Compounds and pharmaceutical compositions thereof for the treatment of proliferative diseases

Abstract

The present invention discloses compounds according to Formula (I), wherein R1a, R1b, R2a, R2b, R4a, R4b, X, Y, Cy, L, A, B, X1, X2, X3 and the subscript m are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of proliferative diseases by administering a compound of the invention.

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF PROLIFERATIVE DISEASES FIELD OF THE INVENTION

[0001] The present invention relates to compounds, methods to produce the compounds of the 5 invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and / or treatment of proliferative diseases by administering the compounds of the invention. In particular, the compounds of the invention may target p53 mutant proteins. More particularly, the compounds of the invention may target the Y220C p53 mutant proteins. BACKGROUND OF THE INVENTION 10

[0002] The tumour suppressor protein p53, also known as Tumour protein P53, cellular tumour antigen p53, or transformation-related protein 53 (TRP53) is a 393 amino acid transcription factor that can regulate cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. p53 has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, 15 induction of senescence, and inhibition of angiogenesis (Wei et al.2006).

[0003] In the absence of stress signals, p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase. In an unstressed cell, Mdm2 can target p53 for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 is disrupted, and p53 accumulates. The critical event leading to the activation of p53 is phosphorylation of the N- terminal 20 domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair (Chen et al.1996; Haupt et al.1996). 25

[0004] Somatic mutation in TP53 gene is one of the most frequent alterations in human cancer (about 35% of all cancer, TCGA database 2024) and is reported in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancer can correlate with less favourable patient prognosis (Robles & Harris 2010).

[0005] P53 y220c mutation is located in the DNA-binding domain of the p53 protein, which is 30 responsible for binding to specific DNA sequences and regulating gene expression. While occurring away from the DNA-binding interface, the Y220C mutation disrupts the structure of the p53 protein, leading to a loss of DNA-binding capacity and therefore a loss in the transcriptional activity of the protein (Joerger et al.2006).

[0006] The TP53 Y220C mutation has been identified in over 30 different solid tumour types, including 35 breast, colon, lung, liver, prostate, bladder, ovarian, pancreatic, and oesophageal cancer . According tothe AACR GENIE database p53 Y220C is present in about 1% of cases, with the highest prevalence in ovarian, pancreatic, breast and colon cancer.

[0007] Recent studies have shown that small molecules can reactivate the transcriptional activity of mutant p53 proteins (defined as mutant reactivator molecule), including Y220C, by stabilizing the 5 protein and restoring its DNA-binding capacity (Bauer et al. 2020). These molecules have shown promising results in preclinical studies and the most advanced molecule is currently being tested in a clinical trial in monotherapy and in combination with Pembrolizumab ( NCT045857502020).

[0008] Although several clinical trials are on-going to identify drug targeting p53 mutations, the exact mechanisms of action and efficient strategies to induce cell death specifically in p53-deleted or -mutated 10 cells by these drugs need to be elucidated (Nishikawa & Iwakuma 2023).

[0009] Thus, there is a need for further small molecules stabilizing mutant p53 proteins, including Y220C, with improved pharmacological profile, for the prophylaxis and / or treatment of cancer and other above-mentioned diseases. SUMMARY OF THE INVENTION 15

[0010] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of proliferative diseases. In particular, the compounds of the invention may target p53 mutant proteins. More particularly, the compounds of the invention may target the Y220C p53 mutant proteins. The present invention also provides methods to produce these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or 20 treatment of proliferative diseases by administering the compounds of the invention.

[0011] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:25 wherein X1is =CR3a- or N-, X2is =CR3b- or =N-, and X3is =CR3c- or =N-; L is 5-15 membered hydrocarbon chain saturated or comprising one or more independently selected double or triple bonds, wherein one or more carbon atoms is optionally replaced by one or more independently selected N, O, P, or S heteroatoms, which chain is optionally substituted with one or more 30 independently selected -C1-4 alkyl, -C1-4 alkoxy, -OH, or =O;Each R1a, R1b, R2a, and R2bis independently selected from: - H - =O (R1atogether with R1b, and / or R2atogether with R2b), - halo, - -OH, - -CN, - -NH2, - -NHR9a, - -NR9bR9c, - -S(=O)2R9d, - -S(=O)2NH2, - -S(=O)2NHR9e, - -S(=O)2NR9eR9f, - -C(=O)R9g, - -C(=O)OH, - -C(=O)OR9h, - -C(=O)NH2, - -C(=O)NHR9g, - -C(=O)NR9gR9h, - -P(=O)R9iR9j, - -S(=O)R9k, - -S(=O)(=NR9l)R9m, - C1-6 alkyl, optionally substituted with one or more independently selected R6a, - C1-6 alkoxy, optionally substituted with one or more independently selected R6b, - C37 cycloalkyl, optionally substituted with one or more independently selected R6c, - C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6d, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6e, and - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6f; or R1aand R2a, together with the atoms to which they are attached together may form a - C3-7membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g,- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6h; or - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6i; Each R3a, R3b, R3cis independently selected from: - H - halo, - -OH, - -CN, - -NH2, - -NHR10a, - -NR10aR10b, - C1-4alkyl optionally substituted with one or more independently selected halo, - C1-4 alkoxy optionally substituted with one or more independently selected halo, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; Each R4aand R4bis independently selected from H, or -C1-4 alkyl optionally substituted with one or more independently selected halo; A is -S- or -O- and B is =CR5-, or A is =CH- or =N- and B is -NR5-; R5is -C1-4 alkyl optionally substituted with one or more independently selected - halo, - -CN, - -OH, - monocyclic C3-6cycloalkyl optionally substituted with one or more independently selected halo, or - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; X is absent, -CH2-, -O-, or -NH-; Each R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, and R6i, is independently selected from: - oxo, - halo, - -OH,- -CN, - -C(=O)OH, - -C(=O)OR11a, - -OC(=O)R11b, - -S(=O)2R11c, - -S(=O)2NH2, - -S(=O)2NHR11d, - -S(=O)2NR11dR11e, - -C(=O)NH2, - -C(=O)NHR11f, - -C(=O)NR11fR11g,- -NH2,- -NHR11h,- -NR11hR11i, - -C(=O)R11j, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, and - C1-4 alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy; Cy is selected from, , , ,wherein * is attached to Y, and ** attac8a1 8a 8a4hedtoLinFormulaI,andeachR,Ran R ,is independently selected from: - H, - halo, - -CN, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4alkoxy, - -OH, - -OR12a, - -NH2, - -NHR12b,- -NR12bR12c, - -S(=O)2R12d, - -S(=O)2NH2, - -S(=O)2NHR12e, - -S(=O)2NR12eR12f, - -C(=O)R12g, - -C(=O)OH, - -C(=O)OR12h, - -C(=O)NH2, - -C(=O)NHR12g, - -C(=O)NR12gR12h, - -P(=O)R12iR12j, - -S(=O)R12k, - -S(=O)(=NR12l)R12m, - C3-7 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, P, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo; Y is -O-, or -NR7, wherein R7is H, C1-6 alkyl, C3-6 cycloalkyl, -C(=O)C1-6 alkyl, -C(=O)C3-6 cycloalkyl, or -C(=O)C1-6 alkoxy; and EachR12mis independently selected from: - C1-4alkyl optionally substituted with one or more independently halo, -OH, oxo, -CN, -C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo, - monocyclic C3-6 cycloalkyl optionally substituted with one or more independently selected halo, - OH, oxo, -CN, -C1-4 alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo, and - monocyclic 4-8 membered monocyclic heterocycloalkyl comprising one or 2 double bonds, comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN-C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo.

[0012] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of proliferative diseases. 5

[0013] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of proliferative diseases. 10

[0014] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0015] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly proliferative diseases, which method comprises administering an effective amount of the pharmaceutical 15 composition or compounds of the invention as described herein.

[0016] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of proliferative diseases. 20

[0017] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0018] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0019] It will be appreciated that compounds of the invention may be metabolized to yield biologically 25 active metabolites. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0020] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. 30

[0021] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within 35 their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set outbelow. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0022] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0023] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2- CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2- dimethylbutyl (-CH(CH3)-CH(CH3)-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0024] ‘Alkenyl’ refers to monovalent unsaturated hydrocarbon groups with the number of carbon atoms and the number of double bonds specified. Particular alkenyl groups have 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 double bonds. Particular alkenyl groups include ethenyl (- CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

[0025] ‘Alkynyl’ refers to monovalent unsaturated hydrocarbon groups with the number of carbon atoms and the number of triple bonds specified. Particular alkynyl groups have 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 triple bonds. Particular alkenyl groups include -C≡CH, -CH2- C≡CH, -CH(CH3)-C≡CH, and the like.

[0026] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (CH2- CH2-), or -CH(CH3)- and the like.

[0027] ‘Alkenylene’ refers to divalent alkene radical groups having the number of carbon atoms and the number of double bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as - CH=CH-, -CH2-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2- C(CH3)=CH-.

[0028] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as - C≡C-, -CH2-C≡C-, and -C(CH3)H-C≡CH-.

[0029] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C1-6 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. 5 Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0030] ‘Amino’ refers to the radical -NH2.

[0031] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. 10 Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0032] ‘Cycloalkyl ’refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such 15 cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0033] ‘Cyano’ refers to the radical -CN.

[0034] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro. 20

[0035] As used herein, term ‘polycyclic’ refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two (bicyclic), three (tricyclic) or four (tetracyclic) rings of atoms, more particularly two (bicyclic) or three (tricyclic) rings of atoms, most particularly two (bicyclic) rings of atoms.

[0036] ‘Hetero’ when used to describe a compound or a group present on a compound means that one 25 or more carbon atoms in the compound or group have been replaced by a O, N, P and S heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0037] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes 30 one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms 35 typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms inthe heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0038] Examples of five membered monocyclic heteroaryl groups include but are not limited to 5 pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0039] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0040] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to 10 another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0041] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, 15 triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0042] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, 20 imidazolyl, oxazolyl and pyrazinyl.

[0043] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0044] ‘Heterocycloalkyl’ means a non-aromatic fully or partially saturated ring structure, monocyclic, 25 fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N, P and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, phosphorus, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 30 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. When partially saturated, the heterocycloalkyl may contain one or two double bonds, and more particularly one double bond. Examples of heterocyclic rings include, but are not limited to azetidinyl,oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g.1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g.4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0045] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein - , - , - , .

[0046] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and –S-.

[0047] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and –S- and eachZ is selected from N or CH.

[0048] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O- and –S-.

[0049] Particular examples of monocyclic partially saturated heterocycloalkyl rings are shown in thewherein each W and Y i independently from -CH , -NH- -O-, and , and Z i P, N, or CH.refer t an or c molec consisting ofnoth elsebucarbon anhydrogen atoms arranged in a chain, which carbon and hydrogen atoms are interconnected to each other by covalent bonding. Each carbon atom in the chain is bonded to one or up to three hydrogen atoms.hydrocarbon chains may be classified as branched, linear, or cyclical. They may also be divided into alkanes, alkenes, alkynes, cycloalkanes, and aryls. A hydrocarbon chain may also be classified as either saturated or unsaturated, or aliphatic or aromatic. A saturated hydrocarbon chain is saturated with hydrogen whereas an unsaturated hydrocarbon chain is one in which hydrogen atom can still be added 5 in the chain by breaking the double-bond (alkene) or triple bond (alkyne) between carbon atoms.

[0051] ‘Hydroxyl’ refers to the radical -OH.

[0052] ‘Oxo’ refers to the radical =O.

[0053] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). 10

[0054] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.

[0055] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or 15 non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0056] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or 20 that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0057] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic 25 acid addition salts and base addition salts. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011). The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically 30 acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, 35 and such as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations areexemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0058] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. 5

[0059] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0060] ‘Solvate’ refers to forms of the compound that are associated with a solvent, usually by a 10 solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent 15 molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0061] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein. 20

[0062] ‘Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0063] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or 25 disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0064] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular 30 weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0065] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at 35 least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically,(e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0066] As used herein the term ‘proliferative disease(s)’ refers to diseases associated with excessive 5 proliferation of cells and turnover of cellular matrix. In particular, the term refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythaemia vera, essential thrombocytosis and myelofibrosis), leukaemia (e.g. acute myeloid leukaemia, acute and chronic lymphoblastic leukaemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to cancer, leukaemia, and multiple myeloma. 10

[0067] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, 15 rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term ‘cancer’ refers to acute lymphoblastic leukaemia, acute myeloid leukaemia, adrenocortical carcinoma, anal cancer, appendix 20 cancer, astrocytomas, atypical teratoid / rhabdoid tumour, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumours, brain and spinal cord tumours, breast cancer, bronchial tumours, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumours, endometrial cancer, 25 ependymoblastoma, ependymoma, oesophageal cancer, Ewing sarcoma family of tumours, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumour, gastrointestinal stromal tumour (GIST), gastrointestinal stromal cell tumour, germ cell tumour, glioma, hairy cell leukaemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumours (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, 30 Langerhans cell histiocytosis, laryngeal cancer, leukaemia, hairy cell leukaemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, 35 ovarian epithelial cancer, ovarian germ cell tumour, ovarian low malignant potential tumour, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumours of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermaltumours, pituitary tumour, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumours, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue 5 sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumours, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumour.

[0068] As used herein the term ‘leukaemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host 10 highly susceptible to infection and bleeding. In particular the term leukaemia refers to acute myeloid leukaemia (AML), and acute lymphoblastic leukaemia (ALL) and chronic lymphoblastic leukaemia (CLL).

[0069] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, 15 and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0070] When ranges are referred to herein, for example but without limitation, C1-8 alkyl, the citation of a range should be considered a representation of each member of said range. 20

[0071] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted 25 or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C1-8 alkyl, C2-8 alkenyl, C6-10 optionally substituted aryl, and (C6-10 aryl)-(C14 alkyl) esters of the compounds of the 30 invention.

[0072] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number 35 different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which theproportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0073] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus- 32 (32P), sulfur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), fluorine-18 (18F) iodine-123 (123I), iodine- 125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0074] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0075] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0076] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0077] ‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures maybe in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. 5

[0078] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0079] The compounds of the invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0080] Unless indicated otherwise, the description or naming of a particular compound in the 10 specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. THE INVENTION

[0081] The present invention is based on the identification of novel compounds, and their use in the 15 prophylaxis and / or treatment of proliferative diseases. In particular, the compounds of the invention may target p53 mutant proteins. More particularly, the compounds of the invention may target the Y220C p53 mutant proteins.

[0082] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or 20 treatment of proliferative diseases by administering the compounds of the invention.

[0083] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):25 wherein X1is =CR3a- or N-, X2is =CR3b- or =N-, and X3is =CR3c- or =N-; L is 5-15 membered hydrocarbon chain saturated or comprising one or more independently selected double or triple bonds, wherein one or more carbon atoms is optionally replaced by one or more independently selected N, O, P, or S heteroatoms, which chain is optionally substituted with one or more 30 independently selected -C1-4 alkyl, -C1-4 alkoxy, -OH, or =O;Each R1a, R1b, R2a, and R2bis independently selected from: - H - =O (R1atogether with R1b, and / or R2atogether with R2b), - halo, - -OH, - -CN, - -NH2, - -NHR9a, - -NR9bR9c, - -S(=O)2R9d, - -S(=O)2NH2, - -S(=O)2NHR9e, - -S(=O)2NR9eR9f, - -C(=O)R9g, - -C(=O)OH, - -C(=O)OR9h, - -C(=O)NH2, - -C(=O)NHR9g, - -C(=O)NR9gR9h, - -P(=O)R9iR9j, - -S(=O)R9k, - -S(=O)(=NR9l)R9m, - C1-6 alkyl, optionally substituted with one or more independently selected R6a, - C1-6 alkoxy, optionally substituted with one or more independently selected R6b, - C37 cycloalkyl, optionally substituted with one or more independently selected R6c, - C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6d, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6e, and - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6f; or R1aand R2a, together with the atoms to which they are attached together may form a - C3-7membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g,- 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6h, or - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6i; Each R3a, R3b, R3cis independently selected from: - H - halo, - -OH, - -CN, - -NH2, - -NHR10a, - -NR10aR10b, - C1-4alkyl optionally substituted with one or more independently selected halo, - C1-4 alkoxy optionally substituted with one or more independently selected halo, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; Each R4aand R4bis independently selected from H, or -C1-4 alkyl optionally substituted with one or more independently selected halo; A is -S- or -O- and B is =CR5-, or A is =CH- or =N- and B is -NR5-; R5is -C1-4 alkyl optionally substituted with one or more independently selected - halo, - -CN, - -OH, - monocyclic C3-6cycloalkyl optionally substituted with one or more independently selected halo, or - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; X is absent, -CH2-, -O-, or -NH-; Each R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, and R6i, is independently selected from: - oxo, - halo,- -OH, - -CN, - -C(=O)OH, - -C(=O)OR11a, - -OC(=O)R11b, - -S(=O)2R11c, - -S(=O)2NH2, - -S(=O)2NHR11d, - -S(=O)2NR11dR11e, - -C(=O)NH2, - -C(=O)NHR11f, - -C(=O)NR11fR11g,- -NH2,- -NHR11h, - -NR11hR11i, - -C(=O)R11j, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, and - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4alkoxy; Cy is selected from, , , ,wherein * is attached to Y, and ** attached to L in Formula I, and each R , R8a2, R8a3, and R8a4, isindependently selected from: - H, - halo, - -CN, - C1-4alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4alkoxy, - C1-4 alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, - -OH, - -OR12a,- -NH2, - -NHR12b, - -NR12bR12c, - -S(=O)2R12d, - -S(=O)2NH2, - -S(=O)2NHR12e, - -S(=O)2NR12eR12f, - -C(=O)R12g, - -C(=O)OH, - -C(=O)OR12h, - -C(=O)NH2, - -C(=O)NHR12g, - -C(=O)NR12gR12h, - -P(=O)R12iR12j, - -S(=O)R12k, - -S(=O)(=NR12l)R12m, - C3-7 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, P, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo; Y is -O-, or -NR7, wherein R7is H, C1-6 alkyl, C3-6 cycloalkyl, -C(=O)C1-6 alkyl, -C(=O)C3-6 cycloalkyl, or -C(=O)C1-6 alkoxy; and Each R9a, R9b, R9c, R9d, R9e, R9f, R9g, R9h, R9i, R9j, R9k, R9l, R9m, R10a, R10b, R11a, R11b, R11c, R11d, R11e, R11f, R11g, R11h, R11i, R11j, R11k, R11l, R11m, R12a, R12b, R12c, R12d, R12e, R12f, R12g, R12h, R12i, R12j, R12k, R12l, and R12mis independently selected from: - C1-4alkyl optionally substituted with one or more independently halo, -OH, oxo, -CN, -C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo, - monocyclic C3-6 cycloalkyl optionally substituted with one or more independently selected halo, - OH, oxo, -CN, -C1-4 alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo, and- monocyclic 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN -C1-4alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo.

[0084] In another aspect of the invention, the compounds of the invention are provided having a Formula (I) wherein X1 is =CR3a- or N-, X2 is =CR3b- or =N-, and X3 is =CR3c- or =N-; L is 5-15 membered hydrocarbon chain saturated or comprising one or more independently selected double or triple bonds, wherein one or more carbon atoms have been replaced by one or more independently selected N, O, P, or S heteroatoms, which chain is optionally substituted with one or more independently selected -C1-4 alkyl, -C1-4 alkoxy, -OH, or =O; Each R1a, R1b, R2a, and R2bis independently selected from: - H - =O (R1atogether with R1b, and / or R2atogether with R2b), - halo, - -OH, - -CN, - -NH2, - -NHR9a, - -NR9bR9c, - -S(=O)2R9d, - -S(=O)2NH2, - -S(=O)2NHR9e, - -S(=O)2NR9eR9f, - -C(=O)R9g, - -C(=O)OH, - -C(=O)OR9h, - -C(=O)NH2, - -C(=O)NHR9g, - -C(=O)NR9gR9h, - -P(=O)R9iR9j, - -S(=O)R9k, - -S(=O)(=NR9l)R9m, - C1-6 alkyl, optionally substituted with one or more independently selected R6a, - C1-6alkoxy, optionally substituted with one or more independently selected R6b, - C37 cycloalkyl, optionally substituted with one or more independently selected R6c,- C5-12 membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6d, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6e, and - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6f; or R1aand R2a, together with the atoms to which they are attached together may form a - C3-7membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g, - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6h, or - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6i; Each R3a, R3b, R3cis independently selected from: - H - halo, - -OH, - -CN, - -NH2, - -NHR10a, - -NR10aR10b, - C1-4 alkyl optionally substituted with one or more independently selected halo, - C1-4 alkoxy optionally substituted with one or more independently selected halo, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; Each R4aand R4bis independently selected from H, or -C1-4 alkyl optionally substituted with one or more independently selected halo; A is -S- or -O- and B is =CR5-, or A is =CH- or =N- and B is -NR5-; R5is -C1-4 alkyl optionally substituted with one or more independently selected - halo,- -CN, - -OH, - monocyclic C3-6 cycloalkyl optionally substituted with one or more independently selected halo, or - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; X is absent, -CH2-, -O-, or -NH-; Each R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, and R6i, is independently selected from: - oxo, - halo, - -OH, - -CN, - - - -- -S(=O)2NH2, - -S(=O)2NHR11d, - -S(=O)2NR11dR11e, - -C(=O)NH2, - -C(=O)NHR11f, - -C(=O)NR11fR11g,- -NH2,- -NHR11h, - -NR11hR11i, - -C(=O)R11j, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, and - C1-4 alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy; Cy is,, , , orwherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, R8a3, and R8a4, is independently selected from: - H, - halo, - -CN, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4alkoxy, - -OH, - -OR12a, - -NH2, - -NHR12b, - -NR12bR12c, - -S(=O)2R12d, - -S(=O)2NH2, - -S(=O)2NHR12e, - -S(=O)2NR12eR12f, - -C(=O)R12g, - -C(=O)OH, - -C(=O)OR12h, - -C(=O)NH2, - -C(=O)NHR12g, - -C(=O)NR12gR12h, - -P(=O)R12iR12j, - -S(=O)R12k, - -S(=O)(=NR12l)R12m, - C3-7 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, P, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo;Y is -O-, or -NR7, wherein R7is H, C1-6alkyl, C3-6cycloalkyl, -C(=O)C1-6alkyl, -C(=O)C3-6cycloalkyl, or -C(=O)C1-6 alkoxy; and Each R9a, R9b, R9c, R9d, R9e, R9f, R9g, R9h, R9i, R9j, R9k, R9l, R9m, R10a, R10b, R11a, R11b, R11c, R11d, R11e, R11f, R11g, R11h, R11i, R11j, R11k, R11l, R11m, R12a, R12b, R12c, R12d, R12e, R12f, R12g, R12h, R12i, R12j, R12k, R12l, and- C1-4 alkyl optionally substituted with one or more independently halo, -OH, oxo, -CN, -C1-4 alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo, - monocyclic C3-6 cycloalkyl optionally substituted with one or more independently selected halo, - OH, oxo, -CN, -C1-4 alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo, and - monocyclic 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN -C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo.

[0085] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula (II):wherein R1a, R1b, R2a, R2b, R3a, R3b, R3c, R4a, R4b, X, Y, Cy, L, A, and B are as previously defined.

[0086] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3ais H.

[0087] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3bis H.

[0088] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3cis H.

[0089] In one embodiment, the compound of the invention is according to Formula I or II, wherein X is -NH-, or -O-

[0090] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula III:wherein R1a, R1b, R2a, R2b, R4a, R4b, Y, Cy, L, A, and B is as previously defined.

[0091] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula (IV):wherein R1a, R1b, R2a, R2b, R4a, R4b, Cy, L, A, and B are as previously defined.

[0092] In one embodiment, the compound of the invention is according to any one of Formula I-IV, wherein R4ais H, -CH3, or -CF3.

[0093] In one embodiment, the compound of the invention is according to any one of Formula I-IV, wherein R4bis H, -CH3, or -CF3.

[0094] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula (V):wherein R1a, R1b, R2a, R2b, Cy, L, A, and B is as previously defined.

[0095] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein A is -S- or -O-, and B is =CR5-. In a particular embodiment, A is S and B is =CR5-. In more particular embodiment, R5is, , or, wherein * represents the attachment point.

[0096] In one the compound of the invention is according to any one of Formula I-V, wherein A is =CH- or =N- and B is -NR5-. In a particular embodiment, A is =CH-, and B is -NR5. Inmore a particular embodiment, R5is wherein * represents the attachment point.the compounds of the invention are provided having a Formula VIa or VIb:wherein R1a, R1b, R2a, R R3, Cy, and L are as previously defined.

[0098] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Cy isand each R8a1, R8a2, R8a3, and R8a4, is as defined above. In a particular embodiment, each R8a1, R8a2, R8a3, and R8a4, is independently selected from H, F, Cl, Br, -CN, -C(=O)NHCH3, -C(=O)NHCH2CF3, - S(=O)2CH3, pyrazolyl, -P(=O)(CH3)2, -OCH3, -C(=O)OH, -C(=O)N(CH3)2, -C(=O)NH2, -C(=O)morpholinyl, -C(=O)NH-oxetanyl, -C(=O)OCH3, -S(=O)2NH2, -S(=O)(=NH)CH3, -S(=O)(=N CH3)CH3, and -CF3.

[0099] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Cy isand each R8a1, R8a2, R8a3, and R8a4, is as defined above. In a particular embodiment, each R8a1, R8a2, R8a3, and R8a4, is independently selected from H, F, Cl, -CN, -C(=O)NHCH3, -C(=O)NHCH2CF3, - S(=O)2CH3, pyrazolyl, -P(=O)(CH3)2, -OCH3, -C(=O)OH, -C(=O)N(CH3)2, -C(=O)NH2, - C(=O)morpholinyl, -C(=O)NH-oxetanyl, -C(=O)OCH3, -S(=O)2NH2, -S(=O)(=NH)CH3, and -CF3.

[0100] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Cy is: ,5, ,w * is attached toY, and ** attached to L in Formula I. 10 101] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein L is 5-15 membered hydrocarbon chain saturated or comprising one or more independently selected double or triple bonds, wherein one or more carbon atoms have been replaced by one or more independently selected N, O, or S heteroatoms, which chain is optionally substituted with one or more independently selected -C1-4alkyl, -C1-4alkoxyl, -OH, or =O. 15

[0102] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein L is,, ,-

[0103] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein L is ,wherein # is attached to Cy and ## is attached to -CR2aR2b- of Formula I.

[0104] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula VIIa or VIIb:VIIa VIIb wherein R1a, R1b, R2a, R2b, R8a1, R8a2, and R8a3are as described for Formula I.

[0105] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R1ais H.

[0106] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R1ais C1-6 alkyl, optionally substituted with one or more independently selected R6aand R6ais a previously described. In a particular embodiment, R1ais -CH3, -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6a. In a more particular embodiment, R6ais halo, -NH2, -N(CH3)2. In a more particular embodiment R1ais -CH2-NH2, -CH2-N(CH3)2, - CH2CH2-NH2, or -CH2CH2-N(CH3)2.

[0107] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R1bis H.

[0108] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R2ais H.

[0109] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R2ais C1-6alkyl, optionally substituted with one or more independently selected R6aand R6ais a previously described. In a particular embodiment, R2ais -CH3, -CH2CH3, -CH2CH2CH3, each of which is optionally substituted with one or more independently selected R6a. In a more particular embodiment, R6ais halo, -NH2, -N(CH3)2. In a more particular embodiment R2ais -CH2-NH2, -CH2-N(CH3)2, - CH2CH2-NH2, or -CH2CH2-N(CH3)2.

[0110] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R2aand R2btogether is =O.

[0111] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R1aand R2a, together with the atoms to which they are attached together may form a C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g, and each R6gis a previously described. In a particular embodiment, each R6gis independently selected from =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i. In a more particular embodiment, each R6gis independently selected from is =O, -CH3, F, Cl, -NH2, and -N(CH3)2.

[0112] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein R1aand R2a, together with the atoms to which they are attached together may form a 4-8 membered monocyclic heterocycloalkyl comprising one or more N, O, P or S atoms, optionally substituted with one or more independently selected R6h, and each R6his a previously described. In a particular embodiment, each R6his independently selected from =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i. In a more particular embodiment, each R6his independently selected from is =O, -CH3, F, Cl, -NH2, and -N(CH3)2.

[0113] In one embodiment, the compound of the invention is according to any one of Formula I-VIIb, wherein is selected from:,H.

[0114] In one embodiment, the compound of the invention is according to any one of Formulae VIIa- VIIIb:VIIIa VIIIb wherein R8a1, R8a2, and R8a3are as described for Formula I.

[0115] In one embodiment, the compound of the invention is according to Formula VIIIa or VIIIb wherein each R8a1, R8a2, and R8a3, is independently selected from H, F, Cl, Br, -CN, -C(=O)NHCH3, -C(=O)NHCH2CF3, -S(=O)2CH3, pyrazolyl, -P(=O)(CH3)2, -OCH3, -C(=O)OH, -C(=O)N(CH3)2, -C(=O)NH2, -C(=O)morpholinyl, -C(=O)NH-oxetanyl, -C(=O)OCH3, -S(=O)2NH2, -S(=O)(=NH)CH3, -S(=O)(=N CH3)CH3, and -CF3.

[0116] In one embodiment, the compound of the invention according to Formula I is selected from: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20] pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13. 015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (15S*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (rac) (15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne,(15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (15S*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 5 N,N-dimethyl-1-[31-(2,2,2-trifluoroethyl)-19,22,25-trioxa-2,14,31-triazatetracyclo [24.3.1.16,9.08,13]hentriaconta-1(29),6,8,10,12,26(30),27-heptaen-4-yn-16-yl]methanamine, 33-methoxy-18-methyl-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (rac) (15R*,20S*)-18-methyl-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 10 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (rac) (15R*,20R*)-18-methyl-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08,13.015,20] 15 pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne, (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne, (15R,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 20 (rac) (15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne, (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne, (15S,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35-tetrazapentacyclo 25 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, (15S,20R)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08, 13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxylic acid, 30 methyl 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08, 13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxylate, N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08, 13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxamide, 35 18-methyl-N,35-bis(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08, 13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxamide,33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16, 9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxylic acid, methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo 5 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31-carboxylate, 33-methoxy-N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-31- carboxamide, 32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 10 tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne, (15S)-15-(2-aminoethyl)-32-(2,2,2-trifluoroethyl)-20,23,26-trioxa-2,14,17,32-tetrazatetracyclo [25.3.1.16,9.08,13]dotriaconta-1(31),6,8,10,12,27,29-heptaen-4-yn-16-one, and (15S)-15-[2-(dimethylamino)ethyl]-32-(2,2,2-trifluoroethyl)-20,23,26-trioxa-2,14,17,32- 15 tetrazatetracyclo [25.3.1.16,9.08,13]dotriaconta-1(31),6,8,10,12,27,29-heptaen-4-yn-16-one.

[0117] In one embodiment, the compound of the invention is selected from: rac-(15R,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- 20 heptaen-4-yne, rac-(15S,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 25 (15S)-15-(2-aminoethyl)-32-(2,2,2-trifluoroethyl)-20,23,26-trioxa-2,14,17,32-tetrazatetracyclo [25.3.1.16,9.08,13]dotriaconta-1(31),6,8,10,12,27,29-heptaen-4-yn-16-one, 15-[2-(dimethylamino)ethyl]-32-(2,2,2-trifluoroethyl)-20,23,26-trioxa-2,14,17,32-tetrazatetracyclo [25.3.1.16,9.08,13]dotriaconta-1(31),6,8,10,12,27,29-heptaen-4-yn-16-one, rac-(15R,20S)-32-methoxy-N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-30 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxamide, rac-(15S,20S)-32-methoxy-N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxamide, 35 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo[28.3.1.16,9.08, 13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-32-carboxylic acid,N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-32- carboxamide, 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo 5 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-32- carboxamide, N,N,18-trimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-32- carboxamide, 10 18-methyl-32-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-32-carbonitrile, 18-methyl-32-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo 15 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne, (15S,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4- yne, (15R,20R)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-20 2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31- heptaen-4-yne, (15R,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4- yne, 25 (15S,20R)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4- yne, 34-methoxy-18-methyl-36-(2,2,2-trifluoroethyl)-23,26-dioxa-2,14,18,29,36-pentazapentacyclo [29.3.1.16,9.08,13.015,20]hexatriaconta-1(35),6,8,10,12,31,33-heptaen-4-yn-30-one, 30 Rac-methyl-methylimino-[(15S,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yn- 32-yl]-oxo-λ⁶-sulfane, imino-methyl-oxo-[rac-(15S,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yn- 35 32-yl]-λ⁶-sulfane, and 18-methyl-36-(2,2,2-trifluoroethyl)-23,26-dioxa-2,14,18,29,36-pentazapentacyclo [29.3.1.1^{6,9}.0^{8,13}.0^{15,20}]hexatriaconta-1(35),6,8,10,12,31,33-heptaen-4-yn-30-one.

[0118] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0119] In one embodiment, a compound of the invention is provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of 5 a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably, the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0120] In one embodiment, a compound of the invention is provided whereby a single atom of the 10 compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0121] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant 15 forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0122] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0123] In one aspect a compound of the invention according to any one of the embodiments herein 20 described is a pharmaceutically acceptable salt of the compound.

[0124] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0125] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of the compound. 25

[0126] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope. 30

[0127] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope. 35

[0128] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0129] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are 5 not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0130] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent 10 acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C1 to C8 alkyl, 15 C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention. PHARMACEUTICAL COMPOSITIONS

[0131] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known 20 in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and 25 response of the individual patient, the severity of the patient’s symptoms, and the like.

[0132] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0133] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a proliferative 30 diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukaemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0134] In a particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent 35 is a cancer treatment agent. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, andmastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukaemia, acute myeloid 5 leukaemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumour, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumours, brain and spinal cord tumours, breast cancer, bronchial tumours, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, 10 craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumours, endometrial cancer, ependymoblastoma, ependymoma, oesophageal cancer, Ewing sarcoma family of tumours, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumour, gastrointestinal stromal tumour (GIST), gastrointestinal stromal cell tumour, germ cell tumour, glioma, hairy cell leukaemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, 15 intraocular melanoma, islet cell tumours (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukaemia, hairy cell leukaemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral 20 cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumour, ovarian low malignant potential tumour, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumours of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumours, pituitary tumour, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, 25 primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumours, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumours, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral 30 cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumour. Most particularly, the term refers to high-grade ovarian serous adenocarcinoma, pancreatic adenocarcinoma, breast invasive ductal carcinoma, lung adenocarcinoma, colon adenocarcinoma, myelodysplastic syndrome, acute myeloid leukaemia, and therapy-related myeloid neoplasms.

[0135] In a further particular embodiment, the present invention provides pharmaceutical compositions 35 comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a leukaemia treatment agent. In particular, the term refers to neoplastic diseases of the blood and bloodforming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0136] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and 5 intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0137] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage 10 forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the 15 case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0138] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous 20 vehicle with buffers, suspending and dispensing agents, colorants, flavours and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose 25 or saccharin; or a flavouring agent such as peppermint or orange flavouring.

[0139] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. 30

[0140] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. 35 Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additionalingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0141] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous 5 membrane type, or of a solid matrix variety.

[0142] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. 10

[0143] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences (Remington & Gennaro 1985).

[0144] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the 15 following pharmaceutical compositions. Formulation 1 - Tablets

[0145] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatine binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound 20 of the invention according to Formula I per tablet) in a tablet press. Formulation 2 - Capsules

[0146] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule). 25 Formulation 3 - Liquid

[0147] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavour, and color 30 may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0148] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatine binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active 5 compound of the invention according to Formula I) in a tablet press. Formulation 5 - Injection

[0149] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL. Formulation 6 - Topical 10

[0150] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 ºC and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals. METHODS OF TREATMENT 15

[0151] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0152] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, 20 myeloproliferative disorders, leukaemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0153] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of proliferative diseases. In particular, the term 25 proliferative diseases refers to cancer, myeloproliferative disorders, leukaemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0154] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with proliferative diseases, which methods comprise the 30 administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukaemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0155] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and 5 types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukaemia, acute myeloid leukaemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumour, basal cell 10 carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumours, brain and spinal cord tumours, breast cancer, bronchial tumours, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumours, endometrial cancer, ependymoblastoma, ependymoma, oesophageal cancer, Ewing sarcoma 15 family of tumours, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumour, gastrointestinal stromal tumour (GIST), gastrointestinal stromal cell tumour, germ cell tumour, glioma, hairy cell leukaemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumours (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukaemia, hairy cell20 leukaemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non- Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumour, 25 ovarian low malignant potential tumour, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumours of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumours, pituitary tumour, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, 30 Ewing sarcoma family of tumours, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumours, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumour. Most particularly, the term refers to high-grade ovarian serous adenocarcinoma, 35 pancreatic adenocarcinoma, breast invasive ductal carcinoma, lung adenocarcinoma, colon adenocarcinoma, myelodysplastic syndrome, acute myeloid leukaemia, and therapy-related myeloid neoplasms.

[0156] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, 5 rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukaemia, acute myeloid leukaemia, adrenocortical carcinoma, anal cancer, appendix cancer, 10 astrocytomas, atypical teratoid / rhabdoid tumour, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumours, brain and spinal cord tumours, breast cancer, bronchial tumours, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumours, endometrial cancer, 15 ependymoblastoma, ependymoma, oesophageal cancer, Ewing sarcoma family of tumours, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumour, gastrointestinal stromal tumour (GIST), gastrointestinal stromal cell tumour, germ cell tumour, glioma, hairy cell leukaemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumours (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, 20 Langerhans cell histiocytosis, laryngeal cancer, leukaemia, hairy cell leukaemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, 25 ovarian epithelial cancer, ovarian germ cell tumour, ovarian low malignant potential tumour, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumours of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumours, pituitary tumour, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, 30 retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumours, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumours, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumour. Most 35 particularly, the term refers to high-grade ovarian serous adenocarcinoma, pancreatic adenocarcinoma, breast invasive ductal carcinoma, lung adenocarcinoma, colon adenocarcinoma, myelodysplastic syndrome, acute myeloid leukaemia, and therapy-related myeloid neoplasms.

[0157] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with cancer, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to both 5 metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic 10 leukaemia, acute myeloid leukaemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumour, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumours, brain and spinal cord tumours, breast cancer, bronchial tumours, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, 15 craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumours, endometrial cancer, ependymoblastoma, ependymoma, oesophageal cancer, Ewing sarcoma family of tumours, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumour, gastrointestinal stromal tumour (GIST), gastrointestinal stromal cell tumour, germ cell tumour, glioma, hairy cell leukaemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, 20 intraocular melanoma, islet cell tumours (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukaemia, hairy cell leukaemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukaemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral 25 cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumour, ovarian low malignant potential tumour, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumours of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumours, pituitary tumour, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, 30 primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumours, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumours, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral 35 cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumour. Most particularly, the term refers to high-grade ovarian serous adenocarcinoma, pancreatic adenocarcinoma,breast invasive ductal carcinoma, lung adenocarcinoma, colon adenocarcinoma, myelodysplastic syndrome, acute myeloid leukaemia, and therapy-related myeloid neoplasms.

[0158] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or 5 treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0159] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a 10 medicament for the prophylaxis and / or treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0160] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with leukemia, which methods comprise the administration of 15 an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). 20

[0161] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0162] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, 25 the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (14) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, 30 dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0163] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg. 35

[0164] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0165] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by 5 genetic testing or screening to be particularly susceptible to developing the condition.

[0166] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or 10 more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0167] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient. 15

[0168] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5- fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. 20 Herceptin®), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g. Avastin®), proteasome inhibitors (e.g. Velcade®), Glivec®and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease 25 or leukaemia.

[0169] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at 30 different times. CHEMICAL SYNTHETIC PROCEDURES General

[0170] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred 35 process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.)are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0171] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may 5 be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).

[0172] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be 10 prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0173] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. 15 Column chromatography is performed on silica gel 60 (35-70 µm) or with Biotage®SNAP KP-NH, Biotage®SNAP Ultra, or Interchim®PuriFlash®Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage®ISOLUTE®phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation.1H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz), a Bruker Avance 300 NMR 20 spectrometer (300 MHz), or a Bruker Avance III HD NMR spectrometer (400 MHz). Chemical shifts (δ) for1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, e.g. CHCl3 (δ 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m) and broad (br). Analytical methods 25 Table I. Description of LC-MS method The analysis below is performed on a Shimadzu LCMS-2020 Column description A Method name B column type 30 C Mobile phase D gradient E Flow (mL / min) F Column temperature (°C) G Run time (mn) 35A B C D E F G From 95% A to 5% A in HALO 90A C18 A: Water+0.05%TFA 0.99min, held for 0.4min, to 1 1.5 40 1.52 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA 95% A in 0.02 min, held for 0.1min From 95% A to 0% A in HALO 90A C18 A: Water+0.05%TFA 0.69min, held for 1.1min, to 2 1.5 40 2 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA 95% A in 0.02 min, held for 0.18min From 95% A to 0% A in HALO 90A C18 A: Water+0.1%FA 0.69min, held for 1.1min, to 3 1.2 40 2 (2.0μm, 3.0*30mm) B: MeCN+0.1%FA 95% A in 0.02 min, held for 0.18min A: 5mM NH4HCO3in From 95% A to 10% A in Shim‐pack Scepter H2O / MeCN 0.99min, held for 0.4min, to 4 C18‐120 1.5 40 1.5 (95:5, v:v); 95% A in 0.02 min, held for (3.0μm, 3.0*33mm) B: MeCN 0.08min From 95% A to 0% A in HALO 90A C18 A: Water+0.1%FA 0.99min, held for 0.4min, to 5 1.2 40 1.5 (2.0μm, 3.0*30mm) B: MeCN+0.1%FA 95% A in 0.02 min, held for 0.08min From 95% A to 0% A in HALO 90A C18 A: Water+0.05%TFA 0.99min, held for 0.4min, to 6 1.5 40 1.5 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA 95% A in 0.02 min, held for 0.08min From 95% A to 0% A in HALO C18 A: Water+0.05%TFA 1.19min, held for 0.6min, to 7 1.5 40 2 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA 95% A in 0.02 min, held for 0.18min From 95% A to 10% A in Shim‐pack Scepter A: 5%MeCN, 1.19min, held for 0.6min, to 8 C18‐120 95%Water / 5mM NH4HCO3 1.5 40 2 95% A in 0.02 min, held for (3.0μm, 3.0*33mm) B: MeCN 0.18min From 95% A to 40% A in HALO C18 A: Water+0.05%TFA 1.69min, to 5% A in 0.6 min, 9 1.5 40 3 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17minA B C D E F G From 95% A to 0% A in Kinetex XB-C18 A: Water+0.05%TFA 0.69min, held for 1.1min, to 0 100A (1.7μm, 1.0 40 2 B: MeCN+0.05%TFA 95% A in 0.02 min, held for 4.6*150mm) 0.18min From 95% A to 0% A in HALO 90A C18 A: Water / 0.1%FA 1.19min, held for 0.6min, to 1 1.2 40 2 (2.0μm, 3.0*30mm) B: MeCN / 0.1%FA 95% A in 0.02 min, held for 0.18min. From 95% A to 50% A in HALO C18 A: Water+0.05%TFA 1.69min, to 5% A in 0.6 min, 2 1.5 40 3 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 95% A to 40% A in HALO C18 A: Water+0.05%TFA 1.69min, to 5% A in 0.6 min, 3 1.5 40 3 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 60% A to 10% A in Shim‐pack Scepter A: 5%MeCN, 1.19min, held for 0.6min, to 4 C18‐120 95%Water / 5mM NH4HCO3 1.5 40 2 95% A in 0.02 min, held for (3.0μm, 3.0*33mm) B: MeCN 0.18min From 95% A to 0% A in HALO 90A C18 A: Water+0.1%FA 0.69min, held for 1.1min, to 5 1.2 40 2 (2.0μm, 3.0*30mm) B: MeCN+0.1%FA 95% A in 0.02 min, held for 0.18min From 90% A to 10% A in Shim‐pack Scepter A: Water / 6.5mM NH4HCO3 0.69min, held for 1.1min, to 6 C18‐120 1.2 40 2 B: MeCN 90% A in 0.02 min, held for (3.0μm, 2.1*33mm) 0.18min From 95% A to 0% A in HALO 90A C18 A: Water+0.1%FA 0.69min, held for 0.4min, to 7 1.2 40 1.2 (2.0μm, 3.0*30mm) B: MeCN+0.1%FA 95% A in 0.02 min, held for 0.08min From 95% A to 0% A in HALO 90A C18 A: Water+0.05%TFA 0.69min, held for 0.4min, to 8 1.5 40 1.2 (2.0μm, 3.0*30mm) B: MeCN+0.05%TFA 95% A in 0.02 min, held for 0.08minA B C D E F G From 70% A to 30% A in Shim‐pack Scepter A: 5%MeCN, 1.69min, to 10% A in 0.6 9 C18‐120 95%Water / 5mM NH4HCO3min, held for 0.5min, to 95% 1.5 40 3 (3.0μm, 3.0*33mm) B: MeCN A in 0.03 min, held for 0.17min From 90% A to 10% A in Shim‐pack Scepter A: Water / 5mM NH4HCO3 0.69min, held for 1.1min, to 0 C18‐120 1.5 40 2 B: MeCN 90% A in 0.02 min, held for (3.0μm, 3.0*33mm) 0.18min A: 5mM NHHCO in Fr ‐pack Scepter 4 om 95% A to 10% A in Shim 3 H2O / MeCN 0.69min, held for 1.1min, to 1 C18‐120 1.5 40 2 (95:5, v:v); 95% A in 0.02 min, held for (3.0μm, 3.0*33mm) B: MeCN 0.08min From 90% A to 10% A in Shim‐pack Scepter A: Water / 6.5mM NH4HCO3 0.69min, held for 0.4min, to 2 C18‐120 1.2 40 1.5 B: MeCN 90% A in 0.02 min, held for (3.0μm, 2.1*33mm) 0.08min From 95% A to 50% A in HALO C18 A: Water+0.05%TFA 1.69min, to 0% A in 0.6 min, 3 1.2 40 3 (2.0μm, 3.0*30mm) B: ACN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 70% A to 30% A in HALO C18 A: Water+0.05%TFA 1.69min, to 5% A in 0.6 min, 4 1.5 40 3 (2.0μm, 3.0*30mm) B: ACN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 95% A to 0% A in CORTECS T3 A: Water+0.1%FA 0.99min, held for 0.4min, to 5a 1.2 40 1.5 (2.7μm, 2.1*30mm) B: ACN+0.1%FA 95% A in 0.02 min, held for 0.08min From 90% A to 10% A in Shim‐pack Scepter A: Water / 5mM NH4HCO3 0.99min, held for 0.4min, to 6 C18‐120 (3.0μm, 1.5 40 1.5 B: MeCN 90% A in 0.02 min, held for 3.0*33mm) 0.08min From 95% A to 0% A in HALO 90A C18 A: Water+0.05%TFA 1.09min, held for 0.3min, to 7 1.5 40 1.5 (2.0μm, 3.0*30mm) B: MECN+0.05%TFA 95% A in 0.02 min, held for 0.08minA B C D E F G From 80% A to 40% A in HALO C18 A: Water+0.05%TFA 1.69 min, to 5% A in 0.6 min, 28 1.5 40 3 (2.0μm, 3.0*30mm) B: ACN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 80% A to 50% A in HALO C18 (2.0μm, A: Water+0.05%TFA 1.69min, to 5% A in 0.6 min, 30 1.5 40 3 3.0*30mm) B: ACN+0.05%TFA held for 0.5min, to 95% A in 0.03 min, held for 0.17min From 90% A to 10% A in Shim‐pack Scepter A: Water / 6.5mM NH4HCO3 0.99min, held for 0.4min, to 31 C18‐120 (3.0μm, 1.5 40 1.5 B: Acetonitrile 90% A in 0.02 min, held for 3.0*33mm) 0.08min From 90% A to 10% A in Shim‐pack Scepter A: Water / 5mM NH4HCO30.69min, held for 0.7min, to 35 C18‐120 (3.0μm, 1.5 40 1.5 B: Acetonitrile 90% A in 0.02 min, held for 3.0*33mm) 0.08min XBridge C18 A: 5mM NH4HCO3 in From 98% A to 85% A in 37 (3.5μm, water / Acetonitrile (90:10, 6min, held for 2 min， 600 1.0 40 8 3.0*100mm) v:v); B: Acetonitrile bar From 70% A to 30% A in Shim‐pack Scepter 1.69min, to 10% A in 0.6 A: Water / 5mM NH 3.0μm, 4HCO 40 C18‐120 ( 3 min, held for 0.5min, to 90% 1.5 40 3 B: Acetonitrile 3.0*33mm) A in 0.03 min, held for 0.17min Additional method name:

[0174] Method 25

[0175] Apparatus: Waters ACQUITY UPLC I-Class PLUS System with Waters SQ Detector 2

[0176] Column: Acquity UPLC BEH C181.7 μm (2.1 x 100 mm), column no.186002352, internal column no. Pur CC – Wat001

[0177] Reagents: - - Formic acid 98-100% for analysis EMSURE® ACS,Reag. Ph Eur, Merck - - Acetonitrile gradient grade for liquid chromatography LiChrosolv® Reag. Ph Eur., Merck - - μQ-water for LCMS.

[0178] UPLC conditions: - - Wavelength range: 200 - 400 nm - - Flow: 0.5 ml / min- - Column temperature: 40 °C - - Autosampler temperature: room temperature - - Analysis time: 3.0 min - - Elution: gradient Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml / min] 0.00 85 15 0.5 0.10 85 15 0.5 1.10 0 100 0.5 2.00 0 100 0.5 2.50 85 15 0.5 3.00 85 15 0.5 5

[0179] For compound 1 and 2 alternative route:

[0180] Preparative HPLC is performed on a Waters AutoPurification System with UV and MS detection using Gemini NX-C18, 00G-4454-P0-AX, 250x21.2 mm, 5µm / 110Å Phenomenex column and ACN / H2O gradients with acidic (0,1% FA in both mobile phases). 10 Table II. List of abbreviations used in the experimental section: Abbreviation Definition Abbreviation Definition 4 A MS 4 Angstrom molecular sieves diisopropyl azodicarboxylate DIAD ACN acetonitrile (CAS# 2446-83-5) N,N-diisopropylethylamine AcOH acetic acid DIPEA (CAS# 7087-68-5) aq. aqueous DMF N,N-dimethylformamide atm atmosphere DMSO dimethylsulfoxide ATP adenosine 5´-triphosphate 1,1′-bis(diphenylphosphino) 9-borabicyclo(3.3.1)nonane 9-BBN dppf ferrocene (CAS# 12150-46- (CAS# 280-64-8) 8) b.i.d. bis in die (twice a day) ethylenediamine EDTA Boc tert-butyloxy-carbonyl tetraAcOH di-tert-butyloxy-carbona eq. equivalent 2 te BocO (CAS# 24424-99-5) EtOAc Ethyl acetate Cpd compound EtOH ethanol D doublet FA Formic acid DCM dichloromethane h hour diethyl azodicarboxylate DEAD (CAS# 1972-28-7)Abbreviation Definition Abbreviation Definition Hexafluorophosphate PBS phosphate-buffered saline Azabenzotriazole HATU Pd(dppf)Cl2.DCM [1,1′-bis(diphenylphosphino) Tetramethyl Uronium ferrocene]dichloropalladium CAS# 148893-10-1 (II) complex with dichloro high-performance liquid HPLC methane (CAS# 95464-05-4) chromatography [1,1′-bis(diphenylphos IPA isopropanol Pd(dppf)Cl2 phino)ferrocene]dichloropall Int intermediate adium(CAS# 72287-26-4) liquid chromatography-mass PIN percentage inhibition LCMS spectrometry p.o. per os (orally) LDA lithium diisopropylamide ppm parts-per-million m multiplet q quartet MeOH MeOH q.d. quaque die (once daily) min minute RT room temperature mmol millimole Rt retention time MS mass spectrometry s singlet MTBE methyl tert-butyl ether sat. saturated Mtd method SM starting material MW molecular weight t triplet NA not available TBS or TBDMS tert–butyldimethylsilyl NaBH3(CN) sodium cyanoborohydride TEA triethylamine sodium TFA trifluoroAcOH NaBH(OAc)3 triacetoxyborohydride THF tetrahydrofuran (CAS# 56553-60-7)SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION Example 1. Overview for the preparation of illustrative compounds of the invention 1.1. Scheme 1: 5Example 2. Methods for the preparation of intermediates of illustrative compounds of the invention 2.1. Intermediates Int-0: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)- 4-oxopiperidine-1-carboxylate 5 Intermediates Int-1: tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)piperidine-1-carboxylate2.1.1. Step 1: 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane

[0181] To a solution of 2-[2-(2-bromoethoxy)ethoxy]ethanol (CAS# 57641-67-5; 10.0 g, 46.9 mmol, 1.010 equiv) in THF (130 mL) was added imidazole (4.79 g, 70.4 mmol, 1.5 equiv) and tert- butyl(chloro)diphenylsilane (15.5 g, 56.3 mmol, 1.2 equiv) at 0 °C under nitrogen. The reaction mixture was stirred for 4 h at RT and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL), and the organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The 15 crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (8% - 10%) to afford the title compound (18.3 g, 69%) as a colourless oil.

[0182] LCMS(ESI-MS) m / z = 473.0, 475.0 [M+Na]+

[0183] Rt 1.175 min; Method 1

[0184] 1H NMR (400 MHz, DMSO) δ 7.66 – 7.63 (m, 3H), 7.51 – 7.35 (m, 7H), 3.79 – 3.69 (m, 4H), 3.60 20 – 3.52 (m, 8H), 1.00 (s, 9H). 2.1.2. Step 2: tert-butyl 4-(2,2-dimethylhydrazin-1-ylidene)piperidine-1-carboxylate

[0185] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (CAS# 79099-07-3; 5.00 g, 25.1 mmol, 1.0 equiv) and 1,1-dimethylhydrazine hydrochloride (2.67 g, 27.6 mmol, 1.1 equiv) in toluene (25 mL) were added TEA (2.79 g, 27.6 mmol, 1.1 equiv) at RT. The reaction mixture was stirred for 4 h at 110 °C. 25 The mixture was cooled down to rt and the solvent was removed under reduced pressure. The residue was taken up in heptane and the formed precipitate was removed by filtration. The heptane filtrate was concentrated under reduced pressure to afford the crude title compound (6.00 g, 89%) as a light-yellow oil, used in the next steps without further purification.

[0186] LCMS(ESI-MS) m / z = 242.2 [M+H]+

[0187] Rt 0.228 min; Method 1

[0188] 1H NMR (400 MHz, DMSO) δ 3.48 – 3.35 (m, 4H), 2.56 – 2.50 (m, 2H), 2.33 (s, 6H), 2.25 – 2.18 (m, 2H), 1.41 (s, 9H). 2.1.3. Step 3: Intermediates Int-0: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- 5 siladodecan-12-yl)-4-oxopiperidine-1-carboxylate

[0189] To a solution of tert-butyl 4-(2,2-dimethylhydrazin-1-ylidene)piperidine-1-carboxylate (4.90 g, 20.3 mmol, 1.0 equiv) in THF (100 mL) was added LDA (15.2 mL, 30.5 mmol, 1.5 equiv, 2.0 M in THF) at -78 °C under nitrogen. After stirred for 1 h at -78 °C, a solution of 12-bromo-2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecane (11.0 g, 24.4 mmol, 1.2 equiv) in THF (20 mL) was added dropwise. The 10 reaction mixture was stirred for 16 h at RT and quenched with saturated aqueous ammonium chloride (150 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 150 mL), and the organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL).100 ml of 10% aq. solution of citric acid was added. The resulting mixture was stirred for 4 h at RT. Then the layers were separated, the aqueous 15 phase was extracted with EtOAc (3 x 150 mL), and the organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was chromatographed on a silica gel column with petroleum ether / EtOAc (33% - 40%) to afford the title compound (8.20 g, 63%) as a light-yellow oil.

[0190] LCMS(ESI-MS) m / z = 592.4 [M+H]+20

[0191] Rt 0.915min; Method 2 2.1.4. Step 4: Intermediates Int-1: tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0192] To a solution of tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4- oxopiperidine-1-carboxylate (6.00 g, 10.5 mmol, 1.0 equiv) and ammonium formate (13.3 g, 211 mmol, 20 25 equiv) in anhydrous MeOH (50 mL) was added formic acid (970 mg, 21.1 mmol, 2.0 equiv) and 4A molecular sieve at RT.After stirred for 5 h at 30 °C, sodium cyanoborohydride (CAS# 25895-60-7; 1.99 g, 31.6 mmol, 3.0 equiv) was added and the reaction mixture was stirred for 1 h. The mixture was filtered and washed with MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was dissolved in EtOAc (300 mL), washed with saturated aqueous sodium 30 bicarbonate (150 mL), brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with DCM / MeOH (10% - 12%) to afford the title compound (4.5 g, 63%) as a yellow oil.

[0193] LCMS(ESI-MS) m / z = 571.4 [M+H]+

[0194] Rt 0.703 min; Method 22.2. Intermediates Int-2: tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-4-oxopiperidine-1- carboxylate2.2.1. Step 1: 12-bromo-2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecane

[0195] To a solution of 2-[2-(2-bromoethoxy)ethoxy]ethan-1-(CAS# 57641-67-5; 2.4 g, 11.3 mmol, 1.0 eq.) in THF (23 ml) were added Imidazole (2.3 g, 33.8 mmol, 3.0 eq.) and TBDMSCl (2.54 g, 16.9 mmol, 1.5 eq). Reaction mixture was stirred overnight at RT. Reaction mixture was then concentrated to dryness. Water and DCM are added, and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with Cy / DCM from 50 / 50 to 100 / 0) to afford the title compound.

[0196] 1H NMR (300 MHz, CDCl3) δ 3.86 – 3.74 (m, 4H), 3.67 (s, 4H), 3.59 – 3.54 (m, 2H), 3.47 (t, J = 6.4 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H). 2.2.2. Step 2: tert-butyl 4-(piperidin-1-ylimino)piperidine-1-carboxylate

[0197] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (CAS# 79099-07-3; 5.0 g, 25.1 mmol, 1.0 eq.) in toluene (50 mL) was added N-aminopiperidine (CAS# 2213-43-6; 2.77 g, 27.6 mmol, 1.1 eq.). Reaction mixture was refluxed for 3 h with Dean-Stark apparatus, then the reaction mixture was concentrated to dryness to afford the title compound used in the next step without any further purification.

[0198] Rt 1.68 min; Method 25

[0199] 1H NMR (400 MHz, CDCl3) δ 3.56 (t, 2H), 3.50 (t, 2H), 2.65 – 2.57 (m, 6H), 2.35 (t, J = 6.0 Hz, 2H), 1.69 – 1.61 (m, 4H), 1.47 (s, 9H), 1.46 – 1.39 (m, 2H). 2.2.3. Step 3: tert-butyl (E)-4-(piperidin-1-ylimino)-3-(2,2,3,3-tetramethyl-4,7,10-trioxa-3- siladodecan-12-yl)piperidine-1-carboxylate

[0200] A solution of tert-butyl 4-(piperidin-1-ylimino)piperidine-1-carboxylate (1 g, 3.55 mmol, 1.0 eq.) in THF (20 ml) was cooled down to -78°C, LDA (1M in THF; 4.3 mL, 4.26 mmol, 1.2 eq.) was added in one portion. Resulting mixture was stirred 10 min at -78°C, then solution of 12-bromo-2,2,3,3-tetramethyl- 4,7,10-trioxa-3-siladodecane (1.16 g, 3.55 mmol, 1.0 eq.) in 10 ml of THF was added in one portion.Reaction mixture was let to warm up to RT and was stirred at RT overnight. Sat. NH4Cl solution and DCM are added, and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with acetone / DCM from 0 / 100 to 30 / 70) to afford the title compound. 5

[0201] LCMS(ESI-MS) m / z = 528.6 [M+H]+

[0202] Rt 2.07 min; method 25 2.2.4. Step 4: Intermediates Int-2: tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-4- oxopiperidine-1-carboxylate

[0203] To a solution of tert-butyl (E)-4-(piperidin-1-ylimino)-3-(2,2,3,3-tetramethyl-4,7,10-trioxa-3- 10 siladodecan-12-yl)piperidine-1-carboxylate (1.2 g, 2.27 mmol,1.0 eq) in 10 ml of DCM, 30 ml of 10% aq. solution of citric acid was added. Reaction mixture was stirred overnight at RT. Addition of trifluoroacetic acid (110 mg, 1.14 mmol, 0.5 eq.) and MeOH (20 mL). Reaction mixture was stirred 1h at RT. Reaction mixture was concentrated to dryness. Water and DCM are added, and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by 15 column chromatography on silica gel (eluting with Cy / Acetone from 100 / 0 to 75 / 25) to afford the title compound. 2.3. Intermediates Int-3: N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-3- ((tert-butyldimethylsilyl)oxy)aniline20 2.3.1. Step 1: 3-((tert-butyldimethylsilyl)oxy)aniline

[0204] To a stirred mixture of m-aminophenol (CAS# 591-27-5; 5.00 g, 45.8 mmol, 1.0 equiv) and Imidazole (12.4 g, 183 mmol, 4.0 equiv) in THF (50 mL) was added tert-butyl(chloro)dimethylsilane (8.29 g, 54.9 mmol, 1.2 equiv). The reaction mixture was stirred for 14 h at RT under nitrogen and was quenched with water (600 mL). The reaction mixture was extracted with EtOAc (3 x 600 mL), and the organic layers 25 were combined, washed with brine (3 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 10) to afford the title compound (9.0 g, 79%) as a yellow oil.

[0205] LCMS(ESI-MS) m / z = 224.1 [M+H]+

[0206] Rt 0.944 min; Method 3 1H NMR (400 MHz, DMSO) δ 6.84 (t, 1H), 6.19 – 6.12 (m, 1H), 6.09 (t, 1H), 6.01 – 5.94 (m, 1H), 4.97 (s, 2H), 0.93 (s, 9H), 0.15 (s, 6H). 2.3.2. Step 2: 3-((tert-butyldimethylsilyl)oxy)-N-(prop-2-yn-1-yl)aniline 5

[0207] To a stirred mixture of 3-((tert-butyldimethylsilyl)oxy)aniline (8.00 g, 35.8 mmol, 1.0 equiv) and propargyl bromide (4.69 g, 39.4 mmol, 1.1 equiv) in DMF (80 mL) was added potassium carbonate (5.44 g, 39.4 mmol, 1.1 equiv). The reaction mixture was stirred for 16 h at RT and quenched with water (800 mL). The reaction mixture was extracted with EtOAc (3 x 800 mL), and the organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under 10 reduced pressure to afford crude product. The crude product was purified by C18 column with MeCN / Water, (93%), the fraction was concentrated under reduced pressure to afford the title compound (4.1 g, 39% yield) as a yellow oil.

[0208] LCMS(ESI-MS) m / z = 262.2 [M+H]+

[0209] Rt 1.222 min; Method 4 15

[0210] 1H NMR (400 MHz, DMSO) δ 6.95 (t, J = 8.0 Hz, 1H), 6.28 – 6.20 (m, 1H), 6.15 (t, J = 2.2 Hz, 1H), 6.11 – 6.06 (m, 1H), 5.93 (t, J = 6.1 Hz, 1H), 3.84 – 3.77 (m, 2H), 3.03 (t, J = 2.4 Hz, 1H), 0.94 (s, 9H), 0.17 (s, 6H). 2.3.3. Step 3: Intermediates Int-3: N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop- 2-yn-1-yl)-3-((tert-butyldimethylsilyl)oxy)aniline 20

[0211] To a stirred mixture of 3-((tert-butyldimethylsilyl)oxy)-N-(prop-2-yn-1-yl)aniline (300 mg, 1.14 mmol, 1.0 equiv), 4-bromo-1-(2,2,2-trifluoroethyl)indol-2-yl trifluoromethanesulfonate (CAS# 2637449- 10-4; 489 mg, 1.14 mmol, 1.0 equiv), bis(triphenylphosphine)palladium(II) chloride (40.2 mg, 0.057 mmol, 0.05 equiv) and cuprous iodide (32.7 mg, 0.172 mmol, 0.15 equiv) in DMF (5 mL) was added TEA (348 mg, 3.44 mmol, 3.0 equiv). The reaction mixture was stirred for 1 h at RT under nitrogen and quenched 25 with water. The reaction mixture was extracted with EtOAc (3 x 100 mL), and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 4) to afford the title compound (500 mg, 72% yield) as a brown semi-solid. 30

[0212] LCMS(ESI-MS) m / z = 537.1 / 539.1 [M+H]+

[0213] Rt 1.276 min; Method 5

[0214] 1H NMR (400 MHz, DMSO) δ 7.62 (d, 1H), 7.35 (d, 1H), 7.21 (dd, 1H), 6.99 (t, 1H), 6.72 (d, 1H), 6.38-6.31 (m, 1H), 6.23 (t, 1H), 6.16 – 6.06 (m, 2H), 5.15 – 5.04 (m, 2H), 4.21 (d, 2H), 0.93 (s, 9H), 0.16 (s, 6H).2.4. Intermediates: Int-4: tert-butyl (3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1- yl)(3-((tert-butyldimethylsilyl)oxy)phenyl)carbamate

[0215] To a solution of Int-3 (9.00 g, 16.7 mmol, 1.0 equiv) in 1-Butanol (72 mL) was added di-tert-butyldicarbonate (36 mL). The reaction mixture was stirred overnight at 40 ℃ and quenched with water (300mL). The resulting mixture was extracted with EtOAc (3 x 300 mL), and the organic layers were combined, washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% TFA), the fraction (100%) was concentrated under reduced pressure to give the title 10 compound (6.7 g, 56%) as a yellow solid. In

[0216] LCMS(ESI-MS) m / z = 581.2 [M-56+H]+

[0217] Rt 1.157 min; Method 3 2.5. Intermediates Int-5: tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-4-((2-iodo-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate 15

[0218] To a solution of Int-2 (400 mg, 1.21 mmol, 1.0 eq) in MeOH (12 ml), 2-iodo-1-(2,2,2- trifluoroethyl)-1H-indol-4-amine (CAS# 2127096-38-0; 410 mg, 1.21 mmol, 1.0 eq.), AcOH (145 mg, 2.42 mmol, 2.0 eq.) and NaBH3(CN) (114 mg, 1.81 mmol, 1.5 eq) were added. Reaction mixture was stirred at RT for 72 hours. Sat. sodium bicarbonate solution and DCM are added, and the layers separated. The 20 combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with acetone / DCM from 0-100 to 50 / 50) to afford the title compound.

[0219] d.r.71 / 29.

[0220] LCMS(ESI-MS) m / z = 656.4 [M+H]+25

[0221] Rt 2.02 min / 2.03 min; Method 252.6. Intermediates Int-6: tert-butyl 4-((2-(3-((3-((tert-butyldimethylsilyl)oxy)phenyl)amino)prop-1- yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)piperidine-1-carboxylate5 , , tris(dibenzylideneacetone)dipalladium (560 mg, 0.614 mmol, 0.1 equiv), 5-[Di(1-adamantyl)phosphino]- 1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (CAS# 1239478-87-5; 400 mg, 0.614 mmol, 0.1 equiv) and sodium benzenolate (2.14 g, 18.4 mmol, 3.0 equiv) in 1,4-dioxane (45 mL) was stirred for 3 h at 70 °C. Water and EtOAc were added and the layers separated. The combined organic layers were washed with brine, dried 10 over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with EtOAc / petroleum ether (1 / 4)) to afford the title compound.

[0223] LCMS(ESI-MS) m / z = 1027.4 [M+H]+

[0224] Rt 1.110 min / 1.174 min; Method 2 2.7. Intermediates Int-7: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert-butyldimethylsilyl)oxy)15 phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate2.7.1. Step 1: tert-butyl (3-((tert-butyldimethylsilyl)oxy)phenyl)(prop-2-yn-1-yl)carbamate

[0225] A solution of 3-((tert-butyldimethylsilyl)oxy)-N-(prop-2-yn-1-yl)aniline (750 mg, 2.87 mmol, 1.0 20 eq) was stirred in excess di-tert-butyl dicarbonate used as a solvent at RT for 16 hours. The reaction was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with cyclohexane / EtOAc from 100 / 0 to 95 / 5) to afford the title compound.

[0226] Rt 2.24 min; Method 25

[0227] 1H NMR (300 MHz, AcN-d3) 7.23 (t, J = 8.0 Hz, 1H), 6.95 – 6.88 (m, 1H), 6.85 – 6.71 (m, 2H), 25 4.33 (d, J = 2.4 Hz, 2H), 2.49 (t, J = 2.5 Hz, 1H), 1.40 (s, 9H), 0.98 (s, 9H), 0.21 (s, 6H).2.7.2. Step 2: Intermediates Int-7: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)- 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate

[0228] To a solution of Int-5 (300 mg, 0.46 mmol, 1.0 eq) in DMF (4.6 ml), tert-butyl (3-((tert- butyldimethylsilyl)oxy)phenyl)(prop-2-yn-1-yl)carbamate (827 mg, 2.29 mmol, 5.0 eq.), CuI (8.7 mg, 0.05 mmol, 0.1 eq.), TEA (0.64 mL, 4.60 mmol, 10 eq.), and Pd(dppf)Cl2.DCM (32 mg, 0.05 mmol, 0.1 eq.) were added. Reaction mixture was purged with argon and reaction vessel was sealed. Reaction mixture was stirred at RT overnight. Reaction mixture was concentrated to obtain crude material. Water and DCM are added, and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with EtOAc / DCM from 0 / 100 to 40 / 60) to afford the title compound.

[0229] Mixture of isomers

[0230] Rt 2.45 min; Method 25 2.8. Intermediates Int-8: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-one

[0231] To a stirred mixture of 4-(2,2-dimethylhydrazin-1-ylidene)-1-methylpiperidine (3.44 g, 22.2 mmol, 1.0 equiv) in THF (90 mL) was added LDA (27.8 mL, 55.4 mmol, 2.5 equiv, 2.0 M in THF) at 0 °C under nitrogen. The mixture was stirred 1 h at 0 °C. Then 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecane (10.0 g, 22.2 mmol, 1.0 equiv, in THF (10 mL)) was added at 0 °C. The reaction mixture was stirred for overnight under nitrogen and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product (50 mL ethyl acetate remaining). Then Citric acid solution (10% in H2O) was added. The mixture was stirred at room temperature for 2 h and adjusted to PH=9 with saturated NaHCO3 solution, and the mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and the organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 2, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 5% - 6% B fractions were collected ) to provide the title product (5.2 g, 43%) as a light yellow solid.

[0232] LCMS(ESI-MS) m / z = 484.3 [M+H]+

[0233] Rt: 1.071 min (Method 20)2.9. Intermediates Int-9: N-(3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine5

[0234] To a stirred mixture of 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (3.0 g, 8.82 mmol, 1.0 equiv) and Int-8 (5.55 g, 11.5 mmol, 1.3 equiv) in AcOH (36 mL) and DCE (18 mL) was added 4A MS (6.0 g) at room temperature. The mixture was stirred at 50 °C for 5 h. Then STAB (3.74 g, 17.64 mmol, 2.0 equiv) was added. The reaction mixture was stirred for overnight at 35 °C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and 10 concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 80 mL / min; Gradient: 0% B to 20% B in 40 min; Wave Length: 220 nm; 11% B fractions were collected) to provide title product (5.7 g, 75%) as a brown solid.

[0235] LCMS (ESI-MS) m / z = 808.2 [M+H]+15

[0236] Rt: 0.846 min (Method 2). 2.10. Intermediates Int-10: methyl 2-hydroxy-4-(prop-2-yn-1-ylamino)benzoate2.10.1. Step 1: methyl 2-hydroxy-4-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)benzoate

[0237] To a solution of methyl 4-amino-2-hydroxybenzoate (10 g, 59.8 mmol, 1.0 equiv) in DCM (500 20 mL) and AcOH (50 mL) was added 3-(trimethylsilyl)prop-2-ynal (7.55 g, 59.8 mmol, 1.0 equiv) at room temperature and stirred for 1 h at 40 °C. Then STAB (50.7 g, 239 mmol, 4.0 equiv) was added and the reaction mixture was stirred for 2 h at 35 °C. The reaction mixture was quenched with water (200 mL) and extracted with DCM (3 x 200 mL), then the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 25 product (16.5 g, crude) as a brown oil.

[0238] LCMS(ESI-MS) m / z = 278.1 [M+H]+

[0239] Rt: 0.942 min (Method 6) 2.10.2. Step 2: methyl 2-hydroxy-4-(prop-2-yn-1-ylamino)benzoate

[0240] To a solution of methyl 2-hydroxy-4-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)benzoate (14.6 g, 30 52.5 mmol, 1.0 equiv) in MeOH (15 mL) was added K2CO3 (14.5 g, 105 mmol, 2.0 equiv) at roomtemperature. The reaction mixture was stirred for 2 h at room temperature and filtered through a celite pad. The filtered cake was washed with ethyl acetate (3 x 200 mL) and the filtrate was concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g x 2, 100 - 200 mesh, Mobile Phase A: PE, Mobile Phase B: EtOAc; Flow rate: 80 mL / min; 5 Gradient: 0% B to 50% B in 40 min; Wave Length: 254 nm; 22% B fractions were collected) to provide the title product (9.0 g, 83%) as a yellow solid.

[0241] LCMS(ESI-MS) m / z = 206.1 [M+H]+

[0242] Rt: 0.759 min (Method 6) 10 2.11. Intermediates Int-11: methyl 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-2-hydroxy-5- methoxybenzoate2.11.1. Step 1: 2-(benzyloxy)-5-hydroxy-4-nitrobenzoic acid 15

[0243] To a solution of 2-(benzyloxy)-5-hydroxybenzoic acid (20.0 g, 81.9 mmol, 1.0 equiv) in MeCN (300 mL) was added Ammonium cerium(IV) nitrate (13.5 g, 24.6 mmol, 0.30 equiv) stirred at room temperature. The reaction mixture was stirred overnight at room temperature and filtered through a celite pad. The filtered cake was washed with ethyl acetate (3 x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was extracted 20 with EtOAc (3 x 500 mL) and water (500 mL), and the organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product 2-(benzyloxy)-5-hydroxy-4-nitrobenzoic acid (11.8 g, crude) as a brown solid.

[0244] LCMS(ESI-MS) m / z = 599.0 [2(M-1) +Na]–

[0245] Rt: 0.762 min (Method 5) 25

[0246] 2.11.2. Step 2: methyl 2-(benzyloxy)-5-methoxy-4-nitrobenzoate

[0247] To a solution of 2-(benzyloxy)-5-hydroxy-4-nitrobenzoic acid (9.80 g, 33.9 mmol, 1.0 equiv) in DMF (200 mL) was added iodomethane (14.4 g, 101 mmol, 3.0 equiv) and K2CO3 (23.4 g, 169 mmol, 5.0 equiv) stirred at room temperature. The reaction mixture was stirred for 3 h at room temperature and 30 quenched with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL) and theorganic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 80 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 30% B 5 in 30 min; 254 nm; 25% B fractions were collected) to provide the title product (5.00 g, 42.3% yield, 91%purity) as a yellow solid.

[0248] GCMS m / z = 317.1 [M] 2.11.3. Step 3: methyl 4-amino-2-hydroxy-5-methoxybenzoate

[0249] To a solution of methyl 2-(benzyloxy)-5-methoxy-4-nitrobenzoate (5.00 g, 15.8 mmol, 1.0 equiv) 10 in EtOH (50 mL) was added Pd / C (3.35 g, 31.5 mmol, 2.0 equiv) (10%) stirred at room temperature under hydrogen. The reaction mixture was stirred for 4 h at room temperature. The mixture was filtered through a celite pad and washed with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product methyl 4-amino-2-hydroxy-5- methoxybenzoate (2.50 g, crude) as a black solid. 15

[0250] LCMS(ESI-MS) m / z =198.1 [M+H]+

[0251] Rt: 0.688 min (Method 5) 2.11.4. Step 4: methyl 2-hydroxy-5-methoxy-4-((3-(trimethylsilyl)prop-2-yn-1- yl)amino)benzoate

[0252] To a solution of methyl 4-amino-2-hydroxy-5-methoxybenzoate (2.33 g, 11.8 mmol, 1.0 equiv) in 20 DCM (30 mL) was added 3-(trimethylsilyl)prop-2-ynal (1.49 g, 11.8 mmol, 1.0 equiv) and HOAc (3 mL) stirred at room temperature . The reaction mixture was stirred for 1 h at 35 °C, then STAB (10.0 g, 47.3 mmol, 4.0 equiv) was added at room temperature. The reaction mixture was stirred for 1 h at 35 °C and quenched with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate,25 filtered and concentrated under reduced pressure to afford crude product methyl 2-hydroxy-5-methoxy-4- {[3-(trimethylsilyl)prop-2-yn-1-yl]amino}benzoate (3.40 g, crude) as a black solid.

[0253] LCMS(ESI-MS) m / z =308.1 [M+H]+

[0254] Rt: 1.031 min (Method 5) 2.11.5. Step 5: methyl 2-hydroxy-5-methoxy-4-(prop-2-yn-1-ylamino)benzoate 30

[0255] To a solution of methyl 2-hydroxy-5-methoxy-4-((3-(trimethylsilyl)prop-2-yn-1- yl)amino)benzoate (3.40 g, 11.1 mmol, 1.0 equiv) in methanol (30 mL) was added K2CO3 (3.06 g, 22.1 mmol, 2.0 equiv) stirred at room temperature. The reaction mixture was stirred for 2 h at room temperature and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, 35 filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 120 g, 100 - 200 mesh; Mobile Phase A: petroleum ether,Mobile Phase B: ethyl acetate; Flow rate: 50 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 20% B in 20 min; 254 nm; 7% B fractions were collected) to provide the title product (1.10 g, 38% yield, 90% purity) as a light yellow solid.

[0256] LCMS(ESI-MS) m / z =236.0 [M+H]+5

[0257] Rt: 0.806 min (Method 5) 2.11.6. Step 6: methyl 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-2-((tert- butoxycarbonyl)oxy)-5-methoxybenzoate

[0258] To a solution of methyl 2-hydroxy-5-methoxy-4-(prop-2-yn-1-ylamino)benzoate (1.00 g, 4.25 mmol, 1.0 equiv) was added di-tert-butyl dicarbonate (5 mL) stirred at room temperature. The reaction 10 mixture was stirred for 24 h at 90 °C. The resulting mixture was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 60 mL / min; Gradient: 0% B to 0% B in 20 min, 0% B to 30% B in 30 min; 254 nm; 15% B fractions were collected) to provide the desired product methyl 4-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-2- [(tert-butoxycarbonyl)oxy]-5-methoxybenzoate (760 mg, crude) as a colorless semi-solid. 15

[0259] LCMS(ESI-MS) m / z =893.4 [2M+Na]+

[0260] Rt: 1.008 min (Method 6) 2.11.7. Step 7: methyl 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-2-hydroxy-5- methoxybenzoate

[0261] To a solution of methyl 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-2-((tert- 20 butoxycarbonyl)oxy)-5-methoxybenzoate (760 mg, 1.75 mmol, 1.0 equiv) in methanol (8 mL) was added K2CO3 (482 mg, 3.49 mmol, 2.0 equiv) stirred at room temperature. The reaction mixture was stirred for 3 h at room temperature and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product 25 was purified by TLC (Mobile phase: ethyl acetate / petroleum ether=1:3; Rf = 0.6; detection: UV) to provide the desired product (390 mg, 59%yield, 90%purity) as a colorless semi-solid.

[0262] LCMS(ESI-MS) m / z =236.1 [M+H-Boc]+

[0263] Rt: 0.859 min (Method 6) 2.12. Intermediates Int-12: tert- (3-bromo-5- 2- 1-yl)carbamate302.12.1. Step 1: 3-bromo-5-((triisopropylsilyl)oxy)aniline

[0264] To a solution of 3-amino-5-bromophenol (450 mg, 2.39 mmol, 1.0 equiv) in DMF (10 mL) was added 1H-imidazole (358 mg, 5.26 mmol, 2.2 equiv) and chlorotris(propan-2-yl)silane (692 mg, 3.59 mmol, 1.5 equiv). The reaction mixture was stirred for 4 h at room temperature and quenched with water (60 mL). 5 The resulting mixture was extracted with ethyl acetate (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was chromatographed on a silica gel column (Column: 80 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 45 mL / min; Gradient: 0% B to 30% B in 30 min; Wave Length: 220 nm; Collected fractions: 10 5% - 10% B) to provide the title product (640 mg, 70% yield) as a yellow oil.

[0265] LCMS (ESI-MS) m / z = 385.1 [M+H+ACN]+

[0266] Rt: 0.978 min (Method 3) 2.12.2. Step 2: 3-bromo-5-((triisopropylsilyl)oxy)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)aniline

[0267] To a solution of 3-bromo-5-((triisopropylsilyl)oxy)aniline (600 mg, 1.74 mmol, 1.0 equiv) in 15 DCM (12 mL) was added 3-(trimethylsilyl)prop-2-ynal (220 mg, 1.74 mmol, 1.0 equiv), acetic acid (1.2 mL) and 4A molecular sieve (1.20 g) at room temperature and stirred for 1 h at -10 °C. Then sodium triacetoxyborohydride (1.48 g, 6.97 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 3 h at 0 °C and quenched with water (80 mL). The resulting mixture was extracted with dichloromethane (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium 20 sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 120 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 50 mL / min; Gradient: 0% B to 30% B in 30 min; Wave Length: 220 nm; Collected fractions: 8% - 12% B) to provide the title product (533 mg, 60% yield) as a yellow oil.

[0268] LCMS (ESI-MS) m / z = 454.2[M+H]+25

[0269] Rt: 1.477 min (Method 7) 2.12.3. Step 3: tert-butyl (3-bromo-5-((tert-butoxycarbonyl)oxy)phenyl)(3-(trimethylsilyl)prop- 2-yn-1-yl)carbamate

[0270] A mixture of 3-bromo-5-((triisopropylsilyl)oxy)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)aniline (450 mg, 0.990 mmol, 1.0 equiv) and di-tert-butyl dicarbonate (20 mL) was stirred for 4 h at 90 ℃ and 30 quenched with water (150 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL) and the organic layers were combined, washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse purification C18 (Column: 20 - 35 μm, 100 Å, 130 g; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 0% B to 100% B in 30 min; 220 nm; Collected 35 fractions: 100% B), the fraction was concentrated under reduced pressure to provide the title product (510 mg, crude, mixture with Boc2O) as a light yellow oil.

[0271] LCMS(ESI-MS) m / z = 498.1 [M+H]+

[0272] Rt: 1.247 min (Method 2) 2.12.4. Step 4: tert-butyl (3-bromo-5-hydroxyphenyl)(prop-2-yn-1-yl)carbamate

[0273] To a solution of tert-butyl (3-bromo-5-((tert-butoxycarbonyl)oxy)phenyl)(3-(trimethylsilyl)prop- 2-yn-1-yl)carbamate (450 mg, 0.90 mmol, 1.0 equiv) in MeOH (9 mL) was added potassium carbonate 5 (250 mg, 1.81 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at room temperature and quenched with water (100 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 80 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, 10 Mobile Phase B: ethyl acetate; Flow rate: 50 mL / min; Gradient: 0% B to 50% B in 40 min; Wave Length: 220nm nm; Collected fractions: 25% - 30% B), the fraction was concentrated under reduced pressure to provide the title product (260 mg, 79%) as a light yellow solid.

[0274] LCMS(ESI-MS) m / z = 270.0 [M+H-56]+

[0275] Rt: 0.811 min (Method 6) 15 2.13. Intermediates Int-13: tert-butyl 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-2-carboxylate20 2.13.1. Step 1: tert-butyl (3-bromo-5-hydroxyphenyl)(3-(4-((3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol- 2-yl)prop-2-yn-1-yl)carbamate

[0276] To a solution of Int-12 (252 mg, 0.772 mmol, 2.5 equiv) in DMSO (5 mL) was Int-9 (250 mg, 0.309 mmol, 1.0 equiv), cuprous iodide (15.9 mg, 0.083 mmol, 0.27 equiv), trimethylamine (125 mg, 1.24 25 mmol, 4.0 equiv) and Bis(triphenylphosphine)palladium(II) chloride (21.7 mg, 0.031 mmol, 0.10 equiv). The reaction mixture was stirred for 2 h at room temperature under nitrogen and quenched with water (100mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: methanol / dichloromethane = 1:12; Rf = 0.4; detection: UV) to afford the title product (220 mg, 63% yield) 5 as a brown solid.

[0277] LCMS(ESI-MS) m / z = 1005.5 [M+H]+

[0278] Rt: 1.056 min (Method 6) 2.13.2. Step 2: tert-butyl (3-bromo-5-hydroxyphenyl)(3-(4-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2- 10 yl)prop-2-yn-1-yl)carbamate

[0279] To a solution of tert-butyl (3-bromo-5-hydroxyphenyl)(3-(4-((3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2- yl)prop-2-yn-1-yl)carbamate (220 mg, 0.219 mmol, 1.0 equiv) in THF (2.4 mL) was added tetrabutylammonium fluoride (68.6 mg, 0.263 mmol, 1.2 equiv, 1 M in THF) at 0 °C. The reaction mixture 15 was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with Ethyl acetate (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: dichloromethane / methanol = 5 / 1; Rf = 0.5; detection: UV) to afford the desired product tert-butyl (3-bromo-5-hydroxyphenyl) (3-(4-((3-(2-(2-(2-20 hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop- 2-yn-1-yl)carbamate (85.0 mg, 44% yield) as a brown solid.

[0280] LCMS(ESI-MS) m / z = 767.3 [M+H]+

[0281] Rt: 0.816 min (Method 6) 2.13.3. Step 3: tert-butyl 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-25 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-2-carboxylate

[0282] To a solution of tert-butyl (3-bromo-5-hydroxyphenyl)(3-(4-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop- 2-yn-1-yl)carbamate (85.0 mg, 0.111 mmol, 1.0 equiv), triphenylphosphine (174 mg, 0.666 mmol, 6.0 30 equiv) and 4A molecular sieve (170 mg) in THF (4.5 mL) was added diisopropyl azodicarboxylate (134 mg, 0.666 mmol, 6.0 equiv, in 4 mL THF) dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred for 2 h at 60 °C under nitrogen and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The 35 crude product was purified by TLC (Mobile phase: methanol / dichloromethane = 1:15; Rf = 0.3; detection: UV) to afford the title product (30.0 mg, 32%) as a brown solid.

[0283] LCMS(ESI-MS) m / z = 749.3 [M+H]+

[0284] Rt: 0.909 min, 0.919 min (Method 6) 2.14. Intermediates Int-14: 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-amine

[0285] Step 1: 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-amine 5

[0286] To a stirred mixture of 2-[2-(2-aminoethoxy)ethoxy]ethanol (10.0 g, 67.0 mmol, 1.0 equiv) and 1H-imidazole (10.5 g, 154 mmol, 2.3 equiv) in DCM (200 mL) was added tert-butyl(chloro)diphenylsilane (22.1 g, 80.4 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred overnight at room temperature and quenched with water (600 mL). The resulting mixture was extracted with DCM (3 x 500 mL) and the organic layers were combined, washed with brine (2 x 400 mL), dried over anhydrous sodium sulfate, 10 filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 80 mL / min; Gradient: 0% B to 50% B in 30 min; Wave Length: 220nm nm; Collected fractions: 18 % - 21 % B) to provide the desired product (18 g, 62% yield) as an oil.

[0287] LCMS(ESI-MS) m / z = 388.2 [M+H]+15

[0288] Rt: 0.660 min (Method 25) 2.15. Intermediates Int-15: methyl 3-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-5- hydroxybenzoate20 2.15.1. Step 1: methyl 3-hydroxy-5-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)benzoate

[0289] A mixture of methyl 3-amino-5-hydroxybenzoate (2 g, 11.9 mmol, 1.0 equiv) and 3- (trimethylsilyl)prop-2-ynal (1.51 g, 11.9 mmol, 1.0 equiv) and 4A MS (4 g) in DCM (50 mL) and AcOH (5 mL) was stirred for 1 h at -15°C. Then STAB (10.1 g, 47.8 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 1 h at -15°C. The resulting mixture was quenched with water (50 mL) and extracted 25 with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 70 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 8% B fractions were collected) to provide the desired (1.1 g, 29% yield) as a brown oil. 30

[0290] LCMS(ESI-MS) m / z = 278.0 [M+H]+

[0291] Rt: 0.697 min (Method 2) 2.15.2. Step 2: methyl 3-((tert-butoxycarbonyl)(3-(trimethylsilyl)prop-2-yn-1-yl)amino)-5- ((tert-butoxycarbonyl)oxy)benzoate

[0292] A mixture of methyl 3-hydroxy-5-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)benzoate (1.4 g, 5.04 5 mmol, 1.0 equiv) in di-tert-butyl dicarbonate (20 mL)was stirred overnight at 90 °C. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse purification C18 (Column: 20 - 35 μm, 100 Å, 350 g; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow 10 rate: 80 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 220nm nm; Collected fractions: 97 % B) to provide the desired product methyl 3-[(tert-butoxycarbonyl)[3-(trimethylsilyl)prop-2-yn-1- yl]amino]-5-[(tert-butoxycarbonyl)oxy]benzoate (1.7 g, 63% yield) as a yellow oil. LCMS(ESI-MS) m / z = 500.2 [M+Na]+. Rt: 0.911 min (Method 18). 2.15.3. Step 3: methyl 3-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-5-hydroxybenzoate15

[0293] To a stirred mixture of methyl 3-((tert-butoxycarbonyl)(3-(trimethylsilyl)prop-2-yn-1-yl)amino)- 5-((tert-butoxycarbonyl)oxy)benzoate (2 g, 4.187 mmol, 1 equiv) in MeOH (20 mL) was added K2CO3 (1.16 g, 8.37 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and 20 concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 70 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 10% B fractions were collected) to provide the desired product (1.1 g, 77% yield) as an off-white solid.

[0294] LCMS(ESI-MS) m / z = 328.0 [M+Na]+25

[0295] Rt: 0.680 min (Method 2) 2.16. Intermediates Int-16: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-N-(2- iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)-1-methylpiperidin-4-amine

[0296] A mixture of 2-iodo-3-(2,2,2-trifluoroethyl)-1-benzothiophen-7-amine (CAS#2903922-15-4, 3 g, 8.40 mmol, 1.0 equiv), Int-8 (5.28 g, 10.9 mmol, 1.3 equiv) and 4A Ms (6.0 g) in AcOH (48 mL) and DCE 30 (24 mL) was stirred for 5 h at 50 °C. Then STAB (3.56 g, 16.8 mmol, 2.0 equiv) was added. The reactionmixture was stirred overnight at 35 °C. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, 5 Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 70 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220 nm; 6% B fractions were collected) to provide the title product (2.9 g, 41% yield) as a brown solid.

[0297] LCMS(ESI-MS) m / z = 825.2 [M+H]+

[0298] Rt: 0.820 min (Method 2) 10 2.17. Intermediates Int-17: tert-butyl 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 7-thia-2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-2-carboxylate2.17.1. Step 1: tert-butyl (3-bromo-5-hydroxyphenyl)(3-(7-((3-(2,2-dimethyl-3,3-diphenyl-15 4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate

[0299] To a solution of Int-12 (728 mg, 2.23 mmol, 2.3 equiv) in DMSO (12 mL) was added Int-16 (800 mg, 0.970 mmol, 1.0 equiv), cuprous iodide (49.9 mg, 0.262 mmol, 0.27 equiv), trimethylamine (393 mg, 3.88 mmol, 4.0 equiv) and Bis(triphenylphosphine)palladium(II) chloride (68.1 mg, 0.097 mmol, 0.10 20 equiv). The reaction mixture was stirred for 2 h at room temperature under nitrogen and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: dichloromethane, Mobile Phase B: methanol; 25 Flow rate: 80 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 254 nm; Collected fractions: 4% - 8% B) to afford the desired product (860 mg, 86% yield) as a brown solid.

[0300] LCMS(ESI-MS) m / z = 1022.3 [M+H]+

[0301] Rt: 0.849 min (Method 2). 2.17.2. Step 2: tert-butyl (3-bromo-5-hydroxyphenyl)(3-(7-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate 5

[0302] To a solution of tert-butyl (3-bromo-5-hydroxyphenyl)(3-(7-((3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (1.00 g, 0.977 mmol, 1.0 equiv) in THF (10 mL) was added tetrabutylammonium fluoride (1.17 mL, 1.172 mmol, 1.2 equiv, 1 M in THF) at 0 °C. The reaction mixture was stirred for overnight at room temperature and quenched with water (150 mL). 10 The resulting mixture was extracted with Ethyl acetate (3 x 150 mL) and the organic layers were combined, washed with brine (2 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile Phase A: dichloromethane, Mobile Phase B: methanol; Flow rate: 80 mL / min; Gradient: 0% B to 20% B in 30 min; Wave Length: 254 nm; Collected fractions: 9% - 13% B) 15 to afford the desired product (700 mg, 82% yield) as a light yellow solid. LCMS(ESI-MS) m / z = 784.3 [M+H]+

[0303] Rt: 0.839 min (Method 6). 2.17.3. Step 3: Intermediates Int-17: tert-butyl 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)- 23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 20 1(33),6(35),8,10,12,30(34),31-heptaen-4-yne-2-carboxylate

[0304] To a solution of tert-butyl (3-bromo-5-hydroxyphenyl)(3-(7-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-2- yl)prop-2-yn-1-yl)carbamate (150 mg, 0.191 mmol, 1.0 equiv), triphenylphosphine (201 mg, 0.764 mmol, 4.0 equiv) and 4A molecular sieve (300 mg) in THF (7.5 mL) was added diisopropyl azodicarboxylate (155 25 mg, 0.764 mmol, 4.0 equiv, in 7.5 mL THF) dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred for 2 h at 60 °C under nitrogen and quenched with water (60 mL). The resulting mixture was extracted with EtOAc (3 x 60 mL) and the organic layers were combined, washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: methanol / dichloromethane =1:15; Rf = 30 0.3; detection: UV) to afford the desired (85 mg, 52% yield) as a brown solid.

[0305] LCMS(ESI-MS) m / z = 766.3 [M+H]+

[0306] Rt: 0.9220.937 min (Method 6).2.18. Int-18: methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate

[0307] To a solution of1.00 equiv) in DMF (50 mL) was added propargyl bromide (4.92 g, 41.4 mmol, 1.50 equiv) and K2CO3 (11.4 g, 82.8 mmol, 3.00 5 equiv) stirred at room temperature. The reaction mixture was stirred overnight at 70 °C and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL) and the organic layers were combined, washed with brine (3 x150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column (Column: 350 g, 20-35 μm, Mobile Phase A: water (0.05% TFA), Mobile Phase B: CH3CN; Flow rate: 80 mL / min; 10 Gradient: 0% B to 100% B in 30 min; Wave Length: 220 / 254 nm; 45% B fractions were collected), the fraction was concentrated under reduced pressure to provide the desired product (4.6 g, 69% yield) as a light yellow solid.

[0308] LCMS(ESI-MS) m / z = 220.2 [M+H]+

[0309] Rt: 0.763 min (Method 6). 15 2.19. Intermediate Int-19: imino(3-methoxy-5-nitrophenyl)(methyl)-^6-sulfanone2.19.1. Step 1: (3-methoxy-5-nitrophenyl)(methyl)sulfane

[0310] A solution of 1-bromo-3-methoxy-5-nitrobenzene (20.0 g, 86.2 mmol, 1.0 equiv) in anhydrous 1,4- dioxane (300 mL) was added (methylsulfanyl)sodium (9.06 g, 129 mmol, 1.5 equiv), Pd2(dba)3 (7.89 g, 20 8.62 mmol, 0.1 equiv) and XantPhos (9.97 g, 17.2mmol, 0.2 equiv) and DIEA (33.4 g, 259 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 4 hours under nitrogen and quenched with water (300 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 ml) and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduce pressure to provide crude product. The crude was chromatographed on a silica gel column (Column: 330 25 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 20% B in 50 min; Wave Length: 254 nm; 7% - 9% B fractions were collected) to provide the desired product (8.5 g, 44% yield) as a yellow solid.

[0311] GCMS(ESI-MS) m / z = 199.0 [M].2.19.2. Step 2: 1-methoxy-3-(methylsulfinyl)-5-nitrobenzene

[0312] A solution of (3-methoxy-5-nitrophenyl)(methyl)sulfane (8.5 g, 42.7 mmol, 1.0 equiv) in HOAc (20 mL) was added H2O2(85 mL, 150 mmol, 3.5 equiv, 6% in water) at room temperature. The reaction mixture was stirred for 1 hour at 70 °C and quenched with saturated aqueous NaHCO3(300 mL). The resulting mixture was extracted with ethyl acetate (2 x 300 ml). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 60% - 65% B fractions were collected) provide the desired product 1- methanesulfinyl-3-methoxy-5-nitrobenzene (5.2 g, 50% yield) as a yellow solid. LCMS(ESI-MS) m / z = 216.0 [M+H]+. Rt: 0.552 min (Method 34). 2.19.3. Step 3: imino(3-methoxy-5-nitrophenyl)(methyl)-^6-sulfanone

[0313] A solution of 1-methoxy-3-(methylsulfinyl)-5-nitrobenzene (5.0 g, 23.2 mmol, 1.0 equiv) and (Diacetoxyiodo)benzene (30.0 g, 92.9 mmol, 4.0 equiv) in methanol (120 mL) was added ammonium acetate (7.2 g, 92.9 mmol, 4.0 equiv). The reaction was stirred for 4 hours at room temperature and filtered. The filter cake was washed with MeOH (2 x 30 ml) and the filtrate was concentrated under reduced pressure. Then H2O (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with brine (2 x 150 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 70% - 75% B fractions were collected) to provide the desired product (2.6 g, 41% yield) as a yellow solid.

[0314] LCMS(ESI-MS) m / z = 230.9 [M+H]+

[0315] Rt: 0.673 min (Method 34). 2.20. Intermediate Int-20: 3-[methyl(methylimino)oxo-lambda6-sulfanyl]-5-(prop-2-yn-1- ylamino)phenol2.20.1. Step 1: [(3-methoxy-5-nitrophenyl)(methyl)oxo-lambda6-sulfanylidene](methyl)amine

[0316] A solution of imino(3-methoxy-5-nitrophenyl)(methyl)-l6-sulfanone (1.3 g, 5.65mmol, 1.0 equiv) in THF (35 mL) was added NaH (0.68 g, 17.0 mmol, 3.0 equiv, 60% in mineral oil) at 0 °C. After the reaction was stirred for 10 minutes, methyl iodide (1.6 g, 11.3 mmol, 2.0 equiv) was added. The reaction mixture was stirred for 2 hours at room temperature and quenched with H2O (50 ml) at 0 °C. The resulting mixture was extracted with DCM (2 x 150 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 85% - 90% B fractions were collected) to provide the desired product [(3-methoxy-5-nitrophenyl)(methyl)oxo-lambda6-sulfanylidene](methyl)amine (900 mg, 65% yield) as a brown solid. LCMS(ESI-MS) m / z = 286.2 [M+ACN]+Rt: 0.602 min (Method 31). 2.20.2. Step 2: product 3-methoxy-5-[methyl(methylimino)oxo-lambda6-sulfanyl]aniline

[0317] A solution of [(3-methoxy-5-nitrophenyl)(methyl)oxo-lambda6-sulfanylidene](methyl)amine (800 mg, 3.28 mmol, 1.0 equiv) and Fe (1097 mg, 19.6 mmol, 6.0 equiv) in EtOH (12 mL) and H2O (12 ml) was added ammonium chloride (526 mg, 9.83 mmol, 3.0 equiv). Then the reaction mixture was stirred for 2 hours at 70 °C. After the reaction was completed, the reaction was diluted with H2O (40 ml) and extracted with ethyl acetate (2 x 60 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 90% - 93% B fractions were collected) to provide the desired product 3- methoxy-5-[methyl(methylimino)oxo-lambda6-sulfanyl]aniline (500 mg, 64% yield) as a yellow solid. LCMS(ESI-MS) m / z = 245.0 [M+H]+. Rt: 0.635 min (Method 34). 2.20.3. Step 3: 3-methoxy-5-[methyl(methylimino)oxo-lambda6-sulfanyl]-N-[3- (trimethylsilyl)prop-2-yn-1-yl]aniline

[0318] A solution of 3-methoxy-5-[methyl(methylimino)oxo-lambda6-sulfanyl]aniline (500 mg, 2.33 mmol, 1.0 equiv) and 3-(trimethylsilyl)prop-2-ynal (265 mg, 2.10 mmol, 0.9 equiv) in DCM (10 mL) was added 4A Ms. After the mixture was stirred for 1 hour at room temperature, STAB (1.98 g, 9.33 mmol, 4.0 equiv) was added to the above reaction and stirred for additional 2 hour at room temperature. After the reaction was completed, the reaction was quenched with H2O (30 ml) and extracted with DCM (2 x 80 ml). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 20% - 25% B fractions were collected) to provide the desired product (3-methoxy-5-((3-(trimethylsilyl)prop-2- yn-1-yl)amino)phenyl)(methyl)(methylimino)-l6-sulfanone (500 mg, 67% yield) as a yellow solid.

[0319] LCMS(ESI-MS) m / z = 325.0 [M+H]+. Rt: 0.731 min (Method 35). 2.20.4. Step 4: 3-[methyl(methylimino)oxo-lambda6-sulfanyl]-5-(prop-2-yn-1-ylamino)phenol

[0320] A solution of 3-methoxy-5-[methyl(methylimino)oxo-lambda6-sulfanyl]-N-[3- (trimethylsilyl)prop-2-yn-1-yl]aniline (500 mg, 1.54 mmol, 1.0 equiv) in DCM (15 mL) was added BBr35 (6 mL, 6.00 mmol, 3.9 equiv, 1M in DCM) in portions at 0 °C for 10 minutes under nitrogen atmosphere. The reaction was stirred for additional 16 hours at room temperature. After the reaction was completed, the reaction was quenched by the addition of saturated sodium bicarbonate at 0 °C and was extracted with DCM (3 x 200 ml). The combined organic layers were washed with brine (2 x 150 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was 10 chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 75% - 80% B fractions were collected) to provide the desired product 3-[methyl(methylimino)oxo- lambda6-sulfanyl]-5-(prop-2-yn-1-ylamino)phenol (130 mg, 32% yield) as an off-white solid.

[0321] LCMS(ESI-MS) m / z = 239.0 [M+H]+. Rt: 0.444 min (Method 34). 15 2.21. Intermediate Int-21: rac-N-[(3S,4R)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan- 12-yl)-1-methylpiperidin-4-yl]-2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amineN-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl]-2-iodo-1- (2,2,2-trifluoroethyl)indol-4-amine (9.50 g) was separated by Achiral column (Column: GreenSep Basic 5*25 20 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 130 mL / min; Gradient (B%): isocratic 22% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 10.17; RT2(min): 11.80; Sample Solvent: MEOH; Injection Volume: 2 mL). Purification resulted in isomer 1 / (RT=10.17 min) rac-N-[(3R,4R)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)- 1-methylpiperidin-4-yl]-2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (3.40 g, 34%yield) as a brown semi-solid. 25 LCMS (ESI-MS) m / z = 808.2 [M+H]+. Rt: 0.846 min (Method 2). And isomer 2 / (RT=11.80 min) rac-N-[(3S,4R)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-1-methylpiperidin-4-yl]-2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (3.80 g, 38%yield) as a brown semi- solid. LCMS (ESI-MS) m / z = 808.2 [M+H]+. Rt: 0.840 min (Method 2).2.22. Intermediate 22: tert-butyl N-{3-hydroxy-5-[imino(methyl)oxo-lambda6-sulfanyl]phenyl}-N- (prop-2-yn-1-yl)carbamate2.22.1. Step 1: (3-amino-5-methoxyphenyl)(imino)(methyl)-l6-sulfanone

[0322] A solution of imino(3-methoxy-5-nitrophenyl)(methyl)-l6-sulfanone (800 mg, 3.48 mmol, 1.00 equiv),Fe (1.16 g, 20.850 mmol, 6.00 equiv) and NH4Cl (558 mg, 10.4 mmol, 3.00 equiv) in EtOH (9 mL) and H2O (3 mL) was stirred for 2 hours at 70 °C. After the reaction was completed, the reaction mixture was diluted with H2O (40 ml) and extracted with ethyl acetate (2 x 60 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (Column: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 50 min; Wave Length: 254 nm; 90% - 93% B fractions were collected) to provide the desired product (3-amino-5-methoxyphenyl)(imino)(methyl)-l6-sulfanone (620 mg, 75% yield) as a yellow solid.

[0323] LCMS(ESI-MS) m / z = 200.9 [M+H]+. Rt: 0.384 min (Method 34). 2.22.2. Step 2: imino(3-methoxy-5-{[3-(trimethylsilyl)prop-2-yn-1-yl]amino}phenyl)methyl- lambda6-sulfanone

[0324] To a mixture of (3-amino-5-methoxyphenyl)(imino)methyl-lambda6-sulfanone (600 mg, 3.00 mmol, 1.0 equiv) and 4A molecular sieve (1.2 g) in DCM (12 mL) were added 3-(trimethylsilyl)prop-2- ynal (360 mg, 2.85 mmol, 0.95 equiv) and HOAc (270 mg, 4.49 mmol, 1.5 equiv) at 0 °C under nitrogen. The reaction mixture was stirred for 1 h at room temperature. Then the mixture was cooled to 0 °C and STAB (2.54 g, 12.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 1 h at room temperature and filtered. The solid was washed with EA (3 x 30 mL). The filtrate was washed with saturated aq. NaHCO3 (20 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 40 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 35 mL / min; Gradient: 0% B to 35% B in 3 min, 35% B to 100% B in 25 min; Wave Length: 254 nm; 80% B fractions were collected) to provide the desired product imino(3-methoxy-5-{[3- (trimethylsilyl)prop-2-yn-1-yl]amino}phenyl)methyl-lambda6-sulfanone (610 mg, 59% yield) as a yellow oil.

[0325] LCMS(ESI-MS) m / z = 311.1 [M+H]+. Rt: 0.777 min (Method 6). 2.22.3. Step 3: [3-hydroxy-5-(prop-2-yn-1-ylamino)phenyl](imino)methyl-lambda6-sulfanone

[0326] To a solution of imino(3-methoxy-5-{[3-(trimethylsilyl)prop-2-yn-1-yl]amino}phenyl)methyl- lambda6-sulfanone (610 mg, 1.97 mmol, 1.0 equiv) in DCM (10 mL) was added Boron tribromide (19.7 5 mL, 19.7 mmol, 10 equiv, 1M solution in methylene chloride) dropwise at 0 °C under nitrogen. The reaction mixture was stirred for 40 h at room temperature. Then the reaction mixture was poured into saturated aq. NaHCO3 (50 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (7 x 40 mL) and the organic layers were combined, washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse 10 phase purification (C18 spherical, 20 - 30 um, 100 A, 80 g; Mobile Phase A: water (0.05% NH4HCO3), Mobile Phase B: MeCN; Flow rate: 50 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 95% B in 30 min; Detector: UV 254 & 210 nm; 20% B fractions were collected) to provide the desired product [3- hydroxy-5-(prop-2-yn-1-ylamino)phenyl](imino)methyl-lambda6-sulfanone (260 mg, 53% yield) as a brown solid. 15

[0327] LCMS(ESI-MS) m / z = 225.2 [M+H]+. Rt: 0.450 min (Method 4). 2.22.4. Step 4: product 3-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-5-[imino(methyl)oxo- lambda6-sulfanyl]phenyl tert-butyl carbonate

[0328] A mixture of [3-hydroxy-5-(prop-2-yn-1-ylamino)phenyl](imino)methyl-lambda6-sulfanone (210 mg, 0.936 mmol, 1.0 equiv) in di-tert-butyl dicarbonate (2 mL) was stirred for 16 h at 80 °C. The reaction mixture 20 was cooled to room temperature and purified by TLC directly (PE / EA = 1 / 1; Rf = 0.2 - 0.6, detection: UV) to provide the crude product 3-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-5-[imino(methyl)oxo-lambda6- sulfanyl]phenyl tert-butyl carbonate (375 mg, 76% yield) as a yellow solid.

[0329] LCMS(ESI-MS) m / z = 425.2 [M+H]+. Rt: 0.768 min (Method 34). 2.22.5. Step 5: tert-butyl N-{3-hydroxy-5-[imino(methyl)oxo-lambda6-sulfanyl]phenyl}-N- 25 (prop-2-yn-1-yl)carbamate

[0330] To a solution of 3-[(tert-butoxycarbonyl)(prop-2-yn-1-yl)amino]-5-[imino(methyl)oxo-lambda6- sulfanyl]phenyl tert-butyl carbonate (370 mg, 0.872 mmol, 1.0 equiv) in methanol (6 mL) was added K2CO3(602 mg, 4.36 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred for 16 h at room temperature and filtered. The solid was washed with DCM (3 x 20 mL). The filtrate was 30 concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (DCM / MeOH =10 / 1; Rf = 0.6; detection: UV) to provide the desired product tert-butyl N-{3-hydroxy-5- [imino(methyl)oxo-lambda6-sulfanyl]phenyl}-N-(prop-2-yn-1-yl)carbamate (140 mg, 47% yield) as a yellow solid.

[0331] LCMS(ESI-MS) m / z = 225.2 [M+H-Boc]+. Rt: 0.709 min (Method 4).2.23. Intermediate Int-23: 3-({3-[4-({2-[(dimethylamino)methyl]-4-[2-(2- hydroxyethoxy)ethoxy]butyl}amino)-1-(2,2,2-trifluoroethyl)indol-2-yl]prop-2-yn-1-yl}amino)phenol To-4-[2-(2- 5- (2,2,2-trifluoroethyl)indol-2-yl]prop-2-yn-1-yl}-N-(3- hydroxyphenyl)carbamate (40.0 mg, 0.059 mmol, 1.0 equiv) in 1,4-dioxane (1.2 mL) was added hydrogen chloride (2.4 mL, 4.0 M in 1,4-dioxane) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature andquenched withsaturated potassium carbonate aqueous (10 mL). The resulting mixture was extractedwith EtOAc (3 x 10 mL)and theorganic layers were combined, washed with brine10 (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to57 % B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.5) to provide 3-({3-[4-({2-[(dimethylamino)methyl]-4-[2-(2-hydroxyethoxy)ethoxy]butyl}amino)-1- 15 (2,2,2-trifluoroethyl)indol-2-yl]prop-2-yn-1-yl}amino)phenol (5.2 mg, 15%) as a brown solid.

[0333] LCMS(ESI-MS) m / z =577.3 [M+H]+. 2.24. Intermediate Int-24:3332.24.1. Step 1: 3-((3(4-((3-(2(2-( -hoxyethoethoethyl)iperdi4-yl)amin -1- 20 (2,2,2trifluoroethyl)-1H-indol-2-yl)prop- -yn-1-yl)amino)p enol

[0334] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphen l)amino)p 1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1- carboxylate (70 mg, 0.090 mmol, 1.0 equiv) in DCM (1.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred for 1 h at room temperature and quenched with saturated aqueous 25 potassium carbonate (10 mL). The resulting mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product 3-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidin-4-yl)amino)- 1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenol (45 mg, crude product) as a light yellow seme-solid. LCMS(ESI-MS) m / z = 575.4 [M+H]+.Rt: 0.595 min (Method ).2.24.2. Step 2: 3-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4- yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenol

[0335] To a solution of 3-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidin-4-yl)amino)-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenol (40.0 mg, 0.070 mmol, 1.0 equiv) in MeOH (2 5 mL) was added Formaldehyde solution (5.65 mg, 0.070 mmol, 1.0 equiv, 37% wt in H2O), acetic acid (8.36 mg, 0.140 mmol, 2.0 equiv) and sodium cyanoborohydride (6.56 mg, 0.105 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h at room temperature and quenched with H2O. The resulting mixture was extracted with of DCM (3 x 15 mL), the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 10 product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 37% B to 52% B in 8min; Wave Length: 254nm / 220nm nm; RT1(min): 5.93) to provide the desired product 3-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin- 4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenol (6.5 mg, 15%yield) as an 15 light yellow solid. LCMS(ESI-MS) m / z = 589.3 [M+H]+. Rt: 1.344 min (Method 12).Example 3. Preparation of illustrative compounds of the invention

[0336] Stereocentres marked with * are arbitrarily assigned as absolute stereochemistry was not determined. For example that the compound is either5 3.1. Compound 1: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, and Compound 2: 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne 103.1.1. Step 1: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert-butyldimethylsilyl)oxy)phenyl) amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0337] A mixture of Int-6 (400 mg, 0.389 mmol, 1.0 equiv) in di-tert-butyl dicarbonate (20 mL) was stirred 15 overnight at 40 °C. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 200 mL), and the organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% NH4HCO3), (100%), the fraction was concentrated under reduced pressure to afford the title compound (400 mg, 82%) as a yellow 20 solid.

[0338] LCMS(ESI-MS) m / z = 1127.6 [M+H]+

[0339] Rt 1.222 min / 1.310 min; Method 23.1.2. Step 2: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine- 1-carboxylate

[0340] To a mixture of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert- 5 butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3- (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (400 mg, 0.355 mmol, 1.0 equiv) in THF (4 mL) was added tetrabutylammonium fluoride (0.7 mL, 0.710 mmol, 1 M in THF) stirred at 0 °C. The reaction mixture was stirred for 1 h and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase:100% EtOAc; Rf = 0.4; 10 detection: UV) to afford the title compound (230 mg, 75%) as a yellow solid.

[0341] LCMS(ESI-MS) m / z = 775.4 [M+H]+

[0342] Rt 0.938 min; Method 1 3.1.3. Step 3: ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4- 15 yne-2,18-dicarboxylate

[0343] To a stirred solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1- yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl) piperidine-1-carboxylate (200 mg, 0.258 mmol, 1.0 equiv) and triphenylphosphine (102 mg, 0.387 mmol, 1.5 equiv) in toluene (35 mL) and THF (8 mL) was added diisopropyl azodicarboxylate (78.3 mg, 0.387 20 mmol, 1.5 equiv, in 5 mL toluene) dropwise over 10 min under nitrogen at RT. The reaction mixture was stirred for 1 h at 90 °C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:1; Rf = 0.4; detection: UV) to afford the 25 title compound (180 mg, 82%) as a yellow solid

[0344] LCMS(ESI-MS) m / z = 757.4 [M+H]+

[0345] Rt 1.075 and 1.105 min; Method 6 3.1.4. Step 4: Compound 1: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne30

[0346] To a solution of ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-2,18- dicarboxylate (180 mg, 0.020 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (2 mL) stirred at RT. The reaction mixture was stirred for 1 h at RT and quenched with saturated aqueous potassium carbonate (10 mL). The resulting mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, 35 washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The residue was purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN;Flow rate: 60 mL / min; Gradient: 17% B to 47% B in 7 min; Wave Length: 254nm / 220nm; RT1(min): 6.27) to afford the title compound (1.6 mg, 16%) as an off-white solid.

[0347] 1H NMR (400 MHz, DMSO) δ 7.27 – 7.05 (m, 1H), 7.04 – 6.93 (m, 2H), 6.76 – 6.64 (m, 1H), 6.36 – 6.12 (m, 5H), 5.49 – 5.35 (m, 1H), 5.09 – 4.72 (m, 2H), 4.29 – 4.16 (m, 2H), 4.12 – 3.93 (m, 2H), 3.78 – 3.25 (m, 8H), 3.18 – 2.63 (m, 5H), 2.10 – 0.98 (m, 6H).

[0348] LCMS(ESI-MS) m / z = 557.4 [M+H]+

[0349] Rt 0.723 min / 0.740 min; Method 7 3.1.5. Step 5: Compound 2: 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0350] To a solution of 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (120 mg, 0.216 mmol, 1 equiv) in MeOH (6 mL) was added formaldehyde solution (6.47 mg, 0.216 mmol, 1.0 equiv, 37% wt in H2O), AcOH (25.9 mg, 0.432 mmol, 2.0 equiv) and sodium cyanoborohydride (CAS# 25895-60-7; 20.3 mg, 0.324 mmol, 1.5 equiv). The reaction mixture was stirred for 20 min at RT and quenched with H2O and the resulting mixture was extracted with DCM (3 x 40 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The residue was purified by preparative HPLC (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to70 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.93) to afford the title compound (30.0 mg, 24%) as an off-white solid.

[0351] LCMS(ESI-MS) m / z = 571.5 [M+H]+

[0352] Rt 1.310 min / 1.352 min; Method 9

[0353] 1H NMR (400 MHz, DMSO) δ 7.27 – 7.04 (m, 1H), 7.02 – 6.93 (m, 2H), 6.73 – 6.63 (m, 1H), 6.36 – 6.10 (m, 5H), 5.35 (m, 1H), 5.07 – 4.70 (m, 2H), 4.27 – 4.13 (m, 2H), 4.12 – 3.93 (m, 2H), 3.83 – 3.19 (m, 8H), 3.05 – 2.50 (m, 3H), 2.23 – 2.10 (m, 3H), 2.05 – 0.95 (m, 7H). 3.2. Alternative route to compounds 1 and 2:3.2.1. Step 1; tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine- 1-carboxylate

[0354] To a solution of Int-7 (245 mg, 0.27 mmol, 1.0 eq.) in THF (2.8 mL) was added a solution of TBAF (1M in THF; 1.37 mL, 1.38 mmol, 5.0 eq.). Reaction mixture was stirred 1h at RT. Water and DCM are added and the layers separated. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to afford the title compound used in the next step without any further purification.

[0355] LCMS(ESI-MS) m / z = 775.6 [M+H]+

[0356] Rt 2.05 min / 2.06 min; Method 25 3.2.2. Step 2: ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(34),6,8(13),9,11,30,32-heptaen-4-yne- 2,18-dicarboxylate

[0357] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1- carboxylate (120 mg, 0.15 mmol, 1.0 eq.) in THF (31 mL) was added PPh3 (61 mg, 0.23 mmol, 1.5 eq.) and DEAD (40% wt. in toluene; 101 mg, 0.23 mmol, 1.5 eq). Reaction mixture was stirred 3h at RT. Reaction mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting EtOAc / cyclohexane from 0 / 100 to 60 / 40) to afford the title compound as mixture of diastereomers (61 / 39).

[0358] Rt 2.22 min / 2.24 min; Method 25 3.2.3. Step 3: Compound 1: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0359] To a solution of ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(34),6,8(13),9,11,30,32-heptaen-4-yne-2,18- dicarboxylate (35 mg, 0.045 mmol, 1.0 eq.) in DCM (1 mL ) was added TFA (1 mL, 4.52 mmol, 100 eq). Reaction mixture was stirred 30 min at RT. Reaction mixture was added dropwise to 10 ml of saturated aq. K2CO3 solution. Resulting mixture was extracted with 3x5ml of DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound as mixture of diastereomers. Crude product was used in the next step without any further purification.

[0360] LCMS(ESI-MS) m / z = 557.5 [M+H]+

[0361] Rt 1.67 min; Method 25 3.2.4. Step 4: Compound 2:18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0362] To a solution of 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(34),6,8(13),9,11,30,32-heptaen-4-yne (25 mg, 0.045 mmol, 1.0 eq.) in MeOH (0.9 mL) were added formaldehyde (37% wt. in water ; 4 mg, 0.049mmol, 1.1 eq.), AcOH (6 mg, 0.090 mmol, 2.0 eq.) and sodium cyanoborohydride (CAS# 25895-60-7; 4.2 mg, 0.067 mmol, 1.5 eq). Reaction mixture was stirred 30 min at RT. Reaction mixture was quenched by addition of sodium bicarbonate solution. Resulting mixture was extracted with 3x5ml of DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue purified 5 preparative HPLC (gradient of [0.1% formic acid in MeCN] in [0.1% formic acid in water]) to afford the title compound as mixture of diastereomers (75 / 25).

[0363] LCMS(ESI-MS) m / z = 571.5 [M+H]+

[0364] Rt 1.67 min / 1.74 min; Method 25

[0365] 1H NMR (400 MHz, DMSO) δ 7.28 – 7.03 (m, 1H), 7.03 – 6.93 (m, 2H), 6.73 – 6.63 (m, 1H), 6.36 10 – 6.10 (m, 5H), 5.41 – 5.30 (m, 1H), 5.06 – 4.73 (m, 2H), 4.22 – 4.16 (m, 2H), 4.10 – 3.96 (m, 2H), 3.76 – 3.25 (m, 8H), 3.06 – 2.55 (m, 3H), 2.21 – 2.13 (m, 3H), 2.06 – 0.97 (m, 7H). - 15 -

[0366] Int-6 (1.50 g, 1.460 mmol, 1.0 equiv) was separated by prep-Achiral SFC-HPLC column (GreenSep 20 Basic 3*15 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA (1%-2M-NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 18% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MEOH; Injection Volume: 0.5 mL) to provide

[0367] Int-6A with Rt 5.34 min, LCMS(ESI-MS) m / z = 1049.6 [M+Na]+,Rt 1.110 min; Method 2; and Int-6B with Rt 6.26 min, LCMS(ESI-MS) m / z = 1027.6 [M+H]+, Rt 1.174 min; Method 2.3.4. Compounds 3A: (15S*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, and Compounds 3B: (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 5 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne10

[0368] Neat Int 6-A rac tert-butyl (3R*,4R*)-4-((2-(3-((3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3- (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (400 mg, 0.389 mmol, 1.0 equiv) in di-tert-butyl carbonate ((CAS# 24424-99-5; 5 mL, 23.0 mmol, 59 equiv) was stirred overnight at 40°C. Water and EtOAc were added and the layers separated. The combined organic layers 15 were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was first purified by column chromatography on silica gel (eluting with EtOAc / petroleum ether (1 / 1)) then purified by C18 column with CH3CN / Water (0.05% FA) to afford the title compound.

[0369] LCMS(ESI-MS) m / z = 1127.5 [M+Na]+

[0370] Rt 1.226 min; Method 2 20 3.4.2. Step 2: (rac) tert-butyl (3R*,4R*)-4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl) amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate

[0371] To a solution of (rac) tert-butyl (3R*,4R*)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3- 25 (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (200 mg, 0.177 mmol, 1.0 equiv) in THF (2 mL) was added tetrabutylammonium fluoride (0.35mL, 0.354 mmol, 1M inTHF) at 0 °C. The reaction mixture was stirred for 1 h at RT and concentrated to dryness The residue was purified by TLC (Mobile phase: 100% EtOAc; Rf = 0.4; detection: UV) to afford the title compound.

[0372] LCMS(ESI-MS) m / z = 775.4 [M+H]+

[0373] Rt 0.799 min; Method 1 5 3.4.3. Step 3: (rac) ditert-butyl (15R*,20R*)-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-2,18-dicarboxylate

[0374] A mixture of (rac) tert-butyl (3R*,4R*)-4-((2-(3-((tert-butoxycarbonyl)(3- hydroxyphenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2- 10 hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate (100 mg, 0.129 mmol, 1.0 equiv) and triphenylphosphine (50.8 mg, 0.194 mmol, 1.5 equiv) in THF (3.6 mL) and toluene (14 mL) was added diisopropyl azodicarboxylate (39.1 mg, 0.194 mmol, 1.5 equiv, in 4 mL toluene) dropwise over 10 min under nitrogen at RT. The reaction mixture was stirred for 1 h at 90 °C under nitrogen. Water and EtOAc were added, and the layers separated. The combined organic layers were washed with brine, dried over 15 Na2SO4, filtered and concentrated to dryness. The residue was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:1; Rf = 0.4; detection: UV) to afford the title compound.

[0375] LCMS(ESI-MS) m / z = 757.4 [M+H]+

[0376] Rt 0.855 min; Method 1 3.4.4. Step 4: (rac) (15R*,20R*)-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 20 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0377] A mixture of (rac) ditert-butyl (15R*,20R*)-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-2,18- dicarboxylate (100 mg, 0.132 mmol, 1.0 equiv) in DCM (0.9 mL) and TFA (0.3 mL) was stirred for 1 h. The reaction mixture was quenched with saturated aqueous potassium carbonate (40 mL). The resulting 25 mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to afford the title compound.

[0378] LCMS(ESI-MS) m / z = 557.4 [M+H]+

[0379] Rt 0.705 min; Method 6 3.4.5. Step 5: Compound 3T (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-30 trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0380] A mixture of (rac) (15R*,20R*)-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (100 mg, 0.180 mmol, 1.0 equiv) in MeOH (3.5 mL) was added formaldehyde solution (11.7 mg, 0.144 mmol, 35 0.8 equiv, 37%wt in H2O), AcOH (21.6 mg, 0.194 mmol, 1.5 equiv) and sodium cyanoborohydride (CAS# 25895-60-7; 16.9 mg, 0.270 mmol, 1.5 equiv) was added and stirred for 1 h at RT. Water and EtOAc wereadded and the layers separated. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford the title compound.

[0381] LCMS(ESI-MS) m / z = 571.4 [M+H]+

[0382] Rt 1.171 min; Method 8 3.4.6. Step 6: Enantiomer 3A (15S*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29- trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34), 31-heptaen-4-yne, and Enantiomer 3B (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0383] (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapenta cyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (45.0 mg, 0.070 mmol, 1 equiv) was separated by prep-Chiral-HPLC column (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 35; Wave Length: 254 / 220nm; Sample Solvent: EtOH-HPLC; Injection Volume: 0.4 mL) to provide enantiomer 3A (Rt 5.705 min) (8.6 mg, 21% ) as a light yellow solid and enantiomer 3B (Rt 9.702 min) (7.6 mg, 19%) as an off - white solid).

[0384] Enantiomer 3A:

[0385] 1H NMR (400 MHz, DMSO) δ 7.05 (s, 1H), 7.02 – 6.93 (m, 2H), 6.66 (d, 1H), 6.35-6.32 (m, 1H), 6.30 – 6.24 (m, 1H), 6.24 – 6.15 (m, 2H), 6.13 (d, 1H), 5.37 (d, 1H), 5.09 – 4.82 (m, 2H), 4.20 (d, 2H), 4.12 – 4.01 (m, 2H), 3.78 – 3.68 (m, 2H), 3.61 – 3.46 (m, 3H), 3.46 – 3.35 (m, 3H), 2.99 – 2.74 (m, 3H), 2.18 (s, 3H), 2.03 – 1.93 (m, 2H), 1.93 – 1.76 (m, 2H), 1.69 – 1.59 (m, 1H), 1.50 – 1.37 (m, 1H), 1.09 – 0.98 (m, 1H).

[0386] LCMS(ESI-MS) m / z = 571.2 [M+H]+

[0387] Rt 0.775 min; Method 11

[0388] Enantiomer 3B:

[0389] 1H NMR (400 MHz, DMSO) δ 7.05 (s, 1H), 7.02 – 6.93 (m, 2H), 6.66 (d, 1H), 6.36 – 6.30 (m, 1H), 6.30 – 6.24 (m, 1H), 6.24 – 6.15 (m, 2H), 6.13 (d, 1H), 5.37 (d, 1H), 5.09 – 4.85 (m, 2H), 4.20 (d, 2H), 4.12 – 4.01 (m, 2H), 3.78 – 3.68 (m, 2H), 3.61 – 3.46 (m, 3H), 3.45 – 3.36 (m, 3H), 2.95 – 2.72 (m, 3H), 2.18 (s, 3H), 2.05 – 1.93 (m, 2H), 1.91 – 1.76 (m, 2H), 1.68 – 1.58 (m, 1H), 1.50 – 1.37 (m, 1H), 1.09 – 0.98 (m, 1H).

[0390] LCMS(ESI-MS) m / z = 571.2 [M+H]+

[0391] Rt 0.783 min; Method 113.5. Compound 3C: (15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, and Compound 3D: (15S*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 5 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0392] A similar approach to the one used for Compounds 3A and 3B was followed towards Compounds 3C and 3D using Int-6B.

[0393] Compound 3CC (50.0 mg, 0.088 mmol, 1.0 equiv) was separated by prep-Chiral-HPLC (Column: 10 CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220nm nm; Sample Solvent: EtOH-HPLC; Injection Volume: 0.6 mL) to afford:

[0394] Compound 3C

[0395] (Rt 8.083 min) (15.8 mg, 31%) as an off-white solid. 15

[0396] 1H NMR (400 MHz, DMSO) δ 7.24 (s, 1H), 6.99 (q, 2H), 6.70 (d, 1H), 6.33 – 6.25 (m, 2H), 6.25 – 6.12 (m, 3H), 5.33 (d, 1H), 5.08 – 4.93 (m, 1H), 4.87 – 4.71 (m, 1H), 4.25 – 4.13 (m, 2H), 4.04 – 3.93 (m, 2H), 3.71 – 3.50 (m, 3H), 3.50 – 3.25 (m, 5H), 3.05 – 2.94 (m, 1H), 2.78 – 2.71 (m, 1H), 2.62 – 2.54 (m, 1H), 2.14 (s, 3H), 2.05 – 1.93 (m, 2H), 1.92 – 1.68 (m, 3H), 1.64 – 1.46 (m, 2H).

[0397] LCMS(ESI-MS) m / z = 571.2 [M+H]+20

[0398] Rt 0.750 min; Method 11

[0399] Compound 3D

[0400] (Rt 11.573 min) (24.4 mg, 32%yield) as a light-yellow solid.

[0401] 1H NMR (400 MHz, DMSO) δ 7.24 (s, 1H), 6.99 (q, 2H), 6.70 (d, 1H), 6.33 – 6.25 (m, 2H), 6.25 – 6.12 (m, 3H), 5.33 (d, 1H), 5.08 – 4.93 (m, 1H), 4.86 – 4.71 (m, 1H), 4.22 – 4.16 (m, 2H), 4.03 – 3.93 25 (m, 2H), 3.71 – 3.50 (m, 3H), 3.50 – 3.24 (m, 5H), 3.05 – 2.94 (m, 1H), 2.78 – 2.71 (m, 1H), 2.61 – 2.54 (m, 1H), 2.14 (s, 3H), 2.04 – 1.97 (m, 2H), 1.90 – 1.69 (m, 3H), 1.64 – 1.48 (m, 2H).

[0402] LCMS(ESI-MS) m / z = 571.2 [M+H]+

[0403] Rt 0.756 min; Method 113.6. Compound 4: N,N-dimethyl-1-[31-(2,2,2-trifluoroethyl)-19,22,25-trioxa-2,14,31- triazatetracyclo[24.3.1.16,9.08,13]hentriaconta-1(29),6,8,10,12,26(30),27-heptaen-4-yn-16- yl]methanamine5 3.6.1. Step 1: 13-((dimethylamino)methyl)-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- silatetradecane-14-nitrile

[0404] To a solution of 3-(dimethylamino)propanenitrile (CAS# 1738-25-6; 1.00 g, 10.2 mmol, 1.0 equiv) in THF (30 mL) was added LDA (15.3 mL, 15.3 mmol, 1.5 equiv, 1 M in THF) at -78 °C under nitrogen. After stirred for 1 h at -78 °C, 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane (5.06 g, 10 11.2 mmol, 1.1 equiv) was added. The reaction mixture was stirred for 1 h at RT and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% FA) to provide the title compound (3.60 g, 67%) as a brown oil. 15

[0405] LCMS(ESI-MS) m / z = 469.3 [M+H]+

[0406] Rt 0.800 min; Method 63.6.2. Step 2: 2-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-N1,N1- dimethylpropane-1,3-diamine

[0407] To a solution of 13-((dimethylamino)methyl)-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- silatetradecane-14-nitrile (1.60 g, 3.41 mmol, 1.0 equiv) in THF (80 mL) was added Lithium aluminum 5 hydride (518 mg, 13.6 mmol, 4.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 2 h at RT and quenched with ice water (300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL), and the organic layers were combined, washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% TFA) to provide the title compound (700 mg, crude) as a light- 10 yellow solid.

[0408] LCMS(ESI-MS) m / z = 473.3 [M+H]+

[0409] Rt 0.663 min; Method 6 3.6.3. Step 3: tert-butyl (3-((tert-butyldimethylsilyl)oxy)phenyl)(3-(4-((13- ((dimethylamino)methyl)-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-silatetradecan-14-yl)amino)-1- 15 (2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate

[0410] To a solution of 2-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-N1,N1- dimethylpropane-1,3-diamine (400 mg, 0.846 mmol, 1.0 equiv) in 1,4-dioxane (8 mL) was added Int-4 (540 mg, 0.847 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium (77.5 mg, 0.085 mmol, 0.1 equiv), 5-[Di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (CAS# 1239478-87-5; 56.1 mg, 20 0.085 mmol, 0.1 equiv) and sodium benzenolate (393 mg, 3.39 mmol, 4.0 equiv) stirred under nitrogen at RT. The reaction mixture was stirred for 1 h at 70 °C and quenched with water (80 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:4; 25 Rf = 0; detection: UV) to afford the title compound (510 mg, crude) as a brown solid.

[0411] LCMS(ESI-MS) m / z =1029.6 [M+H]+

[0412] Rt 1.150 min; Method 6 3.6.4. Step 4: tert-butyl (3-(4-((2-((dimethylamino)methyl)-4-(2-(2- hydroxyethoxy)ethoxy)butyl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)(3- 30 hydroxyphenyl)carbamate

[0413] To a solution of tert-butyl (3-((tert-butyldimethylsilyl)oxy)phenyl)(3-(4-((13- ((dimethylamino)methyl)-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-silatetradecan-14-yl)amino)-1- (2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate (510 mg, 0.495 mmol, 1.0 equiv, major) in THF (10 mL) was added Tetra-n-butylammonium fluoride (1 mL, 1.00 mmol, 2.0 equiv, 1.0 M in THF) 35 stirred at 0 °C. The reaction mixture was stirred for 2 h at RT and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:7; Rf = 0.4; detection: UV) to afford the title compound (190 mg, 51%) as a yellow solid.

[0414] LCMS(ESI-MS) m / z =677.4 [M+H]+

[0415] Rt 0.703 min; Method 6 5 3.6.5. Step 5: tert-butyl 16-[(dimethylamino)methyl]-31-(2,2,2-trifluoroethyl)-19,22,25-trioxa- 2,14,31-triazatetracyclo[24.3.1.16,9.08,13]hentriaconta-1(29),6,8,10,12,26(30),27-heptaen-4-yne-2- carboxylate

[0416] To a solution of tert-butyl (3-(4-((2-((dimethylamino)methyl)-4-(2-(2- hydroxyethoxy)ethoxy)butyl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)(3- 10 hydroxyphenyl)carbamate (170 mg, 0.251 mmol, 1.0 equiv), triphenylphosphine (98.8 mg, 0.377 mmol, 1.5 equiv) in THF (6.8 mL) and Toluene (30 mL) was added diisopropyl azodicarboxylate (76.2 mg, 0.377 mmol, 1.5 equiv, in 4 mL toluene) stirred under nitrogen at RT. The reaction mixture was stirred for 3 h at RT and quenched with water (80 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL), and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, 15 filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:5; Rf = 0.3; detection: UV) to afford the title compound (90 mg, crude) as a yellow solid.

[0417] LCMS(ESI-MS) m / z =659.4 [M+H]+

[0418] Rt 0.782 min; Method 6 20 3.6.6. Step 6: Compound 4 - N,N-dimethyl-1-[31-(2,2,2-trifluoroethyl)-19,22,25-trioxa- 2,14,31-triazatetracyclo[24.3.1.16,9.08,13]hentriaconta-1(29),6,8,10,12,26(30),27-heptaen-4-yn-16- yl]methanamine

[0419] To a solution of tert-butyl 16-[(dimethylamino)methyl]-31-(2,2,2-trifluoroethyl)-19,22,25-trioxa- 2,14,31-triazatetracyclo[24.3.1.16,9.08,13]hentriaconta-1(29),6,8,10,12,26(30),27-heptaen-4-yne-2- 25 carboxylate (80.0 mg, 0.121 mmol, 1.0 equiv) in dioxane (1 mL) was added hydrogen chloride (2 mL, 4 M in 1,4-dioxane) stirred at RT. The reaction mixture was stirred for 1 h at RT. The reaction mixture was quenched with saturated aqueous potassium carbonate (10 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL), and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The 30 crude product was purified by preparative HPLC (Column: Xselect CSH Prep C18 Column, 30*250 mm, 10μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 21% B to51 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.5) to afford the title compound (5.4 mg, 7%) as an off-white solid.

[0420] 1H NMR (400 MHz, DMSO) δ 7.06 – 6.91 (m, 3H), 6.70 (d, J = 8.2 Hz, 1H), 6.37 (t, J = 2.2 Hz, 35 1H), 6.31 – 6.24 (m, 1H), 6.24 – 6.13 (m, 3H), 5.59 (s, 1H), 5.05 – 4.88 (m, 2H), 4.21 (d, J = 5.9 Hz, 2H), 4.12 – 4.06 (m, 2H), 3.76 – 3.70 (m, 2H), 3.59 – 3.32 (m, 7H), 2.89 – 2.79 (m, 1H), 2.20 – 2.11 (m, 7H), 2.09 – 2.00 (m, 1H), 1.98 – 1.85 (m, 1H), 1.71 – 1.59 (m, 1H), 1.52 – 1.39 (m, 1H).

[0421] LCMS(ESI-MS) m / z =559.3 [M+H]+.

[0422] Rt 0.741 min; Method 7 3.7. Compound 5 - 33-methoxy-18-methyl-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29- trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 5 1(33),6,8,10,12,30(34),31-heptaen-4-yne3.7.1. Step 1: 2-(2-fluoro-4-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0423] To a solution of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (CAS# 1352244-77-9; 15.0 g, 60.0 mmol, 1.0 equiv) in 1,4-dioxane (450 mL) was added Pd(dppf)Cl2.CH2Cl2 (2.45 g, 3.00 mmol, 0.050 equiv), 10 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (19.8 g, 78.0 mmol, 1.3 equiv) and AcOK (17.7 g, 180 mmol, 3.0 equiv) stirred under nitrogen at RT. The reaction mixture was stirred overnight at 90 °C and quenched with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL), and the organic layers were combined, washed with brine (2 x 500 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (30.0 g, crude) as a black solid. No purification and H NMR.

[0424] GCMS m / z = 297.1 [M] 3.7.2. Step 2: 2-fluoro-4-methoxy-5-nitrophenol 5

[0425] To a solution of 2-(2-fluoro-4-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.0 g, 101 mmol, 1.0 equiv) in THF (945 mL) was added AcOH (42 mL, 0.001 mmol, 0.01 equiv), then hydrogen peroxide (35% in water) (78 mL, 0.002 mmol, 0.02 equiv) was added at 0 °C. The reaction mixture was stirred for 3 h at RT and quenched with saturated aqueous NaHSO3 (2 L). The resulting mixture was extracted with EtOAc (3 x 2 L), and the organic layers were combined, washed with brine (2 10 x 2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 4) to give the title compound (5.67 g, 29% yield, 97% purity) as a yellow solid.

[0426] LCMS(ESI-MS) m / z = 186.0 [M-H]-

[0427] Rt 0.620 min; Method 5 15 3.7.3. Step 3: 4-methoxy-2-(methylsulfonyl)-5-nitrophenol

[0428] To a solution of 2-fluoro-4-methoxy-5-nitrophenol (5.60 g, 29.9 mmol, 1.0 equiv) in DMSO (60 mL) was added sodium methanesulfinate (3.36 g, 32.9 mmol, 1.1 equiv) stirred at RT. The reaction mixture was stirred overnight at 100 °C and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), and the organic layers were combined, washed with brine (2 x 200 mL), dried 20 over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (6.8 g, crude) as a yellow solid. LCMS(ESI-MS) m / z = 245.9 [M-H]-

[0429] (Rt 0.596 min; Method 5) 3.7.4. Step 4: 5-amino-4-methoxy-2-(methylsulfonyl)phenol

[0430] To a solution of 4-methoxy-2-(methylsulfonyl)-5-nitrophenol (6.30 g, 25.5 mmol, 1.0 equiv) in 25 EtOH (60 mL) was added 10% palladium on activated carbon (2.71 g) stirred under hydrogen at RT. The reaction mixture was stirred for 9 h at RT. The mixture was filtered through a celite pad and washed with EtOAc (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.30 g, crude) as a black solid.

[0431] LCMS(ESI-MS) m / z =218.0 [M+H]+30

[0432] (Rt 0.462 min; Method 5) 3.7.5. Step 5: 2-methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)aniline

[0433] To a solution of 5-amino-2-methanesulfonyl-4-methoxyphenol (3.50 g, 16.1 mmol, 1.0 equiv) in DMF (40 mL, 0.014 mmol) was added chlorotris(propan-2-yl)silane (4.04 g, 20.9 mmol, 1.3 equiv) and imidazole (2.19 g, 32.2 mmol, 2.0 equiv) stirred at RT. The reaction mixture was stirred for overnight at 35 RT and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), andthe organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (6.9 g, crude) as a brown solid.

[0434] LCMS(ESI-MS) m / z =374.1 [M+H]+

[0435] (Rt 1.004 min; Method 5) 5 3.7.6. Step 6: tert-butyl (2-methoxy-4-(methylsulfonyl)-5- ((triisopropylsilyl)oxy)phenyl)carbamate

[0436] A solution of 2-methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)aniline (6.90 g, 18.5 mmol, 1.0 equiv) in di-tert-butyl dicarbonate (30 mL, 0.119 mmol) was stirred at RT. The reaction mixture was stirred for overnight at 90 °C. The resulting mixture was purified by C18 column with CH3CN / Water 10 (0.05% FA), the fraction (100%) was concentrated under reduced pressure to give the title compound (5.20 g, 59% yield, 95% purity) as a brown semi-solid.

[0437] LCMS(ESI-MS) m / z =537.2 [M+Na+ACN]+

[0438] (Rt 1.249 min; Method 5) 3.7.7. Step 7: tert-butyl (2-methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)phenyl)(prop- 15 2-yn-1-yl)carbamate

[0439] To a solution of tert-butyl (2-methoxy-4-(methylsulfonyl)-5- ((triisopropylsilyl)oxy)phenyl)carbamate (2.00 g, 4.22 mmol, 1.0 equiv) in DMF (40 mL, 0.062 mmol) was added sodium hydride (202 mg, 5.07 mmol, 1.2 equiv, 60% in mineral oil) stirred at 0 °C. The reaction mixture was stirred for 0.5 h at RT, then 3-bromoprop-1-yne (552 mg, 4.64 mmol, 1.1 equiv) was added at 20 RT. The reaction mixture was stirred for 1 h at RT and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 6) to give the title compound (930 mg, crude) as a light-yellow solid. 25

[0440] LCMS(ESI-MS) m / z =534.2 [M+Na]+

[0441] (Rt 1.150 min; Method 5) 3.7.8. Step 8: tert-butyl (3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)(2- methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)phenyl)carbamate

[0442] To a solution of tert-butyl (2-methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)phenyl)(prop-30 2-yn-1-yl)carbamate (930 mg, 1.82 mmol, 1.0 equiv) in DMF (10 mL) was added 4-bromo-1-(2,2,2- trifluoroethyl)indol-2-yl trifluoromethanesulfonate (774 mg, 1.82 mmol, 1.0 equiv) , Pd(PPh3)2Cl2 (191 mg, 0.273 mmol, 0.15 equiv), CuI (51.9 mg, 0.273 mmol, 0.15 equiv) and Et3N (552 mg, 5.45 mmol, 3.0 equiv) stirred at RT under nitrogen. The reaction mixture was stirred for 1 h at RT and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the organic layers were combined, 35 washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel columnwith EtOAc / petroleum ether (1 / 4) to give the title compound (420 mg, 29.34% yield, 86.4% purity) as a yellow solid.

[0443] LCMS(ESI-MS) m / z =811.2 [M+Na]+

[0444] (Rt 1.079 min; Method 17) 5 3.7.9. Step 9: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(2-methoxy-4-(methylsulfonyl)-5- ((triisopropylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)- 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0445] To a solution of tert-butyl (3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)(2- methoxy-4-(methylsulfonyl)-5-((triisopropylsilyl)oxy)phenyl)carbamate (420 mg, 0.533 mmol, 1.0 equiv) 10 in 1,4-dioxane (6 mL) was added was added Int-1 (304 mg, 0.533 mmol, 1.0 equiv), Pd2(dba)3 (73.2 mg, 0.0800 mmol, 0.15 equiv), 5-[Di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (CAS# 1239478-87-5; 53.0 mg, 0.0800 mmol, 0.15 equiv) and sodium benzenolate (248 mg, 2.13 mmol, 4.0 equiv) stirred at RT under nitrogen. The reaction mixture was stirred for 3 h at 100 °C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the organic layers were 15 combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:1; Rf = 0.3 / 139-112, 0.9 / 139-112A; detection: UV) to give the title compound (370 mg, mixture with 112A) as a brown oil.

[0446] LCMS(ESI-MS) m / z =1277.6 [M+H]+20

[0447] (Rt 1.367 min; Method 3) 3.7.10. Step 10: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(5-hydroxy-2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2- (2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate

[0448] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(2-methoxy-4-(methylsulfonyl)-5-25 ((triisopropylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3- (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (350 mg, 0.283 mmol, 1.0 equiv) in THF (5 mL) was added Tetra-n-butylammonium fluoride(1.0M in THF) (0.57 mL, 0.566 mmol, 2.0 equiv) stirred at 0 °C. The reaction mixture was stirred overnight at RT and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL), and the organic layers were 30 combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:10; Rf = 0.5; detection: UV) to give the title compound (110 mg, 38% yield, 87% purity) as a yellow solid.

[0449] LCMS(ESI-MS) m / z =883.3 [M+H]+35

[0450] (Rt 0.791 min; Method 17)3.7.11. Step 11: di-tert-butyl 33-methoxy-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29- trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34), 31-heptaen-4-yne-2,18-dicarboxylate

[0451] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(5-hydroxy-2-methoxy-4- 5 (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate (110 mg, 0.125 mmol, 1.0 equiv) and PPh3(49.0 mg, 0.188 mmol, 1.5 equiv) in THF (4.4 mL) and toluene (11 mL) was added DIAD (37.8 mg, 0.188 mmol, 1.5 equiv) in toluene (11 mL) stirred at RT under nitrogen. The reaction mixture was stirred for 1 h at RT and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the organic 10 layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:10; Rf = 0.8; detection: UV) to give the title compound (80.0 mg, 69%yield, 94% purity) as a yellow solid.

[0452] LCMS(ESI-MS) m / z =865.4 [M+H]+15

[0453] (Rt 0.798 min / 0.816 min; Method 18) 3.7.12. Step 12: 33-methoxy-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne

[0454] To a solution of ditert-butyl 33-methoxy-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-20 trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-2,18-dicarboxylate (80.0 mg, 0.0920 mmol, 1.0 equiv) in DCM (1.6 mL) was added TFA (0.4 mL) stirred at 0 °C. The reaction mixture was stirred for 1 h at RT and quenched with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL), and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and 25 concentrated under reduced pressure to give the title compound (70 mg, crude) as a yellow solid.

[0455] LCMS(ESI-MS) m / z =665.3 [M+H]+

[0456] (Rt 0.639 min / 0.654 min; Method 6) 3.7.13. Step 13: Compound 5 - 33-methoxy-18-methyl-31-methylsulfonyl-35-(2,2,2- trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 30 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0457] To a solution of 33-methoxy-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen- 4-yne (55.0 mg, 0.0830 mmol, 1.0 equiv) in MeOH (2.5 mL) was added AcOH (9.94 mg, 0.166 mmol, 2.0 equiv) and Formaldehyde solution (5.37 mg, 0.0660 mmol, 0.8 equiv, 37%wt) at RT, then sodium 35 cyanoborohydride (7.80 mg, 0.124 mmol, 1.5 equiv) was added at 0 °C. The reaction mixture was stirred for 2 h at 0 °C and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL), and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 35% B to65 % B in 10 min; Wave Length: 254nm / 220nm ; RT1(min): 8.5) to give the title compound (18.3 mg, 32% yield, 5 98.3% purity) as a light yellow solid.

[0458] LCMS(ESI-MS) m / z =679.5 [M+H]+

[0459] (Rt 1.285 min / 1.370 min; Method 19) 3.8. Compound 6A (rac) (15R*,20S*)-18-methyl-31-methylsulfonyl-35-(2,2,2-trifluoroethyl)- 10 1 4-3.8.1. Step 1: 2-(methylsulfonyl)-5-nitrophenol

[0460] To a solution of 2-fluoro-5-nitrophenol (CAS# 22510-08-3; 10.0 g, 63.6 mmol, 1.0 equiv) in dimethyl sulfoxide (100 mL) was added sodium methanesulfinate (16.2 g, 159 mmol, 2.5 equiv) stirred at RT. The reaction mixture was stirred overnight at 100 °C and quenched with water (150 mL). The resulting 5 mixture was extracted with EtOAc (3 x 170 mL) and the organic layers were combined, washed with brine (2 x 170 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with petroleum ether / EtOAc (54%) to give the title compound (13.0 g, 84% yield, 90% purity) as a yellow solid.

[0461] LCMS(ESI-MS) m / z = 215.9 [M-H]-. 10

[0462] Rt 0.575 min; Method 5

[0463] 1H NMR (400 MHz, DMSO) δ 12.16 (s, 1H), 8.01 – 7.94 (m, 1H), 7.84 – 7.76 (m, 2H), 3.33 (s, 3H). 3.8.2. Step 2: 5-amino-2-(methylsulfonyl)phenol

[0464] To a solution of 2-(methylsulfonyl)-5-nitrophenol (11.0 g, 50.6 mmol, 1.0 equiv) in EtOH (110 15 mL) was added Pd / C (10%) (4.40 g) stirred at RT under nitrogen. The reaction mixture was stirred for 2 h at RT under hydrogen. The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 130 mL). The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with petroleum ether / EtOAc (65%) to give the title compound (7.2 g, 68% yield, 90% purity) as a brown solid. 20

[0465] LCMS(ESI-MS) m / z = 188.0 [M+H]+.

[0466] Rt 0.377 min; Method 5

[0467] 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.13 (d, J = 2.1 Hz, 1H), 6.09 (dd, J = 8.6, 2.1 Hz, 1H), 5.90 (s, 2H), 3.07 (s, 3H). 3.8.3. Step 3: 2-(methylsulfonyl)-5-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)phenol 25

[0468] To a solution of 5-amino-2-(methylsulfonyl)phenol (7.20 g, 38.4 mmol, 1.0 equiv) in DCM (360 mL) was added 3-(trimethylsilyl)prop-2-ynal (4.85 g, 38.4 mmol, 1.0 equiv) and AcOH (36 mL) stirred at RT and stirred for 1 h at 40 °C. And then sodium triacetoxyborohydride (32.6 g, 154 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 1 h at 35 °C and quenched with water (400 mL). The resulting mixture was extracted with EtOAc (3 x 450 mL) and the organic layers were combined, washed with brine 30 (2 x 450 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with petroleum ether / EtOAc (40%) to give the title compound (9.5 g, 66% yield, 80% purity) as a brown solid.

[0469] LCMS(ESI-MS) m / z = 298.0 [M+H]+

[0470] Rt 0.815 min; Method 53.8.4. Step 4: 2-(methylsulfonyl)-5-(prop-2-yn-1-ylamino)phenol

[0471] To a solution of 2-(methylsulfonyl)-5-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)phenol (4.00 g, 13.4 mmol, 1.0 equiv) in MeOH (40 mL) was added potassium carbonate (3.72 g, 26.9 mmol, 2.0 equiv) stirred at RT. The reaction mixture was stirred for 1 h at RT. The resulting mixture was filtered, the filter 5 cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH / DCM (11%) to give the title compound (2.6 g, 77% yield, 90% purity) as a yellow solid.

[0472] LCMS(ESI-MS) m / z = 226.0 [M+H]+

[0473] Rt 0.549 min; Method 5 10 3.8.5. Step 5: 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-3-((triisopropylsilyl)oxy)aniline

[0474] To a solution of 2-(methylsulfonyl)-5-(prop-2-yn-1-ylamino)phenol (2.60 g, 11.5 mmol, 1.0 equiv) in DMF (26 mL) was added imidazole (2.36 g, 34.6 mmol, 3.0 equiv) and chlorotris(propan-2-yl)silane (6.68 g, 34.6 mmol, 3.0 equiv) stirred at RT. The reaction mixture was stirred for 1 h at RT and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL) and the organic layers 15 were combined, washed with brine (5 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (30%) to give the title compound (3.8 g, 77% yield, 90% purity) as a light yellow solid.

[0475] LCMS(ESI-MS) m / z = 382.1 [M+H]+20

[0476] Rt 1.020 min; Method 5

[0477] 1H NMR (400 MHz, DMSO) δ 7.49 (d, J = 8.7 Hz, 1H), 6.98 (t, J = 5.8 Hz, 1H), 6.32 (dd, J = 8.8, 2.1 Hz, 1H), 6.22 (d, J = 2.1 Hz, 1H), 3.93 – 3.86 (m, 2H), 3.17 (t, J = 2.4 Hz, 1H), 3.10 (s, 3H), 1.48 – 1.34 (m, 3H), 1.12 (d, J = 7.5 Hz, 18H). 3.8.6. Step 6: N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4- 25 (methylsulfonyl)-3-((triisopropylsilyl)oxy)aniline

[0478] To a solution of 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-3-((triisopropylsilyl)oxy)aniline (1.00 g, 2.62 mmol, 1.0 equiv) in DMF (10 mL) was added 4-bromo-1-(2,2,2-trifluoroethyl)indol-2-yl trifluoromethanesulfonate (CAS# 2637449-10-4; 1.12 g, 2.62 mmol, 1.0 equiv), bis(triphenylphosphine)palladium(II) chloride (276 mg, 0.393 mmol, 0.15 equiv), CuI (74.8 mg, 0.393 30 mmol, 0.15 equiv) and TEA (1.09 mL, 7.84 mmol, 3.0 equiv) stirred at RT. The reaction mixture was stirred for 1 h at RT under nitrogen and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (5 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (40%) to give the 35 title compound (1.0 g, 46% yield, 80% purity) as a yellow solid.

[0479] LCMS(ESI-MS) m / z = 681.0 [M+Na]+

[0480] Rt 1.398 min; Method 113.8.7. Step 7: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4-((2- (3-((4-(methylsulfonyl)-3-((triisopropylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate

[0481] To a solution of N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4- 5 (methylsulfonyl)-3-((triisopropylsilyl)oxy)aniline (1.00 g, 1.52 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added Int-1 (0.870 g, 1.52 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium (0.210 g, 0.228 mmol, 0.15 equiv), 5-[Di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (CAS# 1239478- 87-5; 151 mg, 0.228 mmol, 0.15 equiv)() and sodium benzenolate (706 mg, 6.08 mmol, 4.0 equiv) stirred at RT. The reaction mixture was stirred for 1 h at 70 °C under nitrogen and quenched with water (15 mL). 10 The resulting mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% TFA) (86%), the fraction was concentrated under reduced pressure to give the title compound (195 mg, 11% yield, 90% purity) as a brown solid. 15

[0482] LCMS(ESI-MS) m / z = 991.4 [M+H]+.

[0483] Rt 0.902 min / 0.915 min; Method 2 3.8.8. Step 8: tert-butyl 4-((2-(3-((3-hydroxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine- 1-carboxylate 20

[0484] To a solution of tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4-((2- (3-((4-(methylsulfonyl)-3-((triisopropylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-4-yl)amino)piperidine-1-carboxylate (195 mg, 0.197 mmol, 1.0 equiv) in THF (6 mL) was added tetrabutylammonium fluoride (0.39 mL, 0.394 mmol, 2.0 equiv) stirred at RT. The reaction mixture was stirred for 2 h at RT and quenched with water (8 mL). The resulting mixture was extracted with EtOAc (3 25 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with MeOH / DCM (10%) to give the title compound (140 mg, 85% yield, 90% purity) as a brown solid.

[0485] LCMS(ESI-MS) m / z = 753.5 [M+H]+30

[0486] Rt 0.643 min; Method 2 3.8.9. Step 9: tert-butyl 31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-18-carboxylate

[0487] To a solution of tert-butyl 4-((2-(3-((3-hydroxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-35 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1- carboxylate (140 mg, 0.186 mmol, 1.0 equiv) in THF (19.6 mL) was added triphenylphosphine (73.1 mg, 0.279 mmol, 1.5 equiv) and 4A molecular sieve stirred at RT under nitrogen. And then diisopropylazodicarboxylate (56.4 mg, 0.279 mmol, 1.5 equiv) in THF (14 mL) was added to the above mixture in portions over 5 mins at RT. The resulting mixture was stirred at 60°C under nitrogen for additional 1 h and quenched with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and 5 concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% TFA), the fraction (57%) was concentrated under reduced pressure to give the title compound (120 mg, 79% yield, 90% purity) as a brown solid.

[0488] LCMS(ESI-MS) m / z = 735.4 [M+H]+.

[0489] Rt 0.686 min / 0.736 min; Method 2 10 3.8.10. Step 10: 31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0490] To a solution of tert-butyl 31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-18- carboxylate (120 mg, 0.163 mmol, 1.0 equiv) in DCM (4 mL) was added TFA (1 mL) stirred at RT. The 15 reaction mixture was stirred for 1 h at RT and quenched with saturated aqueous K2CO3 (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. The crude product was used in the next step directly without further purification. 20

[0491] LCMS(ESI-MS) m / z = 635.4 [M+H]+.

[0492] Rt 0.502 min / 0.511 min; Method 2 3.8.11. Step 11: Compound 6A - (rac) (15R*,20S*)-18-methyl-31-methylsulfonyl-35-(2,2,2- trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne, 25 and

[0493] To a solution of 31-methylsulfonyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 30 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (100 mg, 0.158 mmol, 1.0 equiv) in MeOH (5 mL) was added formaldehyde (8.95 mg, 0.111 mmol, 0.7 equiv, 37%), AcOH (18.9 mg, 0.316 mmol, 2.0 equiv) and sodium cyanoborohydride (CAS# 25895-60-7; 14.8 mg, 0.237 mmol, 1.5 equiv) stirred at 0 °C. The reaction mixture was stirred for 2 h at RT and quenched with water (8 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers 35 were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 53% B in 8 min; Wave Length: 254 nm / 220 nm) to provide

[0494] compound 6A (Rt 7.02 min) (3.5 mg, 3.42% yield, 99.8% purity) as a light yellow solid.

[0495] 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.8 Hz, 1H), 7.19 – 7.11 (m, 2H), 7.01 (t, J = 8.0 Hz, 5 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 2.1 Hz, 1H), 6.37 (dd, J = 8.7, 2.0 Hz, 1H), 6.21 (d, J = 7.9 Hz, 1H), 5.38 (d, J = 8.7 Hz, 1H), 5.12 – 4.88 (m, 2H), 4.36 (d, J = 6.0 Hz, 2H), 4.30 – 4.20 (m, 2H), 3.72 – 3.56 (m, 2H), 3.55 – 3.46 (m, 1H), 3.33 – 3.27 (m, 3H), 3.27 – 3.17 (m, 2H), 3.11 (s, 3H), 3.10 – 3.04 (m, 1H), 2.78 – 2.69 (m, 1H), 2.62 – 2.55 (m, 1H), 2.14 (s, 3H), 2.07 – 1.87 (m, 3H), 1.83 – 1.70 (m, 1H), 1.70 – 1.56 (m, 3H). 10

[0496] LCMS(ESI-MS) m / z = 649.2 [M+H]+.

[0497] Rt 1.400 min; Method 9

[0498] And Compound 6B (Rt 7.80 min) (4 mg, 3.91% yield, 97.4% purity) as a light yellow solid.

[0499] 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.7 Hz, 1H), 7.18 (t, J = 6.0 Hz, 1H), 7.04 – 6.95 (m, 2H), 6.68 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 2.1 Hz, 1H), 6.35 (dd, J = 8.7, 2.0 Hz, 1H), 6.14 (d, J = 7.8 Hz, 15 1H), 5.28 (d, J = 8.8 Hz, 1H), 5.09 – 4.89 (m, 2H), 4.39 – 4.29 (m, 4H), 3.88 – 3.81 (m, 2H), 3.62 – 3.53 (m, 2H), 3.52 – 3.35 (m, 4H), 3.15 (s, 3H), 3.00 – 2.90 (m, 1H), 2.90 – 2.82 (m, 1H), 2.81 – 2.74 (m, 1H), 2.17 (s, 3H), 2.03 – 1.91 (m, 2H), 1.84 – 1.72 (m, 2H), 1.69 – 1.59 (m, 1H), 1.48 – 1.34 (m, 1H), 1.13 – 0.99 (m, 1H).

[0500] LCMS(ESI-MS) m / z = 649.3 [M+H]+. 20

[0501] Rt 1.447 min; Method 9 3.9. Compound 7: 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne, and Compound 7A: (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne253.9.1. Step 1: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4- methylenepiperidiane-1-carboxylate

[0502] To a solution of methyltriphenylphosphonium bromide (2.82 g, 7.90 mmol, 1.5 equiv) in dry 5 toluene (50 mL) was added n-Butyllithium (506 mg, 7.90 mmol, 1.5 equiv, 2.5 M in n-hexane) at -78 ℃ under nitrogen. After stirred for 1 h at 0 ℃, Int-0 (3.00 g, 5.27 mmol, 1.0 equiv, in 50 mL toluene) was added dropwise. The reaction mixture was stirred for 2 h at RT and quenched with saturated aqueous ammonium chloride (400 mL). The resulting mixture was extracted with EtOAc (3 x 400 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under 10 reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (18%) to give the title compound (1.70 g, 51%) as a colourless oil.

[0503] LCMS(ESI-MS) m / z = 585.5[M+H+NH3]+.

[0504] Rt 1.513 min; Method 20 3.9.2. Step 2: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert-15 butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)methyl)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0505] A mixture of tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4- methylenepiperidine-1-carboxylate (300 mg x 5, 2.64 mmol, 1.0 equiv) and 9-borabicyclo[3.3.1]nonane (1.6 mLx 5, 3.96 mmol, 1.5 equiv, 0.5M in THF) in THF (6 mL x 5) was stirred for 4 h at RT under nitrogen. 20 The combined mixture was diluted with 6 mL x 5 H2O and then was added to a solution of Int-4 (338 mg x 5, 2.64 mmol, 1.0 equiv), caesium carbonate (258 mg x 5, 3.96 mmol, 1.5 equiv), triphenylarsane (24.4 mg x 5, 0.396 mmol, 0.15 equiv) and Pd(dppf)Cl2(58 mg x 5, 0.396 mmol, 0.15 equiv) in DMF (6 mL x 5). The reaction mixture was stirred for 2 d at RT and quenched with saturated aqueous ammonium chloride (300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL) and the organic layers were 25 combined, washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (20%) to give the title compound (650 mg, 21%) as a yellow semi- solid.

[0506] LCMS(ESI-MS) m / z = 1148.6[M+Na]+. 30

[0507] Rt 1.444 min; Method 2 3.9.3. Step 3: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)methyl)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate

[0508] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert-35 butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)methyl)-3- (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (650 mg, 0.576 mmol, 1.0 equiv) in THF (6.5 mL) was added tetrabutylammonium fluoride (1.15 mL, 1.15 mmol, 2.0equiv, 1 M in THF) at 0 °C under nitrogen. The reaction mixture was stirred for 1 h at RT and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC 5 (Mobile phase:100% EtOAc; Rf = 0.5; detection: UV) to give the title compound (220 mg, 80%) as a light yellow solid.

[0509] LCMS(ESI-MS) m / z = 796.4 [M+Na]+

[0510] Rt 0.795 min; Method 2 Step 4: ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35-triazapentacyclo 10 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne-2,18-dicarboxylate

[0511] To a solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)methyl)-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-1- carboxylate (200 mg, 0.258 mmol, 1.0 equiv), triphenylphosphine (102 mg, 0.388 mmol, 1.5 equiv) and 4A molecular sieve (400 mg) in THF (20 mL) was added diisopropyl azodicarboxylate (78.4 mg, 0.388 15 mmol, 1.5 equiv, in 20 mL THF) dropwise over 20 min at RT under nitrogen. The reaction mixture was stirred for 1 h at 60 °C under nitrogen and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:1; Rf = 0.4; 20 detection: UV) to give the title compound (170 mg, 78%) as a light yellow solid.

[0512] LCMS(ESI-MS) m / z = 778.5 [M+Na]+.

[0513] Rt 0.901 min; Method 2 3.9.4. Step 5: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08, 25 13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne

[0514] To a solution of ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne- 2,18-dicarboxylate (230 mg, 0.304 mmol, 1.0 equiv) in DCM (11.5 mL) was added DIPEA (295 mg, 2.28 mmol, 7.5 equiv) and trimethylsilyl trifluoromethanesulfonate (440 mg, 1.98 mmol, 6.5 equiv) at 0 ℃. The 30 reaction mixture was stirred for 5 h at RT and quenched with water (60 mL). The resulting mixture was extracted with DCM (3 x 60 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (170 mg, crude) as a brown semi-solid.

[0515] LCMS(ESI-MS) m / z = 556.3 [M+H]+35

[0516] Rt 0.599 min; Method 23.9.5. Step 7: Compound 7: 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,18,35- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8(13),9,11,30(34),31-heptaen-4-yne (169 mg, 0.304 mmol, 1.0 equiv) in MeOH (11.5 mL) was added formaldehyde solution (21.0 mg, 0.258 mmol, 0.9 equiv, 37%wt in H2O), AcOH (36.5 mg, 0.608 mmol, 2.0 equiv) and sodium cyanoborohydride (CAS# 25895-60-7; 28.7 mg, 0.456 mmol, 1.5 equiv) at 0 ℃. The reaction mixture was stirred for 4 h at RT and quenched with water (80 mL). The resulting mixture was extracted with DCM (3 x 80 mL). The organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was separated by prep- Achiral-SFC-HPLC (Column: Torus Diol OBD 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: MeOH (1%-2M-NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 24% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm) to provide

[0518] Compound 7 (Rt 7.28 min) (22.5 mg, 12%) as an off-white solid.

[0519] LCMS(ESI-MS) m / z = 570.3 [M+H]+

[0520] Rt 1.379 min; Method 9

[0521] And to provide Compound 7A (Rt 7.28 min) (33.1 mg, 18%) as a white solid.

[0522] 1H NMR (400 MHz, DMSO) δ 7.39 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 6.33 (s, 1H), 6.31 – 6.16 (m, 3H), 5.19 – 5.00 (m, 2H), 4.23 (d, J = 6.2 Hz, 2H), 4.12 – 4.03 (m, 2H), 3.81 – 3.68 (m, 2H), 3.62 – 3.40 (m, 5H), 3.39 – 3.27 (m, 3H), 2.89 – 2.80 (m, 1H), 2.66 – 2.55 (m, 2H), 2.21 – 2.01 (m, 4H), 1.89 – 1.65 (m, 3H), 1.63 – 1.49 (m, 1H), 1.45 – 1.35 (m, 2H).

[0523] LCMS(ESI-MS) m / z = 570.3 [M+H]+

[0524] Rt 1.375 min; Method 93.10. Compound 8: (15R,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne3.10.1. Step 1: tert-butyl (3S,4R)-4-(2,5-dimethylpyrrol-1-yl)-3-hydroxypiperidine-1- 5 carboxylate

[0525] To a stirred mixture of tert-butyl (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (CAS# 1523530-36-0; 4.0 g, 18.5 mmol, 1.0 equiv) and 2,5-hexanedione (2.17 g, 19.1 mmol, 1.03 equiv) in MeOH (9.1 mL). The reaction mixture was stirred overnight at RT. The mixture was filtered through a celite pad and washed with MeOH (3 x 30 mL) and was concentrated under reduced pressure to afford the crude 10 product. The crude product was purified by C18 column with CH3CN / Water (0.05% NH4HCO3), (50%), the fraction was concentrated under reduced pressure to give the title compound (1.5 g, 24%) as a light yellow solid.

[0526] LCMS(ESI-MS) m / z = 295.2 [M+H]+.

[0527] Rt 0.775 min; Method 15 15 3.10.2. Step 2: (4-bromobutoxy)(tert-butyl)diphenylsilane

[0528] To a stirred mixture of 4-bromobutan-1-ol (CAS# 33036-62-3; 20.0 g, 130 mmol, 1.0 equiv) and 1H-imidazole (9.79 g, 143 mmol, 1.1 equiv) in DCM (200 mL) was added tert-butyl(chloro)diphenylsilane (35.9 g, 130 mmol, 1.0 equiv) at 0°C. The reaction mixture was stirred for 12 h at RT and quenched withwater (1 L). The resulting mixture was extracted with EtOAc (3 x 1 L) and the organic layers were combined, washed with brine (2 x 800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (51 g, 79%) as a yellow oil (crude). 3.10.3. Step 3: 12,12-dimethyl-1,11,11-triphenyl-2,5,10-trioxa-11-silatridecane 5

[0529] To a stirred mixture of benzyl glycol (CAS# 622-08-2; 5.84 g, 38.3 mmol, 1.5 equiv) in THF (100 mL) was added sodium hydride (4.09 g, 102 mmol, 4.0 equiv, 60% in oil) at 0 °C. After stirred for 1 h at 80 °C, (4-bromobutoxy)(tert-butyl)diphenylsilane (10.0 g, 25.5 mmol, 1.0 equiv) was added at 0 °C. The reaction was repeated 5 batches. The reaction mixture was stirred for 16 h at 80 °C and quenched with water (800 mL). The resulting mixture was extracted with EtOAc (3 x 800 mL) and the organic layers were 10 combined, washed with brine (2 x 600 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 15) to give the title compound (26 g, crude) as a colourless oil.

[0530] LCMS(ESI-MS) m / z = 480.2 [M+H+NH3]+.

[0531] Rt 1.573 min; Method 16 15 3.10.4. Step 4: 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethan-1-ol

[0532] To a stirred mixture of 12,12-dimethyl-1,11,11-triphenyl-2,5,10-trioxa-11-silatridecane (26.0 g, 56.2 mmol, 1.0 equiv) in EtOH (260 mL) was added 10% palladium on activated carbon (26.0 g) at RT under hydrogen. The reaction mixture was stirred for 3 days. The mixture was filtered through a celite pad and washed with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 300 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 3) to give the title compound (2.5 g, 11%) as a colourless oil.

[0533] LCMS(ESI-MS) m / z = 395.2 [M+Na]+.

[0534] Rt 1.104 min; Method 5 25 3.10.5. Step 5: (4-(2-bromoethoxy)butoxy)(tert-butyl)diphenylsilane

[0535] To a stirred mixture of 2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethan-1-ol (1.50 g, 4.03 mmol, 1.0 equiv) and triphenylphosphine (1.58 g, 6.04 mmol, 1.5 equiv) in DCM (37 mL) was added carbon tetrabromide (2.00 g, 6.04 mmol, 1.5 equiv) at 0 °C under nitrogen. The reaction mixture was stirred for 2 h at RT and was quenched with water (50 mL). The resulting mixture was extracted with DCM (3 x 70 mL) 30 and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 10) to give the title compound (1.5 g, 81%) as a colourless oil.

[0536] LCMS(ESI-MS) m / z = 435.1 / 437.1 [M+H]+. 35

[0537] Rt 1.301 min; Method 53.10.6. Step 6: tert-butyl (3S,4R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethoxy)-4-(2,5- dimethyl-1H-pyrrol-1-yl)piperidine-1-carboxylate

[0538] To a stirred mixture of tert-butyl (3S,4R)-4-(2,5-dimethylpyrrol-1-yl)-3-hydroxypiperidine-1- carboxylate (564 mg, 1.92 mmol, 1.0 equiv) in DMF (10 mL) was added sodium hydride (115 mg, 2.88 5 mmol, 1.5 equiv, 60% in oil) at 0 °C. After stirred for 20 min at 0 °C, (4-(2-bromoethoxy)butoxy)(tert- butyl)diphenylsilane (1.0 g, 2.29 mmol, 1.2 equiv) was added. The reaction mixture was stirred overnight at RT and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was 10 chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 10) to give the title compound (350 mg, 23%) as a yellow oil.

[0539] LCMS(ESI-MS) m / z = 671.6 [M+Na]+.

[0540] Rt 1.194 min; Method 15 3.10.7. Step 7: tert-butyl (3S,4R)-4-amino-3-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethoxy) 15 piperidine-1-carboxylate

[0541] To a stirred mixture of tert-butyl (3S,4R)-3-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethoxy)-4- (2,5-dimethyl-1H-pyrrol-1-yl)piperidine-1-carboxylate (340 mg, 0.524 mmol, 1.0 equiv) and hydroxylamine hydrochloride (364 mg, 5.24 mmol, 10 equiv) in MeOH (3.4 mL) was added hydroxylamine (346 mg, 5.24 mmol, 10 equiv, 50% wt in water). The reaction mixture was stirred overnight at 60 °C and 20 diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column with MeOH / DCM (1 / 10) to give the title compound (160 mg, 50%) as a yellow semi- solid. 25

[0542] LCMS(ESI-MS) m / z = 571.4 [M+H]+.

[0543] Rt 0.971 min; Method 6 3.10.8. Step 8: tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)- 3-(2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethoxy)piperidine-1-carboxylate 30

[0544] To a stirred mixture of tert-butyl (3S,4R)-4-amino-3-(2-(4-((tert- butyldiphenylsilyl)oxy)butoxy)ethoxy)piperidine-1-carboxylate (150 mg, 0.263 mmol, 1.0 equiv), Int-4 (167 mg, 0.263 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium (24.1 mg, 0.026 mmol, 0.1 equiv) and 5-[Di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (CAS# 1239478-87-5; 17.4 mg, 0.026 mmol, 0.1 equiv) in 1,4-dioxane (2 mL) was added sodium benzenolate (122 mg, 1.05 mmol, 4.0 35 equiv) under nitrogen. The reaction mixture was stirred at 70 °C for 2 h and quenched with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:4; Rf = 0.5; detection: UV) to give the title compound (240 mg, 72%) as a yellow semi-solid.

[0545] LCMS(ESI-MS) m / z = 1127.6 [M+H]+.

[0546] Rt 1.592 min; Method 15 5 3.10.9. Step 9: tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(3- hydroxyphenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(4- hydroxybutoxy)ethoxy)piperidine-1-carboxylate

[0547] To a stirred mixture of tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3- 10 (2-(4-((tert-butyldiphenylsilyl)oxy)butoxy)ethoxy)piperidine-1-carboxylate (230 mg, 0.204 mmol, 1.0 equiv) in THF (5 mL) was added tetrabutylammonium fluoride (0.41 mL, 0.408 mmol, 2.0 equiv, 1 M in THF) at 0 °C. The reaction mixture was stirred for 2 h at RT and was quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced 15 pressure to afford crude product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =1:1; Rf = 0.1; detection: UV) to give the title compound (120 mg, 72%) as a yellow semi-solid.

[0548] LCMS(ESI-MS) m / z = 775.5 [M+H]+.

[0549] Rt 0.717 min; Method 2 3.10.10. Step 10: ditert-butyl (15R,20S)-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35-20 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4- yne-2,18-dicarboxylate

[0550] To a stirred mixture of tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(3- hydroxyphenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-(2-(4- hydroxybutoxy)ethoxy)piperidine-1-carboxylate (110 mg, 0.142 mmol, 1.0 equiv) and triphenylphosphine 25 (55.8 mg, 0.213 mmol, 1.5 equiv) in THF (5.5 mL) and toluene (20 mL) was added diisopropyl azodicarboxylate (43.1 mg, 0.213 mmol, 1.5 equiv, in 2 mL toluene) under nitrogen. The reaction mixture was stirred for 1 h at 90 °C under nitrogen and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 30 product. The crude product was purified by TLC (Mobile phase: EtOAc / petroleum ether =2:1; Rf = 0.4; detection: UV) to give the title compound (70 mg, 61%) as a yellow semi-solid.

[0551] LCMS(ESI-MS) m / z = 757.6 [M+H]+.

[0552] Rt 1.383 min; Method 43.10.11. Step 11: (15R,20S)-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0553] To a stirred mixture of di-tert-butyl (15R,20S)-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen- 5 4-yne-2,18-dicarboxylate (65.0 mg, 0.086 mmol, 1.0 equiv) in DCM (3.25 mL) was added TFA (0.65 mL). The reaction mixture was stirred for 1 h at RT and quenched with H2O (5 mL). The mixture was adjusted to PH = 8 with saturated aqueous potassium carbonate and extracted with DCM (3 x 15 mL). The reaction mixture was concentrated under reduced pressure to give the title compound (65 mg, crude) as a yellow semi-solid. LCMS(ESI-MS) m / z = 557.3 [M+H]+. 10

[0554] Rt 1.360 min; Method 13 3.10.12. Step 12: Compound 8: (15R,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne

[0555] To a stirred mixture of (15R,20S)-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35- 15 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (50.0 mg, 0.090 mmol, 1.0 equiv), formaldehyde (5.83 mg, 0.072 mmol, 0.8 equiv, 37% wt in H2O) and AcOH (10.8 mg, 0.180 mmol, 2.0 equiv) in MeOH (1.4 mL) was added sodium cyanoborohydride (CAS# 25895- 60-7; 8.47 mg, 0.135 mmol, 1.5 equiv). The reaction mixture was stirred for 40 min at RT and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers 20 were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 50 % B in 10 min; Wave Length: 254nm / 220nm; Rt 6.32 min to give the title compound (2.0 mg, 3%) as an off-white solid. 25

[0556] LCMS(ESI-MS) m / z = 571.3 [M+H]+

[0557] Rt 1.367 min; Method 11

[0558] 1H NMR (400 MHz, DMSO) δ 7.03 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.80 – 6.72 (m, 2H), 6.44 – 6.39 (m, 1H), 6.31 – 6.13 (m, 4H), 5.08 – 4.90 (m, 3H), 4.25 – 4.19 (m, 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.75 – 3.67 (m, 2H), 3.63 – 3.55 (m, 2H), 3.48 – 3.35 (m, 4H), 3.00 – 2.93 (m, 1H), 2.72 – 2.65 30 (m, 1H), 2.16 (s, 3H), 2.10 – 2.00 (m, 2H), 1.77 – 1.69 (m, 4H), 1.69 – 1.59 (m, 2H).3.11. Compound 9A - (rac) (15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia- 2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31- 53.11.1. Step 1: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4-((2- iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate

[0559] To a solution of 2-iodo-3-(2,2,2-trifluoroethyl)-1-benzothiophen-7-amine (CAS# 2903922-15-4; 10 2.00 g, 5.60 mmol, 1.0 equiv) and Int-0 (4.79 g, 8.40 mmol, 1.5 equiv) in DMF (33.3 mL) was added chlorotrimethylsilane (7.54 g, 69.4 mmol, 12 equiv) at RT. The reaction mixture was stirred for 2 h at RT. Then borane-THF complex (1.0M in THF) (50.40 mL, 50.4 mmol, 9.0 equiv) was added at 0°C and the mixture was stirred for 3 h at RT. The reaction mixture was quenched with ice-water (80 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed 15 with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by C18 column with CH3CN / Water (0.05% FA, 100% MeOH), the fraction was concentrated under reduced pressure to give the title compound (2.5 g, 44%) as a yellow oil.

[0560] LCMS(ESI-MS) m / z = 911.6 [M+H]+. 20

[0561] (Rt 1.217 min; Method 3)3.11.2. Step 2: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert- butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7- yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0562] A solution of tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4-((2- 5 iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)piperidine-1-carboxylate (500 x 2 mg, 0.549 mmol, 1.0 equiv), tert-butyl (3-((tert-butyldimethylsilyl)oxy)phenyl)(prop-2-yn-1-yl)carbamate (746 mg, 1.032 mmol, 1.8 equiv), Pd(PPh3)2Cl2 (84.6 mg, 0.060 mmol, 0.11 equiv) and cuprous iodide (56.4 mg, 0.148 mmol, 0.27 equiv) in DMSO (8.5 mL) was added TEA (444 mg, 2.196 mmol, 4.0 equiv) under nitrogen. The reaction was stirred for 2 h at RT and quenched with water (50 mL). The resulting mixture 10 was extracted with EtOAc (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (120 g) with EtOAc / petroleum ether (17 / 83) to give the title compound (1.0 g, 79%) as a brown yellow semi-solid.

[0563] LCMS(ESI-MS) m / z = 1166.5 [M+Na]+15

[0564] Rt 1.466 min; Method 2 3.11.3. Step 3: tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1-yn-1- yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate To a mixture of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-((tert-20 butyldimethylsilyl)oxy)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7- yl)amino)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (1.0 g, 0.874 mmol, 1.0 equiv) in THF (10 mL) was added tetrabutylammonium fluoride (1.0M in THF) (457 mg, 1.75 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred for 1 h and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column 25 (120 g) with MeOH / DCM (1 / 9) to give the title compound (600 mg, 86%) as a brown solid. LCMS(ESI-MS) m / z = 792.3 [M+H]+Rt 846 min; Method 2 3.11.4. Step 4: ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18- triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4- 30 yne-2,18-dicarboxylate

[0565] To a stirred solution of tert-butyl 4-((2-(3-((tert-butoxycarbonyl)(3-hydroxyphenyl)amino)prop-1- yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)piperidine-1-carboxylate (90 x 8 mg, 0.912 mmol, 1.0 equiv) and triphenylphosphine (358 mg, 1.37 mmol, 1.5 equiv) in toluene (72 mL) and THF (28.8 mL) was 35 added diisopropyl azodicarboxylate (276 mg, 1.37 mmol, 1.5 equiv, in toluene (72 mL)) dropwise over 10 min under nitrogen at RT. Then the mixture was stirred for 2 h at 90°C under nitrogen and quenched with water (60 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL) and the organic layers werecombined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (120 g) with EtOAc / petroleum ether (23 / 77) to give the title compound (600 mg, 85%) as a yellow solid. 5

[0566] LCMS(ESI-MS) m / z = 796.3 [M+Na]+

[0567] Rt 0.889 min; Method 2 3.11.5. Step 5: 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne

[0568] To a solution of ditert-butyl 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-10 triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne- 2,18-dicarboxylate (50.0 mg, 0.065 mmol, 1.0 equiv) in DCM (0.6 mL) was added TFA (0.2 mL). The reaction mixture was stirred for 1 h at RT and quenched with saturated aqueous potassium carbonate (10 mL). The resulting mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under 15 reduced pressure to give the title compound (crude) as a yellow solid.

[0569] LCMS(ESI-MS) m / z = 574.4 [M+H]+.

[0570] Rt 1.150 min; Method 8 3.11.6. Step 6: Compound 9A: (rac) (15R*,20S*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29- trioxa-7-thia-2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 20 1(33),6(35),8,10,12,30(34),31-heptaen-4-yne, and Compound 9B: (rac) (15R*,20R*)-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia- 2,14,18-triazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31- heptaen-4-yne

[0571] To a solution of 35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-7-thia-2,14,18-triazapentacyclo 25 [28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6(35),8,10,12,30(34),31-heptaen-4-yne (444 mg, 0.697 mmol, 1.0 equiv, 90%) in MeOH (9.3 mL) was added formaldehyde solution (4.5 mL(~45.0 mg), 0.558 mmol, 0.8 equiv, 37%)(note: 100 mg formaldehyde in 10 mL MeOH)), AcOH (8.4 mL ~84.0 mg), 1.39 mmol, 2.0 equiv) (note: 100 mg AcOH in 10 mL MeOH)) and sodium cyanoborohydride (66.0 mg, 1.05 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 80 min at 0 °C and quenched with water (50 30 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was separated by prep-Achiral-SFC-HPLC (Column: Torus Diol OBD 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: ACN: MeOH=4:1 (1% 2M NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 24% B; Column Temperature(℃): 35; Back 35 Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 11.44; RT2(min): 13.38; Sample Solvent: MeOH; Injection Volume: 2.5 mL) to provide:

[0572] Compound 9A with Rt 11.44 min (107.4 mg, 26%) as a white solid.

[0573] 1H NMR (400 MHz, DMSO) δ 7.26 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.32 – 6.25 (m, 2H), 6.25 – 6.14 (m, 2H), 5.06 (d, J = 8.1 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.08 – 3.98 (m, 2H), 3.95 – 3.57 (m, 5H), 3.55 – 3.42 (m, 2H), 3.42 – 3.33 (m, 3H), 3.18 – 3.08 (m, 1H), 2.76 – 2.63 (m, 1H), 2.60 – 2.53 (m, 1H), 2.15 (s, 3H), 2.12 – 1.97 (m, 2H), 1.93 – 5 1.84 (m, 1H), 1.83 – 1.59 (m, 4H).

[0574] LCMS(ESI-MS) m / z = 588.2 [M+H]+

[0575] Rt 1.400 min; Method 13; and

[0576] Compound 9B with Rt 13.38 min (6.5 mg, 1%) as a white solid.

[0577] 1H NMR (400 MHz, DMSO) δ 7.24 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 8.0 10 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.34 (t, J = 2.3 Hz, 1H), 6.29 – 6.25 (m, 1H), 6.25 – 6.16 (m, 2H), 5.04 (d, J = 8.8 Hz, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.10 (q, J = 4.1 Hz, 2H), 3.95 – 3.71 (m, 4H), 3.65 – 3.39 (m, 6H), 3.05 – 2.93 (m, 1H), 2.88 (d, J = 10.4 Hz, 1H), 2.78 (d, J = 11.0 Hz, 1H), 2.18 (s, 3H), 2.06 – 1.95 (m, 2H), 1.93 – 1.79 (m, 2H), 1.72 – 1.62 (m, 1H), 1.54 – 1.41 (m, 1H), 1.15 – 1.02 (m, 1H).

[0578] LCMS(ESI-MS) m / z = 588.4 [M+H]+. 15

[0579] Rt 0.995 min; Method 14 3.12. Compound 10: (15S,20S)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0580] Compound synthesized in the same manner as compound 8 using tert-butyl (3S,4S)-4-amino-3- 20 hydroxypiperidine-1-carboxylate (CAS# 1161932-04-2).

[0581]

[0582] LCMS(ESI-MS) m / z = 571.4 [M+H]+

[0583] Rt: 1.365 min; Method 9

[0584] 1H NMR (400 MHz, DMSO) δ 7.00 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.71 25 (d, J = 8.3 Hz, 1H), 6.41 (t, J = 2.2 Hz, 1H), 6.28 – 6.23 (m, 1H), 6.22 – 6.14 (m, 3H), 5.41 (d, J = 6.6 Hz, 1H), 5.06 – 4.84 (m, 2H), 4.21 (d, J = 5.8 Hz, 2H), 4.02 (t, J = 6.2 Hz, 2H), 3.69 – 3.60 (m, 1H), 3.60 – 3.51 (m, 2H), 3.49 – 3.23 (m, 4H), 3.16 – 3.05 (m, 2H), 2.73 – 2.66 (m, 1H), 2.20 (s, 3H), 2.14 – 2.05 (m, 1H), 2.02 – 1.92 (m, 1H), 1.78 – 1.48 (m, 5H), 1.40 – 1.26 (m, 1H).3.13. Compound 11: (15S,20R)-18-methyl-35-(2,2,2-trifluoroethyl)-21,24,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0585] Compound synthesized in the8 using tert-butyl (3R,4S)-4-amino- 5 3-hydroxypiperidine-1-carboxylate (CAS# 1821799-48-7)

[0586] LCMS (ESI-MS) m / z = 571.3 [M+H]+

[0587] Rt: 1.548 min; Method 13

[0588] 1H NMR (400 MHz, DMSO) δ 7.03 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.80 – 6.72 (m, 2H), 6.44 – 6.39 (m, 1H), 6.31 – 6.13 (m, 4H), 5.08 – 4.90 (m, 3H), 4.25 – 4.19 (m, 2H), 4.05 (t, J = 6.1 10 Hz, 2H), 3.75 – 3.67 (m, 2H), 3.63 – 3.55 (m, 2H), 3.48 – 3.35 (m, 4H), 3.00 – 2.93 (m, 1H), 2.72 – 2.65 (m, 1H), 2.16 (s, 3H), 2.10 – 2.00 (m, 2H), 1.77 – 1.69 (m, 4H), 1.69 – 1.59 (m, 2H). 3.14. Compound 13: methyl 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxylate15 3.14.1. Step 1: methyl 4-((3-(4-((3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2- hydroxybenzoate

[0589] To a mixture of Int-9 (400 mg, 0.495 mmol, 1.0 equiv) in DMSO (6.4 mL) was added Int-10 (191 20 mg, 0.931 mmol, 1.9 equiv),dichlorobis(triphenylphosphine)palladium(II) (38.2 mg, 0.054 mmol, 0.11eq), CuI (25.5 mg, 0.134 mmol, 0.3 equiv) and TEA (200 mg, 1.98 mmol, 4.0 equiv) at room temperature. The reaction mixture was stirred for 2 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure toafford crude product. The crude product was purified by TLC (MeOH / DCM = 1 / 10; Rf = 0.5; detection: UV) to provide the title product (400 mg, 90%) as a brown oil.

[0590] LCMS(ESI-MS) m / z = 885.4 [M+H]+

[0591] Rt1: 1.158 min, Rt2: 1.167 min (Method 7) 5 3.14.2. Step 2: methyl 2-hydroxy-4-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1- methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)benzoate

[0592] To a solution of methyl 4-((3-(4-((3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2- hydroxybenzoate (400 mg, 0.452 mmol, 1.0 equiv) in THF (4.0 mL) was added TBAF (1 mL, 0.994 mmol, 2.2 10 equiv, 1M in THF) at 0 °C. The reaction mixture was stirred for 2 h at room temperature and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 80 g, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 0% B to 20% B in 40 min; Wave Length: 220 nm; 14% B fractions were collected) to provide the desired product methyl 2-hydroxy-4-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1-methylpiperidin-4- 15 yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)benzoate (280 mg, 95%) as a yellow oil.

[0593] LCMS(ESI-MS) m / z = 647.3 [M+H]+

[0594] Rt: 0.570 min (Method 2) 3.14.3. Step 3: Compound 13: methyl 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- 20 heptaen-4-yne-31-carboxylate

[0595] To a stirred solution of methyl 2-hydroxy-4-((3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1- methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)benzoate (160 mg, 0.248 mmol, 1.0 equiv), triphenylphosphine (97.4 mg, 0.372 mmol, 1.5 equiv) and 4A MS (320 mg) in THF (8.0 mL) was added diisopropyl azodicarboxylate (75.0 mg, 0.372 mmol, 1.5 equiv, in 8.0 mL 25 THF) dropwise over 10 min under nitrogen at room temperature. The reaction mixture was stirred for 2 h at 60 °C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (MeOH / DCM =1 / 5; Rf = 0.4; detection: UV) to provide the desired product (75 mg, ~90% pure).15 30 mg product was purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 46% B in 7 min; Wave Length: 220 nm; RT1(min): 6.37) to provide title product.

[0596] LCMS(ESI-MS) m / z = 629.4 [M+H]+

[0597] Rt1: 1.463 min, Rt2: 1.513 min (Method 23).3.15. Compound 12: 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxylic acid5

[0598] To a - 2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-31- carboxylate (60 mg, 0.095 mmol, 1.0 equiv) in tetrahydrofuran (0.6 mL), H2O (0.2 mL) and MeOH (0.2 mL) was added NaOH (7.63 mg, 0.190 mmol, 2.0 equiv) and stirred for 2 h at 50°C. The reaction mixture was diluted with water (5 mL) and acidified to PH=4 with hydrochloric acid (2M in H2O). The resulting 10 mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product (40 mg crude).15 mg crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 49% B in 10 min; Wave Length: 220nm; 15 RT1(min): 8.5) to provide title product (2.8 mg, 4%) as a light yellow solid.

[0599] LCMS(ESI-MS) m / z = 615.4 [M+H]+

[0600] Rt1: 1.416 min, Rt2: 1.462 min (Method 12). 3.16. Compound 14: N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 20 31-carboxamide

[0601] To a stirred mixture of 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-31- carboxylic acid (50 mg, 0.081 mmol, 1.0 equiv) and methylamine hydrochloride (8.79 mg, 0.130 mmol, 25 1.6 equiv) in DMF (1.0 mL) was added HATU (37.1 mg, 0.097 mmol, 1.2 equiv) and DIEA (63.1 mg, 0.486 mmol, 6.0 equiv) at 0 °C. The resulting mixture was stirred for 2 h and quenched with water (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 40 mL) and the combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative 30 HPLC (Column: SHIMADZU Shim-pack Scepter C18-120, 30*150 mm, 5μm; Mobile Phase A:Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 66% B in 10 min; Wave Length: 220nm; RT1(min): 9) to provide the title product (4.1 mg, 8%) as a light yellow solid.

[0602] LCMS(ESI-MS) m / z = 628.4 [M+H]+5

[0603] Rt1: 1.662 min, Rt2: 1.700 min (Method 12). 3.17. Compound 15: 18-methyl-N,35-bis(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxamide10

[0604] To a st mix of 18-methyl-35-(2,2,2-t oroeth -23,26,29-2,1 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-31- carboxylic acid (30.0 mg, 0.049 mmol, 1.0 equiv) and 2,2,2-trifluoroethylamine (7.25 mg, 0.074 mmol, 1.5 equiv) in DMF (0.5 mL) was added HATU (33.4 mg, 0.088 mmol, 1.8 equiv) and DIEA (37.9 mg, 0.294 mmol, 6.0 equiv) at 0 °C. The reaction mixture was stirred for 2 h and quenched with water (20 mL) at 15 room temperature. The resulting mixture was extracted with ethyl acetate (3 x 40 mL) and the combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 41% B to 71% B in 10 min; Wave 20 Length: 220nm; RT1(min): 8.68) to provide the title (10.0 mg, 29%) as a light yellow solid.

[0605] LCMS(ESI-MS) m / z = 696.4 [M+H]+

[0606] Rt: 1.258 min (Method 20).3.18. Compound 17: methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-31-carboxylate5 3.18.1. Step 1: methyl 4-((tert-butoxycarbonyl)(3-(4-((3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2- yl)prop-2-yn-1-yl)amino)-2-hydroxy-5-methoxybenzoate

[0607] To a solution of Int-9 (500 mg, 0.619 mmol, 1 equiv) in DMSO (5 mL) was added Int-11 (390 mg, 1.16 mmol, 1.9 equiv) , Pd(PPh3)2Cl2 (47.8 mg, 0.0680 mmol, 0.11 equiv) , CuI (31.8 mg, 0.167 mmol, 10 0.27 equiv) and Et3N (251 mg, 2.48 mmol, 4.0 equiv) stirred at room temperature under nitrogen. The reaction mixture was stirred for 1 h at room temperature and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 80 g, 100 15 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 50 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 15% B in 30 min; 254 nm; 8% B fractions were collected) to provide the title product (660 mg, 88% yield, 84% purity) as a brown solid.

[0608] LCMS(ESI-MS) m / z =1015.6 [M+H]+

[0609] Rt: 1.056 min (Method 6) 20 3.18.2. Step 2: methyl 4-((tert-butoxycarbonyl)(3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)- 1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2- hydroxy-5-methoxybenzoate

[0610] To a solution of methyl 4-((tert-butoxycarbonyl)(3-(4-((3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2- 25 yn-1-yl)amino)-2-hydroxy-5-methoxybenzoate (660 mg, 0.650 mmol, 1.0 equiv) in THF (7 mL) was added TBAF (1.3 mL, 1.30 mmol, 2.0 equiv, 1M in THF) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. Thecrude product was chromatographed on a silica gel column (Column: 80 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 50 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 15% B in 30 min; 254 nm; 9% B fractions were collected) to provide the title product (360 mg, 59% yield, 84% purity) as a brown solid. LCMS(ESI-MS) m / z =777.4 [M+H]+5

[0611] Rt: 0.950 min (Method 6) 3.18.3. Step 3: O2-tert-butyl O31-methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)- 23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 1(33),6,8,10,12,30(34),31-heptaen-4-yne-2,31-dicarboxylate

[0612] To a solution of methyl 4-((tert-butoxycarbonyl)(3-(4-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-10 1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2-hydroxy- 5-methoxybenzoate (340 mg, 0.438 mmol, 1.0 equiv), PPh3 (344 mg, 1.31 mmol, 3.0 equiv) and 4A-MS (1.36 g) in THF (34 mL) was added DIAD (266 mg, 1.31 mmol, 3.0 equiv) in THF (34 mL) stirred under nitrogen at room temperature. The reaction mixture was stirred for 1 h at 60 °C and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were 15 combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (MeOH / DCM =1:10; Rf = 0.4; detection: UV) to provide the title product (240 mg, 62% yield, 87% purity) as a solid.

[0613] LCMS(ESI-MS) m / z =759.4 [M+H]+

[0614] Rt: 0.892 min, 0.908 min (Method 6) 20 3.18.4. Step 4: methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne-31-carboxylate

[0615] To a solution of O2-tert-butyl O31-methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)- 23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 25 1(33),6,8,10,12,30(34),31-heptaen-4-yne-2,31-dicarboxylate (200 mg, 0.264 mmol, 1.0 equiv) in DCM (1.6 mL) was added trifluoroacetic acid (0.4 mL) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature and quenched with saturated aqueous K2CO3 (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 30 crude title product (140 mg, crude) as a yellow solid.30 mg of the crude product was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 41% B to71 % B in 10 min; Wave Length: 254nm / 220nm ; RT1(min): 9.25) to provide the desired product

[0616] LCMS(ESI-MS) m / z =659.3 [M+H]+, Rt: 1.126 min, 1.191 min (Method 24).3.19. Compound 16: 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxylic acid

[0617] To a solution of methyl 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa- 5 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen- 4-yne-31-carboxylate (110 mg, 0.167 mmol, 1.0 equiv) in THF (1.2 mL) was added NaOH (13.4 mg, 0.334 mmol, 2.0 equiv), H2O (0.4 mL) and methanol (0.4 mL) stirred at room temperature. The reaction mixture was stirred overnight at 50 °C and adjusted the pH to 6 with HCl (1 M). The mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were 10 combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crudetitle product (80 mg, crude) as a brown solid.25 mg of the crude product was purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm,5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 20% B to 35% B in 10 min; Wave Length: 254nm / 220nm ; RT1(min): 8.8, 9.6(min): ) to provide the title product 15

[0618] LCMS(ESI-MS) m / z =645.3 [M+H]+

[0619] Rt: 1.466 min, 1.506 min (Method 13). 3.20. Compound 18: 33-methoxy-N,18-dimethyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne- 31-carboxamide20

[0620] To a of 33-methoxy-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne-31-carboxylic acid (55.0 mg, 0.0850 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (38.9 mg, 0.102 mmol, 1.2 equiv), DIEA (44.1 mg, 0.340 mmol, 4.0 equiv) and Methylamine hydrochloride (6.34 mg, 25 0.0940 mmol, 1.1 equiv) stirred at room temperature. The reaction mixture was stirred for 1 h at room temperature and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: Xselect CSH Prep Fluoro-Phenyl Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 14% B to 30% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.9 and 10.8 ) to provide the title product (24.5 mg, 5 41% yield, 95.7% purity) as a yellow solid.

[0621] LCMS(ESI-MS) m / z =658.4 [M+H]+

[0622] Rt: 1.691 min, 1.730 min (Method 12). 3.21. Compound 19A: rac-(15R,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)- 23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-10 1(33),6,8,10,12,30(34),31-heptaen-4-yne and Compound 19B: rac-(15S,20S)-32-dimethylphosphoryl- 18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne3.21.1. Step 1: 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- 15 tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0623] To a stirred mixture of Int-13 (80.0 mg, 0.107 mmol, 1.0 equiv) in 1,4-dioxane (0.8 mL) was added hydrogen chloride (3.2 mL, 1.0 M in 1,4-dioxane). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to afford product (HCl salt). The salt was free with saturated aqueous sodium bicarbonate (30 mL) to provide the title product (50.0 mg, crude) as a yellow 20 solid.

[0624] LCMS (ESI-MS) m / z = 649.3 [M+H]+

[0625] Rt: 0.773 min (Method 6)3.21.2. Step 2: Compound 19A: rac-(15R,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2- trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne / Compound 19B: rac-(15S,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)- 23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0626] To a solution of 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (50.0 mg, 0.077 mmol, 1.0 equiv) in DMF (2 mL) was added (methylphosphonoyl)methane (9.01 mg, 0.115 mmol, 1.5 equiv), Xantphos (4.45 mg, 0.008 mmol, 0.1 equiv), palladium(II) acetate (1.73 mg, 0.008 mmol, 0.1 equiv) and potassium phosphate (24.5 mg, 0.115 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h at 120 ℃ under nitrogen and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 15% B to 29% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.4, RT2(min): 10.4) to afford the desired product RT1(min): rac-(15R,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2- trifluoroethyl)-23,26,29-trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta- 1(33),6,8,10,12,30(34),31-heptaen-4-yne (4.8 mg, 9%) as a yellow solid1H NMR (400 MHz, DMSO-d6) δ 7.17 - 7.65 (m, 1H), 6.96 - 7.08 (m, 1H), 6.65 - 6.79 (m, 2H), 6.35 - 6.57 (m, 3H), 6.18 - 6.28 (m, 1H), 5.29 - 5.41 (m, 1H), 4.91 - 5.09 (m, 1H), 4.72 - 4.89 (m, 1H), 4.20 - 4.30 (m, 2H), 4.00 - 4.10 (m, 2H), 3.60 - 3.70 (m, 2H), 3.42 - 3.60 (m, 6H), 2.94 - 3.08 (m, 1H), 2.64 - 2.80 (m, 1H), 2.53 - 2.60 (m, 1H), 2.08 - 2.19 (m, 3H), 1.94 - 2.06 (m, 2H), 1.72 - 1.92 (m, 3H), 1.50 - 1.65 (m, 8H).

[0627] LCMS (ESI-MS) m / z = 647.4 [M+H]+

[0628] Rt: 1.369 min (Method 12).

[0629] RT2(min):rac-(15S,20S)-32-dimethylphosphoryl-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29- trioxa-2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31- heptaen-4-yne (6.5 mg, 13%).1H NMR (400 MHz, DMSO-d6) δ 6.94 - 7.11 (m, 2H), 6.63 - 6.76 (m, 2H), 6.41 - 6.57 (m, 3H), 6.08 - 6.17 (m, 1H), 5.33 - 5.43 (m, 1H), 4.81 - 5.08 (m, 2H), 4.20 - 4.29 (m, 2H), 4.07 - 4.20 (m, 2H), 3.68 - 3.82 (m, 2H), 3.53 - 3.60 (m, 2H), 3.44 - 3.53 (m, 4H), 2.84 - 3.00 (m, 2H), 2.66 - 2.84 (m, 1H), 2.17 (s, 3H), 1.93 - 2.05 (m, 2H), 1.73 - 1.91 (m, 2H), 1.52 - 1.67 (m, 7H), 1.37 - 1.48 (m, 1H), 0.97 - 1.10 (m, 1H).

[0630] LCMS (ESI-MS) m / z = 647.4 [M+H]+

[0631] Rt: 1.418 min (Method 12).3.22. Compound 19-1: 32-bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne

[0632] - trioxa- 5 2,14,18,35-tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen- 4-yne-2-carboxylate (30.0 mg, 0.040 mmol, 1.0 equiv) in 1,4-dioxane (0.2 mL) was added hydrogen chloride (0.8 mL, 1.0 M in 1,4-dioxane). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: 10 Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 52% B to 69 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.68 ) to provide the desired product 32- bromo-18-methyl-35-(2,2,2-trifluoroethyl)-23,26,29-trioxa-2,14,18,35- tetrazapentacyclo[28.3.1.16,9.08,13.015,20]pentatriaconta-1(33),6,8,10,12,30(34),31-heptaen-4-yne (4.5 mg, 17%) as an off-white solid. 15

[0633] LCMS (ESI-MS) m / z = 649.2 [M+H]+

[0634] Rt: 1.327, 1.363 min (Method 28). 3.23. Compound 20: (15S)-15-(2-aminoethyl)-32-(2,2,2-trifluoroethyl)-20,23,26-trioxa-2,14,17,32- tetrazatetracyclo[25.3.1.16,9.08,13]dotriaconta-1(31),6,8,10,12,27,29-heptaen-4-yn-16-one3.23.1. Step 1: (9H-fluoren-9-yl)methyl tert-butyl (2,2-dimethyl-14-oxo-3,3-diphenyl-4,7,10- trioxa-13-aza-3-silaheptadecane-15,17-diyl)(S)-dicarbamate

[0635] To a stirred mixture of Int-14 (1.00 g, 2.58 mmol, 1.0 equiv), HATU (1.18 g, 3.09 mmol, 1.2 equiv) and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butanoic acid 5 (1.17 g, 2.65 mmol, 1.03 equiv) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.33 g, 10.3 mmol, 4.0 equiv) at 0°C. The reaction mixture was stirred for 2 h at room temperature and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on 10 a silica gel column (Column: 120 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 50 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 220 nm; Collected fractions: 48% - 52% B) to provide the title product (1.98 g, 90%yield) as a brown semi-solid.

[0636] LCMS(ESI-MS) m / z = 832.5 [M+Na]+

[0637] Rt: 0.962 min (Method 18) 15 3.23.2. Step 2: tert-butyl (S)-(15-amino-2,2-dimethyl-14-oxo-3,3-diphenyl-4,7,10-trioxa-13- aza-3-silaheptadecan-17-yl)carbamate

[0638] To a stirred mixture of (9H-fluoren-9-yl)methyl tert-butyl (2,2-dimethyl-14-oxo-3,3-diphenyl- 4,7,10-trioxa-13-aza-3-silaheptadecane-15,17-diyl)(S)-dicarbamate (1.00 g, 1.23 mmol, 1.0 equiv) in tetrahydrofuran (12.5 mL) was added diethylamine (2.55 mL, 24.6 mmol, 20.0 equiv). The reaction mixture 20 was stirred for 3 h at room temperature and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL) and the organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was chromatographed on a silica gel column (Column: 120 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 50 mL / min; Gradient: 0% B to 15% B in 30 25 min; Wave Length: 220nm nm; Collected fractions: 7% - 8% B) to provide the desired product (400 mg, 49% yield) as a yellow oil.

[0639] LCMS(ESI-MS) m / z = 588.3 [M+H]+

[0640] Rt: 0.860 min (Method 5) 3.23.3. Step 3: tert-butyl (S)-(3-((tert-butyldimethylsilyl)oxy)phenyl)(3-(4-((2,2,21,21-30 tetramethyl-14,19-dioxo-3,3-diphenyl-4,7,10,20-tetraoxa-13,18-diaza-3-siladocosan-15-yl)amino)- 1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate and tert-butyl (S)-(3- hydroxyphenyl)(3-(4-((2,2,21,21-tetramethyl-14,19-dioxo-3,3-diphenyl-4,7,10,20-tetraoxa-13,18- diaza-3-siladocosan-15-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate

[0641] To a stirred mixture of tert-butyl (S)-(15-amino-2,2-dimethyl-14-oxo-3,3-diphenyl-4,7,10-trioxa- 35 13-aza-3-silaheptadecan-17-yl)carbamate (200 mg, 0.340 mmol, 1.0 equiv), Int-4 (217 mg, 0.340 mmol, 1.0 equiv), tris(dibenylideneacetone)dipalladium (62.3 mg, 0.068 mmol, 0.2 equiv) and 1',3',5'-triphenyl- 5-{[(1r,3R,5S,7s)-adamantan-1-yl][(3R,5S,7s)-adamantan-1-yl]phosphanyl}-1'H-1,4'-bipyrazole (45.1mg, 0.068 mmol, 0.2 equiv) in 1,4-dioxane (3 mL) was added sodium benzenolate (158 mg, 1.36 mmol, 4.0 equiv). The reaction mixture was stirred for 3 h at 70 °C under nitrogen and quenched with water (70 mL). The resulting mixture was extracted with EtOAc (3 x 70 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under 5 reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: ethyl acetate / petroleum ether =1.5:1; Rf = 0.5, 0.7; detection: UV) to provide tert-butyl (S)-(3-((tert- butyldimethylsilyl)oxy)phenyl)(3-(4-((2,2,21,21-tetramethyl-14,19-dioxo-3,3-diphenyl-4,7,10,20- tetraoxa-13,18-diaza-3-siladocosan-15-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)p...

Claims

CLAIMS 1. A compound, or a pharmaceutically acceptable salt, solvate, salt of a solvate thereof, according to Formula I:wherein X1 is =CR3a- or N-, X2 is =CR3b- or =N-, and X3 is =CR3c- or =N-; L is 5-15 membered hydrocarbon chain saturated or comprising one or more independently selected double or triple bonds, wherein one or more carbon atoms is optionally replaced by one or more independently selected N, O, P, or S heteroatoms, which chain is optionally substituted with one or more independently selected -C1-4alkyl, -C1-4alkoxy, -OH, or =O; Each R1a, R1b, R2a, and R2bis independently selected from: - H - =O (R1atogether with R1b, and / or R2atogether with R2b), - halo, - -OH, - -CN, - -NH2, - -NHR9a, - -NR9bR9c, - -S 2R9d, - - -- - - -C(=O)OH, - - - - -- -S(=O)R9k,- -S(=O)(=NR9l)R9m, - C1-6alkyl, optionally substituted with one or more independently selected R6a, - C1-6alkoxy, optionally substituted with one or more independently selected R6b, - C37cycloalkyl, optionally substituted with one or more independently selected R6c, - C5-12membered fused, spiro or bridged polycyclic cycloalkyl, optionally substituted with one or more independently selected R6d, - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6e, and - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6f; or R1aand R2a, together with the atoms to which they are attached together may form a - C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g, - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6h; or - 5-12 membered fused, spiro or bridged polycyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, optionally substituted with one or more independently selected R6i; Each R3a, R3b, R3cis independently selected from: - H - halo, - -OH, - -CN, - -NH2, - -NHR10a, - -NR10aR10b, - C1-4 alkyl optionally substituted with one or more independently selected halo, - C1-4 alkoxy optionally substituted with one or more independently selected halo, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, and - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; Each R4aand R4bis independently selected from H, or -C1-4alkyl optionally substituted with one or more independently selected halo; A is -S- or -O- and B is =CR5-, or A is =CH- or =N- and B is -NR5-;R5is -C1-4alkyl optionally substituted with one or more independently selected - halo, - -CN, - -OH, - monocyclic C3-6cycloalkyl optionally substituted with one or more independently selected halo, or - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo; X is absent, -CH2-, -O-, or -NH-; Each R6a, R6b, R6c, R6d, R6e, R6f, R6g, R6h, and R6i, is independently selected from: - oxo, - halo, - -OH, - -CN, - -C(=O)OH, - -C(=O)OR11a, - -OC(=O)R11b, - -S(=O)2R11c, - -S(=O)2NH2, - -S(=O)2NHR11d, - -S(=O)2NR11dR11e, - -C(=O)NH2, - -C(=O)NHR11f,- -C(=O)NR11fR11g,- -NH2, - -NHR11h, - -NR11hR11i, - -C(=O)R11j, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, - C1-4 alkoxy optionally substituted with one or more independently selected h , -CN, or -C1-4 alkoxy, Cy is,, , , orwherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8, R8a3, and R8a4, is independently selected from:- H, - halo, - -CN, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or -C1-4 alkoxy, - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, or -C1-4alkoxy, - -OH, - -OR12a, - -NH2, - -NHR12b, - -NR12bR12c, - -S(=O)2R12d, - -S(=O)2NH2, - -S(=O)2NHR12e, - -S(=O)2NR12eR12f, - -C(=O)R12g, - -C(=O)OH, - -C(=O)OR12h, - -C(=O)NH2, - -C(=O)NHR12g, - -C(=O)NR12gR12h, - -P(=O)R12iR12j, - -S(=O)R12k, - -S(=O)(=NR12l)R12m, - C3-7 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo, - 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, P, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, or -C1-4 alkoxy optionally substituted with one or more independently selected halo; Y is -O-, or -NR7, wherein R7is H, C1-6 alkyl, C3-6 cycloalkyl, -C(=O)C1-6 alkyl, -C(=O)C3-6 cycloalkyl, or -C(=O)C1-6 alkoxy; and Each R9a, R9b, R9c, R9d, R9e, R9f, R9g, R9h, R9i, R9j, R9k, R9l, R9m, R10a, R10b, R11a, R11b, R11c, R11d, R11e, R11f, R11g, R11h, R11i, R11j, R11k, R11l, R11m, R12a, R12b, R12c, R12d, R12e, R12f, R12g, R12h, R12i, R12j, R12k, R12l, and R12mis independently selected from:- C1-4alkyl optionally substituted with one or more independently halo, -OH, oxo, -CN, -C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo, - monocyclic C3-6cycloalkyl optionally substituted with one or more independently selected halo, - OH, oxo, -CN, -C1-4alkyl optionally substituted with one or more halo, or -C1-4alkoxy optionally substituted with one or more halo, or - monocyclic 4-8 membered monocyclic heterocycloalkyl comprising one or 2 double bonds, comprising one, two or three heteroatoms independently selected from N, O, P, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN -C1-4 alkyl optionally substituted with one or more halo, or -C1-4 alkoxy optionally substituted with one or more halo.

2. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is according to Formula IV:

3. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein A is S, or O, and B is -CR5. In a particular embodiment, R5is, wherein * represents the attachment point.

4. The compound, pharmaceutically salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claim 1-2, wherein A is =CH-, and B is -NR5. In a particular embodiment, R5is,,, wherein * represents the attachment point.

5. The compound, acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the subscript m is 0.

6. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable to claim 1-5, wherein Cy is:

7. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 6, wherein Cy is phenyl and each R8a1, R8a2, R8a3, and R8a4is independently selected from: H, F, Cl, -CN, -C(=O)NHCH3, -C(=O)NHCH2CF3, -S(=O)2CH3, pyrazolyl, -P(=O)(CH3)2, -OCH3, -C(=O)OH, -C(=O)N(CH3)2, -C(=O)NH2, -C(=O)morpholinyl, - C(=O)NH-oxetanyl, -C(=O)OCH3, -S(=O)2NH2, or -CF3.

8. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein L is , , ,wherein # is attached to Cy and ## is attached to -CRaR2b- of Formula I.

9. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R1aand R2a, together with the atoms to which they are attached together may form a C3-7 membered monocyclic cycloalkyl ring, optionally substituted with one or more independently selected R6g, and each R6gis independently selected from =O, -C1-4 alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i.

10. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R1aand R2a, together with the atoms to which they are attached together may form a 4-7 membered heterocycloalkyl comprising one or more N, O, or S atoms, optionally substituted with one or more independently selected R6h, and each R6his independently selected from =O, -C1-4alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-10.

12. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or a pharmaceutical composition according to claim 12 for use in medicine.

13. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or a pharmaceutical composition according to claim 12 for use in the prophylaxis and / or treatment of proliferative diseases.

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