration, if applicable. 4 preparations (obtained from 4 animals) were studied per compound. Only one concentration-response curve was evaluated on the same preparation. The concentrations inducing 50% and 90% of the maximum response (EC50 and EC90, respectively) were determined from each individual concentration-response curve.

[0609] The second phase was duration of action determination. After tissue viability evaluation, the preparations were pre-contracted with an agonist (1 pM carbachol) for 20 minutes or until a stable tonic contraction was reached. One concentration of test substance (EC90 determined in the potency assay) was then added into the bath and relaxation was recorded for 60 minutes. Then, the preparation was washed two times (15 minutes apart). 10 minutes after the last washing and then every 45 minutes, the preparation was contracted with 1 pM carbachol for 20 minutes. Between each carbachol challenge, the preparation was washed two times (15 minutes apart). 6-7 successive carbachol challenges are performed over a 5 to 6-hour period. The time-related changes were evaluated in the vehicle control group (DMSO diluted in distilled water) for the same duration. 4 preparations (obtained from 4 animals) were studied. Only one concentration was evaluated on the same preparation. The contraction responses of each carbachol challenge were expressed as the percentage of the last carbachol-induced contraction. The percent inhibition of each carbachol response will be reported over a 4 to 6-hour test period (one value every 45 minutes). Half-life, i.e. time taken for response to carbachol to return to 50% recovery calculated using linear regression (% inhibition of carbachol response versus time), was determined from each individual preparation.

[0610] In guinea pig trachea precontracted with carbachol the test compounds elicited concentration-dependent relaxation, either in the presence or absence of propranolol, with ICso ranging from 11 .6 - 1 ,545 nM (Table 3). In the duration of action experiment, compounds inhibited the carbachol-elicited contractile responses for up 400 min.

[0611 ] [Table 3], Potency of test compounds for relaxation of precontracted guinea pig isolated trachea.

precontracted tissue in the absence of propranolol. MA potency was obtained by relaxation of carbachol precontracted tissue in the presence of propranolol. Data is shown as mean ± SD (n=4-5/condition) for study batch.

Claims

Claims [Claim 1] A COMPOUND characterized in that it is defined by a general Formula I:

[Chem.1] - Formula I or its pharmaceutically acceptable salts, crystals, hydrates, prodrugs, metabolites, enantiomers, diastereomers or solvates, wherein:

• a is an integer from 0 to 2;

• the symbol * indicates a chiral center at the carbon atom;

• R8 is independently selected from (1 -4C)alkyl, (3-10C)cycloalkyl, - CH2-phenyl, -CH2-CH2-phenyl or -CH2-(3-10C)cycloalkyl;

• W is independently carbon or nitrogen;

• the 0 attached to the phenyl ring is at ortho, meta or para position;

• R1 is selected from anyone of: a) [Chem. I] - Radical i: wherein: o b is an integer from 1 to 4; c is an integer from 1 to 3; o A is -NR18C(O)-, -C(0)NR19- -C(O)O- or -OC(O)- wherein R18 or R19 is independently hydrogen or (1 -4C)alkyl; o each R11 , R12, R13 and R14 is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, or halogen; o R11 and R12 optionally form together -CH=CH-S-; -S-CH=CH-; - CH2-CH2-CH2-; -CH2-CH2-CH2-CH2-; -CH=CH-CH=CH-; -CH=CH- NH-; -NH-CH=CH-; -NH-CH=N-; -CH=CH-O-; -O-CH=CH-; -N=CH-O-; -O-CH=N-; -NH-N=N- ; -N=CH-CH=CH-; -CH=N-CH=CH-; -CH=CH- N=CH-; -CH=CH-CH=N-; -N=CH-CH=N-; -CH=N-CH=N-; -N=CH- N=CH-; -CH=CH-N=N-; -CH=N-N=CH- or -N=N-CH=CH-; o each Y or Z is independently selected from carbon or nitrogen, where when Z or Y is nitrogen, R13 and/or R14 is an empty value; b) -(CH2)2-(phen-1 ,4-ylene)-CH2- or -(CH2)2-(OCO)-(phen-1 ,4- ylene)-CH2- c) -R15-X-; o where R15 is (1 -10C)Alkyl or (1-10C)-alkoxy and o X is independently hydrogen, NH, N-Boc or 0 d) -CH2-CH2-NH(CO)-CH2-(phen-1 ,4-ylene)-(CH2)d-NH- o where d is an integer from 1 to 3 e) -(CH2)e-(phen-1 ,4-ylene)-(CH2)f-NH-

-(CH2)e-(phen-1 ,3-ylene)-(CH2)f-NH- or -(CH2)e-(phen-1 ,2-ylene)-(CH2)f-NH- where e is an integer from 1 to 4 and f is an integer from 1 to 2; f) [Chem. I] - Radical ii: o where g is an integer from 1 to 3; o A’ is -NR20C(O)- or -C(0)NR21- where R20 or R21 is independently hydrogen or (1 -4C)alkyl; o X is independently selected from carbon or oxygen; o W is independently hydrogen, (1 -4C)alkyl, (1-4C)alkoxy, carboxy, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, or halogen; g) [Chem. I] - Radical iii: o where h is an integer from 1 to 3; o X’ is independently nitrogen or CO and o Y’ is independently oxygen, nitrogen or sulfur h) optionally, R1 can be selected from: o -(CH2)2-(CO)NH-(CH2)2-NH- o -(CH2)2-(CO)NH-(CH2)3-NH- o -CH2-(CO)NH(CH2)3-NH- o -(CH2)3-(CO)N(CH3)-(CH2)-NH- o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : R isomer o -(CH2)2-*CH(CH3)-(CO)NH-CH2-NH- : S isomer o -CH2-*CH(CH3)-CH2-(CO)NH-CH2-NH- : R isomer o -CH2-*CH(CH3)-(CH2)-(CO)NH-(CH2)-NH- : S isomer o -(CH2)2-NH(CO)-CH2-NH- o -(CH2)2-NH(CO)-(CH2)2-NH- o -(CH2)3-NH(CO)-*CH(NH2)-CH2- R isomer o -(CH2)3-NH(CO)-*CHNH2)-CH2- S isomer o -(CH2)3-NH(CO)- C(CH3)2-NH- o -(CH2)3-NH(CO)- (CH2)2-NH- o -(CH2)3-C(CH3)2-NH(CO)-(CH2)-NH- o -CH2-C(CH3)2-CH2-NH(CO)-(CH2)-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-CH2-NH- o -(CH2)2-NH(CO)-CH2-(phen-1 ,3-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-CH2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-(CH2)2-NH- o -(CH2)2-(phen-1 ,4-ylene)-O-(phen-1 ,4-ylene)-(CH2)3-NH-

• R2 is independently selected from hydrogen or a particular value by the formula iv, which can assume a R or S configuration:

[Chem. I] - Radical iv: wherein:

• R16 is hydrogen, -NR16a CR16b(O), -CR16cR16dOR16e and

• R17 is hydrogen, -CR17aR17bOR17c, -NR17dCR17e(O) ; or

• R16 and R17 together form -NR17fC(O)-CR17g=CR17h-, -

CR17i=CR17j- C(O)-NR17k-, -NR17IC(O)-CR17mR17n-

CR17oR17p-, -CR17q, R17r-CR17sR17t-C(O)- NR17u- or - NR17vC(0)-CR17xR17y-O-;

• each of R16a, R16b, R16c, R16d and R16e is independently hydrogen or (1 -4C)alkyl; and • each of R17a, R17b, R17c, R17d, R17e, R17f, R17g, R17h, R17i, R17j, R17I, R17m, R17n, R17o, R17p, R17q, R17r, R17s, R17t, R17u, R17v, R17x or R17y is independently selected from hydrogen or (1- 4C)alkyl;

■ R15 is independently selected from hydrogen or OH attached on the phenyl ring at ortho, meta or para position;

• optionally, R2 can be selected from formula v:

[Chem. I] - Radical v: wherein: e) the amide moiety is attached on the six-membered ring at ortho, meta or para position; f) R22 and R23 is independently selected from hydrogen or (1- 4C)alkyl.

[Claim 2] THE COMPOUND, according to claim 1 , characterized in that R7 and R9 optionally form together -CH2-CH2-.

[Claim 3] THE COMPOUND, according to claim 1 , characterized in that the compound of formula I is selected from:

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide;

N-(4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)-3-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy- 2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methylphenyl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-2- yl)propenamide;

3-(3-((5-((R)-1 -(4-cycloheptylpiperazin-1 -y l)ethy l)py rid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((4-((S)-1 -(4-cycloheptylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide;

5-((1 R)-2-((6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)hexyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

N-(4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)-2-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)acetamide; N-(2-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)-4-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)butanamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)propenamide; N-(3-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-3-(3-((4-((S)-1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide;

N-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-3-(3-((4-((S)-1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide; 3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)py rid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen- 7-yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)py rid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen-7- yl)propenamide;

3-(3-((4-((S)-1 -(4-cycloheptylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((S)-1 -(4-cycloheptylpiperazin-1 -y l)ethy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen-7- yl)propenamide; 4-((((R)-2-hydroxy-2-(8-hydroxy-2 -oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl 3-(3-((4-((S)-1-(4-cyclohexylpiperazin-

1-yl)ethyl)phenyl)sulfonyl)phenoxy)propanoate;

3-(3-((4-((S)-1 -((R)-4-cyclohexyl-3-methylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methoxyphenyl)propenamide;

N-(3-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-3-(3-((4-((S)-1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

5-((1 R)-2-((9-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)nonyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

3-(3-((4-((R)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide; 3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-(2-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)ethyl)phenyl)propenamide;

2-(3-((3-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-(((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)butyl)acetamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(3-(((R)-2-hydroxy-2-(8-hydroxy- 2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)propyl)propenamide; N-(3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)-3-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)propenamide;

5-((R)-2-((3-(2-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethoxy)propyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

5-((R)-2-((4-(2-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)benzyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)butanamide;

5-((R)-2-((3-((3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)methyl)phenethyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one; 5-((R)-2-((4-(4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)benzyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(2-(((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)butanamide;

5-((R)-2-((3-(4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)benzyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

5-((R)-2-((3-(3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propoxy)propyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

3-(3-((4-((S)-1 -(4-cyclopentylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide;

3-(3-chloro-5-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5- yl)ethyl)amino)methyl)phenyl)propenamide;

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2- methylphenyl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy- 2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2- methoxyphenyl)propenamide; 3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-6-methylpyridin-2- yl)propenamide;

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-4-methylpyridin-2- yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(7-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen-

4-yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methylphenyl)propenamide;

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2,3-dihydro-1 H- inden-4-yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methylphenyl)propenamide;

5-((R)-2-((6-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)hexyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(7-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-2,3-dihydro-1 H-inden-4- yl)propenamide; 3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(7-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-2,3-dihydro-1 H-inden-4- yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-2- yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen-7- yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-4,6- dimethylpyridin-2-yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-4,6- dimethylpyridin-2-yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)propyl)phenyl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-6- methylpyridin-2-yl)propenamide;

3-(3-((5-((S)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methylphenyl)propenamide; 3-(3-((5-((S)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)py rid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3- methylphenyl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)py rid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)propenamide;

3-(3-((5-((S)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((S)-1 -(4-cycloheptylpiperazin-1 -y l)ethy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((R)-1 -(4-(bicyclo[2.2.2]octan-1 -yl)piperazin-1 - yl)ethyl)pyridin-2-yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((S)-1 -(4-(bicyclo[2.2.2]octan-1 -yl)piperazin-1 - yl)ethyl)pyridin-2-yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3,5- dimethylphenyl)propenamide;

3-(3-((5-((S)-1 -(4-cyclohexylpiperazin-1 -y l)propy l)pyrid in-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)benzo[b]thiophen-7- yl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy- 2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-N- methylpropanamide;

5-((1 R)-2-((8-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)octyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

5-((1 R)-2-((7-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)heptyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

5-((1 R)-2-((4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

5-((1 R)-2-((5-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)pentyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

5-((1 R)-2-((3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

5-((R)-2-((6-(3-((4-((S)-1-((R)-4-cyclohexyl-3-methylpiperazin-1- yl)ethyl)phenyl)sulfonyl)phenoxy)hexyl)amino)-1-hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one;

N-(2-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)-3-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)propenamide; 2-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(3-(((R)-2-hydroxy-2-(8-hydroxy- 2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)propyl)acetamide; N-(3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)-2-(((R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)acetamide; 3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(6-((((R)-2-hydroxy-2-(8-hydroxy-

2-oxo-1 ,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-3- yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-2-yl)propenamide;

3-(3-((5-((R)-1 -(4-cyclohexylpiperazin-1 -y l)ethy l)pyridin-2- yl)sulfonyl)phenoxy)-N-(7-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-2,3-dihydro-1 H-inden-4- yl)propenamide;

3-(3-((5-((S)-1-(4-cycloheptylpiperazin-1-yl)propyl)pyridin-2- yl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)am ino)methyl)-3,5- dimethylphenyl)propenamide;

1-(1-(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)-4-methylpiperazine;

1-cyclohexyl-4-(4-((4-methoxyphenyl)sulfonyl)benzyl)piperazine;

4-((4-(1-(4-cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenol;

1 -cyclohexyl-4-(1 -(4-((2- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1 -cyclohexyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

(R)-1 -cyclohexyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

(S)-1 -cyclohexyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1 -cyclohexyl-4-(1 -(4-((4- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

(R)-1-cyclohexyl-4-(1-(6-((3-methoxyphenyl)sulfonyl)pyridin-3- yl)ethyl)piperazine;

(S)-1-cyclohexyl-4-(1-(6-((3-methoxyphenyl)sulfonyl)pyridin-3- yl)ethyl)piperazine;

1-hexyl-4-(1-(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1 '-(1 -(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)-1 , 4'-bipiperid ine;

6-(4-((4-(1 -(4-methylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)hexan-1 -amine; (R)-1-(1-(4-((3-chloro-5-methoxyphenyl)sulfonyl)phenyl)ethyl)-4- cyclohexylpiperazine;

(S)-1-(1-(4-((3-chloro-5-methoxyphenyl)sulfonyl)phenyl)ethyl)-4- cyclohexylpiperazine;

(2R)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-

2-methylpiperazine;

(2R)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-

2-methylpiperazine;

(2S)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-2- methylpiperazine;

1-benzyl-4-(1-(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1 -(cyclohexylmethyl)-4-(1 -(4-((4- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

(S)-1 -cyclohexyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)propyl)piperazine;

(2S)-4-cyclohexyl-1-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-2- methylpiperazine;

(2R)-4-cyclohexyl-1-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-

2-methylpiperazine;

(2R)-4-cyclohexyl-1-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)- 2-methylpiperazine;

1 '-(1 -(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)-4-methyl-1 ,4'- bipiperidine;

1 -(1 -(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)-4- phenethylpiperazine;

(R)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)-2- methylpropyl)piperazine; (S)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)-2- methylpropyl)piperazine;

1 -cyclohexyl-4-(1 -(4-((4- methoxyphenyl)sulfonyl)phenyl)butyl)piperazine;

(1 R,5S)-8-cyclohexyl-3-((R)-1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)-3,8-diazabicyclo[3.2.1]octane;

(1 R,5S)-8-cyclohexyl-3-((S)-1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)-3,8-diazabicyclo[3.2.1]octane;

7-(4-(1-(4-((4-methoxyphenyl)sulfonyl)phenyl)ethyl)piperazin-1- yl)heptan-1 -amine;

1 -cyclohexyl-4-(1 -(4-((4- propoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

6-(4-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)hexan-1 -amine;

6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)hexan-1 -amine;

(S)-1 -cyclopentyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1-cyclohexyl-4-(4-((3-methoxyphenyl)sulfonyl)benzyl)piperazine;

(S)-1-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)-4-(tetrahydro-

2H-pyran-4-yl)piperazine;

N-(2-aminoethyl)-3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide;

7-(4-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)heptan-1 -amine;

7-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)heptan-1 -amine;

8-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)octan-1-ol;

8-(4-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)octan-1 -amine; 8-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)octan-1 -amine; (S)-2-amino-N-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)acetamide; (S)-N-(3-aminopropyl)-2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)acetamide;

(S)-1-cyclohexyl-4-(1-(4-((3-methoxyphenyl)sulfonyl)phenyl)ethyl)- 1 ,4-diazepane;

(S)-1 -cycloheptyl-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

1-cyclohexyl-4-(2-(4-((3-methoxyphenyl)sulfonyl)phenyl)propan-2- yl)piperazine;

2-amino-N-((S)-3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-2-methylpropyl)acetamide; 2-amino-N-((R)-3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-2-methylpropyl)acetamide; (S)-2-amino-N-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)-N-methylacetamide;

2-amino-N-((R)-4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butan-2-yl)acetamide; 2-amino-N-((S)-4-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butan-2-yl)acetamide;

(R)-2-amino-N-(3-(3-((4-((S)-1-(4-cyclohexylpiperazin-1- yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)propenamide;

(S)-2-am ino-N-(3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)propenamide;

(S)-6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-3,3-dimethylhexan-1 -amine; (S)-6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-5,5-dimethylhexan-1 -amine;

9-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)nonan-1-ol; (S)-1 -(bicyclo[2.2.2]octan-1 -y l)-4-(1 -(4-((3- methoxyphenyl)sulfonyl)phenyl)ethyl)piperazine;

9-(4-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)nonan-1 -amine;

9-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)nonan-1 -amine;

10-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)decan-1-ol;

(S)-2-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)phenoxy)ethan-1 -amine;

10-(4-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)decan-1 -amine;

10-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)decan-1 -amine;

(S)-2-amino-N-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)-2-methylpropanamide;

(S)-2-amino-N-(4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-2-methylbutan-2-yl)acetamide;

(S)-2-amino-N-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-2,2-dimethylpropyl)acetamide;

(S)-3-amino-N-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)propenamide;

(4-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenyl)methanamine;

(4-(4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)phenyl)methanamine;

(3-(4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)phenyl)methanamine;

5-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)pentan-1 -amine;

N-(4-(aminomethyl)-2-fluorophenyl)-3-(3-((4-(1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenyl)propenamide; (S)-2-(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propoxy)ethan-1 -amine; (S)-3-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethoxy)propan-1 -amine; 6-(aminomethyl)-3-(2-(3-((4-(1-(4-cyclohexylpiperazin-1- yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)benzo[d]oxazol-2(3H)-one; 2-(3-(4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)phenyl)ethan-1 -amine; 2-(4-(4-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)butyl)phenyl)ethan-1 -amine;

6-(aminomethyl)-3-(3-(3-((4-(1-(4-cyclohexylpiperazin-1- yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)benzo[d]oxazol-2(3H)-one; N-(4-(aminomethyl)-3-methoxyphenyl)-3-(3-((4-(1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide;

(S)-6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-2,2-dimethylhexan-1 -amine;

(S)-6-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-4,4-dimethylhexan-1 -amine; N-(4-(aminomethyl)-2-chloro-5-methoxyphenyl)-3-(3-((4-(1-(4- cyclohexylpiperazin-1-yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide; (3-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenyl)methanamine;

(S)-2-(3-((3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)methyl)phenyl)ethan-1 -amine; 2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl (4-(aminomethyl)-2-chloro-5- methoxyphenyl)carbamate;

2-(3-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenyl)ethan-1 -amine; 2-(4-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenyl)ethan-1 -amine; 2-(3-((R)-2-aminopropyl)phenyl)-N-(2-(3-((4-((S)-1-(4- cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)acetamide;

2-(3-((S)-2-aminopropyl)phenyl)-N-(2-(3-((4-((S)-1-(4- cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)acetamide;

3-(4-(4-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenoxy)phenyl)propan-1- amine;

(1 -(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)-1 H-benzo[d][1 ,2,3]triazol-5- yl)methanamine;

(S)-2-(3-(aminomethyl)phenyl)-N-(2-(3-((4-(1-(4-cyclohexylpiperazin-

1-yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)acetamide;

(1 -(3-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propyl)-1 H-benzo[d][1 ,2,3]triazol-5- yl)methanamine;

2-(4-(4-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenoxy)phenyl)ethan-1- amine;

(S)-2-(3-(2-aminoethyl)phenyl)-N-(2-(3-((4-(1-(4-cyclohexylpiperazin-

1-yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)acetamide;

(4-(4-(2-(3-((4-(1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)ethyl)phenoxy)phenyl)methanamine

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-((((R)-2-hydroxy-2-(6-hydroxy-

3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-8- yl)ethyl)amino)methyl)phenyl)propenamide;

3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)-N-(4-(2-(((R)-2-hydroxy-2-(6- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-8-yl)ethyl)amino)- 2-methylpropyl)phenyl)propenamide;

N-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1 ,2- dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)-3-(3-((4- ((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propenamide;

5-((R)-2-((2-(3-(3-((4-((S)-1 -(4-cyclohexylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propoxy)ethyl)amino)-1- hydroxyethyl)-8-hydroxyquinolin-2(1 H)-one;

(S)-1 -(4-(3-(3-((5-(1 -(4-cycloheptylpiperazin-1 -yl)ethyl)pyridin-2- yl)sulfonyl)phenoxy)propanamido)benzyl)piperidine-4-carboxamide;

(S)-1 -(4-(3-(3-((4-(1 -(4-cycloheptylpiperazin-1 - yl)ethyl)phenyl)sulfonyl)phenoxy)propanamido)benzyl)piperidine-4- carboxamide.

[Claim 4] A PROCESS FOR OBTAINING THE COMPOUND of general Formula I characterized in that it comprises the steps of: a) reacting a reagent compound I, or a salt thereof, with a reagent compound II:

[Chem. 2] - Reagent compound 1 b) to obtain the general compound Intermediate a and then removing any protecting group P1 to provide the compound of formula I; and optionally, forming a pharmaceutically acceptable salt thereof, [Chem. 4] - Intermediate a wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an amino-protecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in claim 1 .

[Claim 5] AN INTERMEDIATE COMPOUND in the synthesis of the compounds as defined in claim 1 , characterized in that it is a general intermediate a:

[Chem. 4] - Intermediate a wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an amino-protecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect.

[Claim 6] A REAGENT COMPOUND for use in the preparation of compounds of formula I, as defined in claim 1 , characterized in that the reagent compound is selected from:

[Chem. 2] - Reagent compound 1 wherein Nu represents a nucleophile, P1 represent a hydrogen atom or an amino-protecting group; and wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 , R12, R13, R14, R15, R16, R17, W, Y, Z, a, b and c are as described for the compound of general formula I in the first aspect.

[Claim 7] THE REAGENT COMPOUND, according to claim 6, characterized in that it is selected from:

[Chem. 22] - Reagent compound 20:

[Chem. 23] - Reagent compound 21 :

[Chem. 24] - Reagent compound 22:

[Claim 8] A PHARMACEUTICAL COMPOSITION characterized in that it comprises at least one compound of general Formula I or pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, prodrugs, metabolites or solvates thereof, as defined in claim 1 , in a therapeutically effective amount and at least one pharmaceutically acceptable excipient.

[Claim 9] THE PHARMACEUTICAL COMPOSITION, according to claim 8, characterized in that the at least one pharmaceutically acceptable excipient is suitable for the administration to a patient via oral, inhalation, parenteral, topical or nasal delivery.

[Claim 10] THE PHARMACEUTICAL COMPOSITION, according to claim 8 or 9, characterized in that the pharmaceutically acceptable excipient comprises lactose, mannitol, glucose, chitosan or cyclodextrin.

[Claim 11 ] THE PHARMACEUTICAL COMPOSITION, according to claim 8, characterized in that the therapeutically effective amount of a compound of formula I comprises from 0.0001 mg to 10,000 mg.

[Claim 12] A PHARMACEUTICAL 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 the list comprising a non-steroidal glucocorticoid receptor agonist; a PDE4 inhibitor; a modulator of chemokine receptor function; a corticosteroid; and an inhibitor of p38 kinase function.

[Claim 13] THE COMBINATION, according to claim 12, characterized in that the one or more agents is corticosteroid.

[Claim 14] THE COMBINATION, according to claim 12 or 13, characterized in that the corticosteroid selected from the group comprising budesonide, beclomethasone dipropionate, triamcinolone, mometasone furoate, ciclesonide, fluticasone propionate and fluticasone furoate and their pharmaceutically acceptable salts, crystals, stereoisomers, hydrates, solvates, prodrugs, metabolites or solvates.

[Claim 15] A MEDICAMENT characterized in that it comprises a compound of general Formula I, as defined in claim 1 , for use in treating a disease, said disease comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[Claim 16] THE MEDICAMENT, according to claim 15, characterized in that it is for use in treating a respiratory disease, such as asthma, COPD or rhinitis.

[Claim 17] THE MEDICAMENT, according to claim 15 or 16, characterized in that the disease is a human or veterinary disease.

[Claim 18] AN USE of at least one compound of general Formula I, as defined in claim 1 , characterized in that it is for the manufacture of a medicament for treating a disease comprising respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, preterm labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[Claim 19] THE USE of at least one compound of general Formula I, according to claim 18, characterized in that it is for the manufacture of a medicament for the treatment of respiratory diseases, said respiratory disease comprising asthma, COPD and rhinitis.

[Claim 20] THE USE, according to claims 18 or 19, characterized in that the disease is a human or veterinary disease.

[Claim 21] A METHOD OF TREATING a disease characterized in that it comprises the administration of a therapeutically effective amount of at least one compound of general Formula I, as defined in claim 1 , to a patient in need.

[Claim 22] THE METHOD OF TREATMENT, according to claim 21 , characterized in that the disease comprises respiratory diseases, such as asthma, chronic obstructive pulmonary disease, rhinitis, preterm labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders, such as urinary incontinence and gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis.

[Claim 23] THE METHOD OF TREATMENT, according to claim 21 or 22, characterized in that the therapeutically effective amount of the compound of general Formula I is from 0.0001 to 10,000 mg, optionally from 0.001 to 5,000 mg.

[Claim 24] THE METHOD OF TREATMENT, according to any one of claims 21 to 23, characterized in that the compound of formula I is administered orally, inhaled, parenterally, topically or via nasal delivery. [Claim 25] THE METHOD OF TREATMENT, according to claim 21 , characterized in that the patient is a human or animal.