Compounds and pharmaceutical compositions thereof for the treatment of proliferative diseases

Abstract

The present invention discloses compounds according to Formula I: (I) wherein R1a, R1b, R2a, R2b, R4a, R4b, X, Y, Cy, L, A, B, X1, X2, X3, Z1 and Z2 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 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

[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, 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 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).

[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 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 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 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 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

[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 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:I wherein X1is =CR3a- or =N-, X2is =CR3b- or =N-, and X3is =CR3c- or =N-; Each Z1and Z2is independently selected from C and 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 C1-4alkyl, 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(=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,- -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, - C3 7cycloalkyl, 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, - 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, - C1-4alkyl 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 C1-4alkyl optionally substituted with one or more independently selected halo; A is selected from N, CH, S or O; B is selected from CR5, or NR5; R5is C1-4alkyl or C1-4thioalkyl, each of which is 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, OH, or C1- 4 alkoxy, - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, OH, or C1-4 alkoxy; - monocyclic C3-6cycloalkyl optionally substituted with one or more independently selected halo, -CN, OH, C1-4alkyl or C1-4alkoxy, - 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, -CN, OH, C1-4alkyl or C1-4alkoxy; Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8; Each R8is independently selected from - halo, - -CN, - 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 halo, -CN, or C1-4 alkoxy, - -OH,- -OR12a, - -NH2, - -NHR12b, - -NR12bR12c, - -S(=O)2R12d,- Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, 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, - 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,

[0012] C1-4 alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n, and

[0013] C1-4 alkynyl comprising 1 or 2 triple bonds, optionally substituted with one or more independently selected R12o; Y is -C(=O)NR7a-, or -NR7bC(=O)-; each R7a, and R7bis H, C1-6alkyl, C3-6cycloalkyl, -C(=O)C1-6alkyl, -C(=O)C3-6cycloalkyl, or -C(=O)C1-6alkoxy; andEach R9a, R9b, R9c, R9d, R9e, R9f, R9g, R9h, R9i, R9j, R9k, R9l, R9m, R10a, R10b, R11a, R11b, R11c, R11d, R11e, R11f,independently selected from: - 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 C3-6cycloalkyl 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, 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.

[0014] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of proliferative diseases.

[0015] 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.

[0016] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0017] 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 composition or compounds of the invention as described herein.

[0018] 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.

[0019] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0020] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0021] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.DETAILED DESCRIPTION OF THE INVENTION Definitions

[0022] 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.

[0023] 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 their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0024] 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.

[0025] ‘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.

[0026] ‘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.

[0027] ‘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.

[0028] ‘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 straightchained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (CH2- CH2-), or -CH(CH3)- and the like.

[0029] ‘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-.

[0030] ‘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-.

[0031] ‘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. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0032] ‘Amino’ refers to the radical -NH2.

[0033] ‘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. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0034] ‘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 cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0035] ‘Cyano’ refers to the radical -CN.

[0036] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0037] 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.

[0038] ‘Hetero’ when used to describe a compound or a group present on a compound means that one 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.

[0039] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes 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 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 in the 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.

[0040] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1,3- dihydroisobenzofuran, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2- benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4- tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0041] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0042] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0043] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0044] 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, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0045] 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, imidazolyl, oxazolyl and pyrazinyl.

[0046] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0047] ‘Heterocycloalkyl’ means a non-aromatic fully or partially saturated ring structure, monocyclic, 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 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.

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

[0049] 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-.

[0050] 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 each Z is selected from N or CH.

[0051] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O- and –S-.

[0052] Particular examples of monocyclic partially saturated heterocycloalkyl rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, and –S-, and Z is P, N, or CH.

[0053] ‘hydrocarbon chain’ refers to an organic molecule consisting of nothing else but carbon and hydrogen 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 in the chain by breaking the double-bond (alkene) or triple bond (alkyne) between carbon atoms.

[0054] ‘Hydroxyl’ refers to the radical -OH.

[0055] ‘Oxo’ refers to the radical =O.

[0056] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0057] 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.

[0058] 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 non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of theheteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0059] ‘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 that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0060] ‘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 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 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, 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 are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0061] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0062] ‘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.

[0063] ‘Solvate’ refers to forms of the compound that are associated with a solvent, usually by a 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 molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses bothsolution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0064] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0065] ‘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.

[0066] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or 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.

[0067] 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 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.

[0068] ‘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 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.

[0069] As used herein the term ‘proliferative disease(s)’ refers to diseases associated with excessive 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.

[0070] 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, 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 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, 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, 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, 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, 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.

[0071] 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 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).

[0072] ‘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, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where thecontext 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.

[0073] When ranges are referred to herein, for example but without limitation, C1-8alkyl, the citation of a range should be considered a representation of each member of said range.

[0074] 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 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 invention.

[0075] 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 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 the proportion 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.

[0076] 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.

[0077] 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.

[0078] 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’.

[0079] 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’.

[0080] ‘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 may be 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.

[0081] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0082] 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.

[0083] Unless indicated otherwise, the description or naming of a particular compound in the 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

[0084] 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.

[0085] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or treatment of proliferative diseases by administering the compounds of the invention.

[0086] Accordingly, in a first 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-; Each Z1 and Z2 is independently selected from C and 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, - C1-6alkyl, optionally substituted with one or more independently selected R6a, - C1-6 alkoxy, optionally substituted with one or more independently selected R6b, - C3 7cycloalkyl, 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 - C3-7membered 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, - C1-4alkoxy 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 selected from N, CH, S or O; B is selected from CR5, or NR5; R5is C1-4alkyl or C1-4thioalkyl, each of which is 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, - C1-4alkyl optionally substituted with one or more independently selected halo, -CN, OH, or C1-4alkoxy, - C1-4 alkoxy optionally substituted with one or more independently selected halo, -CN, OH, or C1-4alkoxy; - monocyclic C3-6 cycloalkyl optionally substituted with one or more independently selected halo, - 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; Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8; Each R8is independently selected from: - halo, - -CN, - C1-4alkyl optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy, - 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, - Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo, - C3-7 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy 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, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo,

[0087] C1-4alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n, and

[0088] C1-4alkynylcomprising 1 or 2 triple bonds, optionally substituted with one or more independently selected R12o; Y is -C(=O)NR7a-, or -NR7bC(=O)-; Each R7a, and R7bis 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,independently selected from: - 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 C3-6cycloalkyl 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, 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, C1-4 alkyl optionally substituted with one or more halo, or C1-4 alkoxy optionally substituted with one or more halo.

[0089] Accordingly, in another aspect of the invention, the compounds of the invention are provided having a Formula (I), wherein X1is =CR3a- or =N-, X2is =CR3b- or =N-, and X3is =CR3c- or =N-; Each Z1and Z2is independently selected from C and 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, - C3 7cycloalkyl, 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,- 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 C1-4alkyl optionally substituted with one or more independently selected halo; A is selected from N, CH, S or O; B is selected from CR5, or NR5; R5is C1-4alkyl or C1-4thioalkyl, each of which is 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 a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8; Each R8is independently selected from: - halo, - -CN,- C1-4alkyl optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy, - 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,- Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo, - C3-7cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy 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 C1-4alkoxy optionally substituted with one or more independently selected halo; Y is -C(=O)NR7a-, or -NR7bC(=O)-; Each R7a, and R7bis H, C1-6alkyl, C3-6cycloalkyl, -C(=O)C1-6alkyl, -C(=O)C3-6cycloalkyl, or -C(=O)C1-6alkoxy; andEach 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, R12a, R12b, R12c, R12d, R12e, R12f, R12g, R12h, R12i, R12j, R12k, R12l, and R12mis independently selected from: - 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 C3-6cycloalkyl 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, 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.

[0090] Accordingly, 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-; Each Z1and Z2is independently selected from C and 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,- C1-6 alkyl, optionally substituted with one or more independently selected R6a, - C1-6alkoxy, optionally substituted with one or more independently selected R6b, - C3 7cycloalkyl, 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, - C1-4alkyl 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 C1-4alkyl optionally substituted with one or more independently selected halo; A is selected from N, CH, S or O; B is selected from CR5, or NR5; R5is C1-4alkyl or C1-4thioalkyl, each of which is 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, - -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, - C1-4alkyl optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy, and - C1-4alkoxy optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy; Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8; Each R8is independently selected from: - halo, - -CN, - 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 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,- 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 independentlyselected 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, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo; Y is -C(=O)NR7a-, or -NR7bC(=O)-; Each R7a, and R7bis 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, R12a, R12b, R12c, R12d, R12e, R12f, R12g, R12h, R12i, R12j, R12k, R12l, and R12mis independently selected from: - 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 C3-6cycloalkyl 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, 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, C1-4 alkyl optionally substituted with one or more halo, or C1-4 alkoxy optionally substituted with one or more halo.

[0091] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula (II):II wherein R1a, R1b, R2a, R2b, R3a, R3b, R3c, R4a, R4b, X, Y, Cy, Z1, Z2, L, A, and B are as previously defined.

[0092] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3ais H.

[0093] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3bis H.

[0094] In one embodiment, the compound of the invention is according to Formula I or II, wherein R3cis H.

[0095] In one embodiment, the compound of the invention is according to Formula I or II, wherein X is O or NH.

[0096] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula III:III wherein R1a, R1b, R2a, R2b, R4a, R4b, Y, Cy, Z1, Z2, L, A, and B is as previously defined.

[0097] In one embodiment, the compound of the invention is according to any one of Formula I-III, wherein Y is -NR7bC(=O)-. In a particular embodiment, R7bis H.

[0098] In one embodiment, the compound of the invention is according to any one of Formula I-III, wherein Y is -C(=O)NR7a. In a particular embodiment, R7ais H.

[0099] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula IV:wherein R1a, R1b, R2a, R2b, R4a, R4b, Cy, Z1, Z2, L, A, and B are as previously defined.

[0100] In one embodiment, the compound of the invention is according to any one of Formula I-IV, wherein R4ais H, -CH3, or -CF3.

[0101] In one embodiment, the compound of the invention is according to any one of Formula I-IV, wherein R4bis H, -CH3, or -CF3.

[0102] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula (V):V wherein R1a, R1b, R2a, R2b, Cy, Z1, Z2, L, A, and B is as previously defined.

[0103] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein B is selected from CR5, or NR5, wherein R5is C1-4 alkyl or C1-4 thioalkyl, each of which is 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. In a particular embodiment, R5is -CH3 or -SCH3, each of which 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. In a more particular embodiment, R5is -CH3 or -SCH3, each of which optionally substituted with one or more independently selected F, Cl, -CN, -OH, cyclopropyl optionally substituted with one or more independently selected halo. In a most particular embodiment, R5is, wherein * represents the attachment point.

[0104] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein Z1is C, Z2is C, A is -S- or -O-, and B is =CR5-. In a particular embodiment, Z1is C, Z2is C, A is S and B is =CR5-. In more particular embodiment, R5is ,, wherein * represents the attachment point.

[0105] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein Z1 is C, Z2 is C, A is =CH- or =N- and B is -NR5-. In a particular embodiment, A is =CH-, and B is -NR5. In more a particular embodiment, R5is, , , wherein * represents the attachment point.

[0106] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein Z1 is N, Z2 is C, A is =N- and B is =CR5-. In a particular embodiment, R5is ,, wherein * represents the attachment point.

[0107] In one embodiment, the compound of the invention is according to any one of Formula I-V, wherein Z1 is C, Z2 is N, A is =N- and B is =CR5-. In a particular embodiment, R5is ,, wherein * represents the attachment point.

[0108] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh:

[0109] Accordingly, in a second embodiment, the compounds of the invention are provided having a Formula VIa, or VIb: wherein

[0110] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S. In a particular embodiment, Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, or thiadiazolyl.

[0111] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8. In a particular embodiment, Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one, two or three independently selected R8. In a particular embodiment, Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one, or two independently selected R8. In a particular embodiment, Cy is a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one R8.

[0112] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted with one or more independently selected R8. In a particular embodiment, Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with one, two or three independently selected R8. In a particular embodiment, Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with one, or two independently selected R8. In a particular embodiment, Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with one R8.

[0113] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is halo. In a particular embodiment, one or more independently selected R8is F, Cl, or I.

[0114] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is CN.

[0115] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is C1-4alkyl optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy. In a particular embodiment, one or more independently selected R8is -CH3-CH2CH3, each of which is optionally substituted with one or more independently selected halo, -CN, or C1-4alkoxy. In a more particular embodiment, one or more independently selected R8is -CH3, or -CF3.

[0116] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8 is -NH2, -NHR12h, or -NR12hR12i. In a particular embodiment, R8is -NH2.

[0117] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is -C(=O)NH2, -C(=O)NHR12f, -C(=O)NR12fR12g. In a particular embodiment, R8is -C(=O)NH2, or -C(=O)NH(CH)3.

[0118] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is 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. In a particular embodiment, R8is cyclopropyl or cyclobutyl, each of which 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. In a more particular embodiment, R8is cyclopropyl.

[0119] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is C1-4 alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n, wherein R12nis as defined for Formula I. In a particular embodiment, R8is C1-4 alkenyl comprising 1 double bond, optionally substituted with one or more independently selected halo, or R12n.In a more particular embodiment, R8 iswherein * representsthe attachment point, each of which is optionally substituted with one or more independently selectedhalo, or R12n. In a most particular embodiment, R8 is ,wherein* represents the attachment point, each of which is optionally substituted with one or more independently selected F, Cl, cyclopropyl, -CN, -OH, -OCF3, or -OCH3.

[0120] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as previously described and one or more independently selected R8is C1-4 alkynyl comprising 1 or 2 triple bonds, optionally substituted with one or more independently selected halo, orR12o, wherein R12ois as defined for Formula I. In a particular embodiment, R8is C1-4 alkynyl comprising 1 triple bond, optionally substituted with one or more independently selected halo, or R12o. In a more particular embodiment, R8is, wherein * represents the attachment point, each of which is optionally substituted with one or more independently selected halo, or R12o. In a most particular embodiment, R8is, wherein * represents the attachment point, each of which is optionally substituted with one or more independently selected F, Cl, cyclopropyl, -CN, -OH, -OCF3, - OCH3, or oxetane.

[0121] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy iswherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, and R8a3is independently 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,- Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo, - C3-7cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, C1-4alkyl 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 C1-4alkoxy optionally substituted with one or more independently selected halo,

[0122] C1-4 alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n, and

[0123] C1-4 alkynyl comprising 1 or 2 triple bonds, optionally substituted with one or more independently selected R12o;

[0124] In one embodiment, the compound of the invention is according to any one of Formula I-VIh,wherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, and R8a3is independently selected from: - H,- halo, - -CN, - 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 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,- Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, 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, - 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, C1-4alkyl optionally substitutedwith one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0125] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy iswherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, and R8a3is independently 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,- -S(=O)R12k, - -S(=O)(=NR12l)R12m, - C3-7cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected halo, -OH, -CN, =O, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy 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;

[0126] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is:wherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, and R8a3is as previously described.

[0127] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein Cy is ,wherein * is attached to Y, and ** attached to L in Formula I, and each R8a1, R8a2, and R8a3is as previously described.

[0128] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a1is selected from H, halo, -CN, C1-4alkyl optionally substituted with one or more independently selected halo, -CN, -C(=O)NH2, - C(=O)NH(CH)3, NH2, C3-7cycloalkyl. In a particular embodiment, each R8a1is selected from H, F, Cl, I, -CN, -CH3, -CF3, -C(=O)NH2, -C(=O)NH(CH)3, -NH2, cyclopropyl. In a more particular embodiment, each R8a1is H.

[0129] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a2is selected from H, halo. C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -C(=O)NH2, - C(=O)NH(CH)3, NH2, C3-7 cycloalkyl.

[0130] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a2is a C1-4-alkenyl or C1-4-alkynyl, said C1-4- alkenyl or C1-4-alkynyl being optionally substituted with one or more independently selected halo, - C(=O)NH2, -C(=O)NH(CH)3, NH2, C3-7cycloalkyl, or 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, or C1-4alkyl, which C1-4alkyl is optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0131] In a particular embodiment, each R8a2is selected from H, F, Cl, I, -CN, -CH3, -CF3, -C(=O)NH2, -C(=O)NH(CH)3, NH2, cyclopropyl ,more particular embodiment, each R8a2is H.

[0132] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a3is selected from H, halo, -CN, C1-4 alkyl, optionally substituted with one or more independently selected halo, -C(=O)NH2, -C(=O)NH(CH)3, NH2, C3-7 cycloalkyl.

[0133] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a3is a C1-4-alkenyl or C1-4-alkynyl, said C1-4- alkenyl or C1-4-alkynyl being optionally substituted with one or more independently selected halo, - C(=O)NH2, -C(=O)NH(CH)3, NH2, C3-7 cycloalkyl, or 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, or C1-4 alkyl, which C1-4 alkyl is optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0134] In a particular embodiment, each R8a3is selected from H, F, Cl, I, -CN, -CH3, -CF3, -C(=O)NH2,-C(=O)NH(CH)3, NH2, cyclopropyl,moreparticular embodiment, each R8a3is H.

[0135] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a1, R8a2, and R8a3is independently selected from H, F, Cl, I, -NH2, -CN, -CH3, -CH2CH3, -CHF2, -CF3, cyclopropyl, cyclobutyl, phenyl, -C(=O)NH2, - C(=O)NHCH3, -C(=O)N(CH3)2, -OCH3, -OCHF2, , , and , .

[0136] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy is as described previously, wherein each R8a1, R8a2, and R8a3is independently selected from H, F, Cl, I, -NH2, -CN, -CH3, -CH2CH3, -CHF2, -CF3, cyclopropyl, cyclobutyl, phenyl, -C(=O)NH2, - C(=O)NHCH3, and -C(=O)N(CH3)2.

[0137] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy iswherein * is attached to Y, and ** attached to L in Formula I.

[0138] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein Cy iswherein * is attached to Y, and ** attached to L in Formula I.

[0139] In one embodiment, the compound of the invention is according to any one of Formula I-VIh,whereinwherein * is attached to Y, and ** attached to L in Formula I.

[0140] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, 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.

[0141] 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.

[0142] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein L is ,wherein # is attached to Cy and ## is attached to -CR2aR2b- of Formula I.

[0143] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein L iswherein # is attached to Cy and ## is attached to -CR2aR2b- of Formula I.

[0144] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R1ais H.

[0145] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein R1ais H.

[0146] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R1ais C1-6alkyl, 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.

[0147] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, 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.

[0148] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R1bis H.

[0149] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein R1bis H.

[0150] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R2ais H.

[0151] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein R2ais H.

[0152] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R2ais C1-6 alkyl, 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.

[0153] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, 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.

[0154] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein R2aand R2btogether is =O.

[0155] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein R2aand R2btogether is =O.

[0156] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, wherein 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, and each R6gis a previously described. In a particular embodiment, each R6gis independently selected from =O, halo,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.

[0157] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, 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, halo,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.

[0158] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, 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, halo, 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.

[0159] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, 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, halo, C1-4 alkyl or C1-4 monocyclic cycloalkyl 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,

[0160] In one embodiment, the compound of the invention is according to any one of Formula I-VIh, whereinselected from: ,Wherein R1band R2bis as previously described. In a particular embodiment, R1band R2bare both H.

[0161] In one embodiment, the compound of the invention is according to any one of Formula I-VIb, wherein is selected from:Wherein R1band R2bis as previously described. In a particular embodiment, R1band R2bare both H.

[0162] In one embodiment, a compound of the invention is selected from the illustrative compounds of Table IV.

[0163] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0164] 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 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.

[0165] In one embodiment, a compound of the invention is provided whereby a single atom of the 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.

[0166] 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 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.

[0167] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0168] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt of the compound.

[0169] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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 not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0175] 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 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, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention. PHARMACEUTICAL COMPOSITIONS

[0176] 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 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 response of the individual patient, the severity of the patient’s symptoms, and the like.

[0177] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0178] 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 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.

[0179] In a particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent 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 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, 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, 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 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, 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 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.

[0180] In a further particular embodiment, the present invention provides pharmaceutical compositions 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).

[0181] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and 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.

[0182] 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 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 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.

[0183] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous 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 or saccharin; or a flavouring agent such as peppermint or orange flavouring.

[0184] 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.

[0185] 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. 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.

[0186] 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 membrane type, or of a solid matrix variety.

[0187] 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.

[0188] 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).

[0189] 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 following pharmaceutical compositions. Formulation 1 - Tablets

[0190] 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 of the invention according to Formula I per tablet) in a tablet press. Formulation 2 - Capsules

[0191] 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). Formulation 3 - Liquid

[0192] 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 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

[0193] 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 compound of the invention according to Formula I) in a tablet press. Formulation 5 - Injection

[0194] 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

[0195] 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

[0196] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0197] 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, myeloproliferative disorders, leukaemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.

[0198] 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 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.

[0199] 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 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.

[0200] 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 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 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 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 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, 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, 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 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.

[0201] 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, 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, 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, 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, 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, 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, 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 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.

[0202] 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 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 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, 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, 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 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, 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 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.

[0203] 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 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).

[0204] 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 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).

[0205] 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 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).

[0206] 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.

[0207] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, 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, 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.

[0208] 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.

[0209] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0210] 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 genetic testing or screening to be particularly susceptible to developing the condition.

[0211] 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 more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0212] 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.

[0213] 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. 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 or leukaemia.

[0214] In one embodiment, a compound of the invention can be co-administered with an MDM2 (Mouse double minute 2 homolog, also known as E3 ubiquitin-protein ligase Mdm2) inhibitor or degrader, in particular Nutlin-1 (CAS#548472-58-8) , Nutlin-2 (CAS#548472-76-0), Nutlin-3 (CAS#548472-68-0), RG7112 (CAS#939981-39-2), Idasanutlin (CAS#1229705-06-9), AMG-232 (CAS#1352066-68-2), APG-115 (CAS#1818393-16-6), APG-265, NVP-CGM097 (CAS#313363-54- 0), Siremadlin (CAS#1448867-41-1), SAR405838 (CAS#1303607-60-4), MK-8242 (CAS# 69-74-9), Milademetan (CAS# 1398568-47-2), OM-301 (CAS# not found), NW-8184, AA-267, BI-907828 (CAS# 2095116-40-6), ASTX-295 (NCT03975387) & KT-293 (NCT05775406).

[0215] 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 pharmaceuticalcomposition, this is not essential. The agents may be administered in different formulations and at different times. CHEMICAL SYNTHETIC PROCEDURES General

[0216] 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 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.

[0217] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may 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).

[0218] 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 prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0219] 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. 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 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 Table I. Description of LC-MS method The analysis below is performed on a Shimadzu LCMS-2020Description Description A method name E flow (mL / min) B column type F column temperature (°C) C mobile phase G run time (mn) D gradient A B C D E F G From 95% A to 5% A in 0.99min, held for HALO 90A C18 A: Water+0.05%TFA 1 0.4min, to 95% A in 1.5 40 1.52 (2.0μm, 3.0*30mm) B: MECN+0.05%TFA 0.02 min, held for 0.1min From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.05%TFA 2 1.1min, to 95% A in 1.5 40 2 (2.0μm, 3.0*30mm) B: MECN+0.05%TFA 0.02 min, held for 0.18min From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.1%FA 3 1.1min, to 95% A in 1.2 40 2 (2.0μm, 3.0*30mm) B: MECN+0.1%FA 0.02 min, held for 0.18min From 95% A to 10% A Shim‐pack Scepter A: 5mM NH4HCO3 in in 0.99min, held for 4 C18‐120 (3.0μm, H2O / MeCN(95:5, v:v); 0.4min, to 95% A in 1.5 40 1.5 3.0*33mm) B: MeCN 0.02 min, held for 0.08min From 95% A to 0% A in 0.99min, held for HALO 90A C18 A: Water+0.1%FA 5 0.4min, to 95% A in 1.2 40 1.5 (2.0μm, 3.0*30mm) B: MECN+0.1%FA 0.02 min, held for 0.08min From 95% A to 0% A in 0.99min, held for HALO 90A C18 A: Water+0.05%TFAB: 6 0.4min, to 95% A in 1.5 40 1.5 (2.0μm, 3.0*30mm) MECN+0.05%TFA 0.02 min, held for 0.08minA B C D E F G From 95% A to 0% A in 1.19min, held for HALO C18(2.0μm, A: Water+0.05%TFA 7 0.6min, to 95% A in 1.5 40 2 3.0*30mm) B: MECN+0.05%TFA 0.02 min, held for 0.18min From 95% A to 10% A A: Shim‐pack Scepter in 1.19min, held for 5%MeCN,95%Water / 5mM 8 C18‐120 (3.0μm, 0.6min, to 95% A in 1.5 40 2 NH4HCO33.0*33mm) 0.02 min, held for B: MeCN 0.18min From 95% A to 40% A in 1.69min, to 5% A in HALO C18(2.0μm, A: Water+0.05%TFA 0.6 min, held for 9 1.5 40 3 3.0*30mm) B: MECN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 95% A to 0% A in Kinetex XB-C18 0.69min, held for A: Water+0.05%TFA 0 100A (1.7μm, 1.1min, to 95% A in 1.0 40 2 B: MECN+0.05%TFA 4.6*150mm) 0.02 min, held for 0.18min From 95% A to 0% A in HALO 90A 1.19min, held for A: Water / 0.1%FA 1 C18(2.0μm, 0.6min, to 95% A in 1.2 40 2 B: MeCN / 0.1%FA 3.0*30mm) 0.02 min, held for 0.18min. From 95% A to 50% A in 1.69min, to 5% A in HALO C18(2.0μm, A: Water+0.05%TFA 0.6 min, held for 2 1.5 40 3 3.0*30mm) B: MECN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 95% A to 40% A in 1.69min, to 5% A in HALO C18(2.0μm, A: Water+0.05%TFA 0.6 min, held for 3 1.5 40 3 3.0*30mm) B: MECN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17minA B C D E F G From 60% A to 10% A A: Shim‐pack Scepter in 1.19min, held for 5%MeCN,95%Water / 5mM 4 C18‐120 (3.0μm, 0.6min, to 95% A in 1.5 40 2 NH4HCO33.0*33mm) 0.02 min, held for B: MeCN 0.18min From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.1%FA 5 1.1min, to 95% A in 1.2 40 2 (2.0μm, 3.0*30mm) B: MECN+0.1%FA 0.02 min, held for 0.18min From 90% A to 10% A Shim‐pack Scepter A: Water / 6.5mM in 0.69min, held for 6 C18‐120 (3.0μm, NH4HCO31.1min, to 90% A in 1.2 40 2 2.1*33mm) B: MeCN 0.02 min, held for 0.18min From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.1%FA 7 0.4min, to 95% A in 1.2 40 1.2 (2.0μm, 3.0*30mm) B: MECN+0.1%FA 0.02 min, held for 0.08min From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.05%TFA 8 0.4min, to 95% A in 1.5 40 1.2 (2.0μm, 3.0*30mm) B: MECN+0.05%TFA 0.02 min, held for 0.08min From 70% A to 30% A A: in 1.69min, to 10% A in Shim‐pack Scepter 5%MeCN,95%Water / 5mM 0.6 min, held for 9 C18‐120 (3.0μm, 1.5 40 3 NH4HCO3 0.5min, to 95% A in 3.0*33mm) B: MeCN 0.03 min, held for 0.17min From 90% A to 10% A Shim‐pack Scepter in 0.69min, held for A: Water / 5mM NH4HCO30 C18‐120 (3.0μm, 1.1min, to 90% A in 1.5 40 2 B: MeCN 3.0*33mm) 0.02 min, held for 0.18minA B C D E F G From 95% A to 10% A Shim‐pack Scepter A: 5mM NH4HCO3in in 0.69min, held for 1 C18‐120 (3.0μm, H2O / MeCN(95:5, v:v); 1.1min, to 95% A in 1.5 40 2 3.0*33mm) B: MeCN 0.02 min, held for 0.08min From 90% A to 10% A Shim‐pack Scepter A: Water / 6.5mM in 0.99min, held for 2 C18‐120 (3.0μm, NH4HCO3 0.4min, to 90% A in 1.2 40 1.5 2.1*33mm) B: MeCN 0.02 min, held for 0.08min From 95% A to 50% A in 1.69min, to 0% A in HALO C18(2.0μm, A: Water+0.05%TFA 0.6 min, held for 3 1.2 40 3 3.0*30mm) B: MECN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 70% A to 30% A in 1.69min, to 5% A in HALO C18(2.0μm, A: Water+0.05%TFA 0.6 min, held for 4 1.5 40 3 3.0*30mm) B: MECN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 95% A to 0% A in 0.99min, held for CORTECS T3 A: Water+0.1%FA 5 0.4min, to 95% A in 1.2 40 1.5 (2.7μm, 2.1*30mm) B: MECN+0.1%FA 0.02 min, held for 0.08min From 90% A to 10% A Shim‐pack Scepter in 0.99min, held for A: Water / 5mM NH4HCO36 C18‐120 (3.0μm, 0.4min, to 90% A in 1.5 40 1.5 B: MeCN 3.0*33mm) 0.02 min, held for 0.08min From 95% A to 0% A in 1.09min, held for HALO 90A C18 A: Water+0.05%TFA 7 0.3min, to 95% A in 1.5 40 1.5 (2.0μm, 3.0*30mm) B: MECN+0.05%TFA 0.02 min, held for 0.08minA B C D E F G From 80% A to 40% A in 1.69 min, to 5% A in HALO C18 A: Water+0.05%TFA 0.6 min, held for 8 1.5 40 3 (2.0μm, 3.0*30mm) B: ACN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 90% A to 10% A Shim‐pack Scepter in 0.69min, held for A: Water / 6.5mM 9 C18‐120 (3.0μm, 0.4min, to 90% A in 1.2 40 1.2 NH4HCO3B: Acetonitrile 2.1*33mm) 0.02 min, held for 0.08min From 80% A to 50% A in 1.69min, to 5% A in HALO C18 (2.0μm, A: Water+0.05%TFA B: 0.6 min, held for 0 1.5 40 3 3.0*30mm) ACN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min From 90% A to 10% A Shim‐pack Scepter in 0.99min, held for A: Water / 6.5mM 1 C18‐120 (3.0μm, 0.4min, to 90% A in 1.5 40 1.5 NH4HCO3B: Acetonitrile 3.0*33mm) 0.02 min, held for 0.08min XBridge C18 A: 5mM NH4HCO3 in From 80% A to 40% A 2 (3.5μm, water / Acetonitrile (90:10, in 6min, to 5% A in 2 1.0 40 8 3.0*100mm) v:v); B: Acetonitrile min， 600 bar HALO 90A C18 From 90% A to 50% A A: Water+0.1%FA B: 3 (2.7μm, in 6min, held 2 min， 1.0 40 8 ACN+0.1%FA 3.0*100mm) 1300 bar From 90% A to 5% A in Shim‐pack Scepter 0.69min, held for A: Water / 5mM NH4HCO3 4 C18‐120 (3.0μm, 0.4min, to 90% A in 1.5 40 1.2 B: Acetonitrile 3.0*33mm) 0.02 min, held for 0.08min From 90% A to 10% A Shim‐pack Scepter in 0.69min, held for A: Water / 5mM NH4HCO35 C18‐120 (3.0μm, 0.7min, to 90% A in 1.5 40 1.5 B: Acetonitrile 3.0*33mm) 0.02 min, held for 0.08minA B C D E F G From 95% A to 60% A in 1.69min, to 5% A in HALO C18 (2.0μm, A: Water+0.05%TFA 0.6 min, held for 6 1.5 40 3 3.0*30mm) B: ACN+0.05%TFA 0.5min, to 95% A in 0.03 min, held for 0.17min XBridge C18 A: 5mM NH4HCO3in From 98% A to 85% A 7 (3.5μm, water / Acetonitrile (90:10, in 6min, held for 2 min 1.0 40 8 3.0*100mm) v:v); B: Acetonitrile ， 600 bar From 95% A to 0% A in 0.69min, held for HALO 90A C18 A: Water+0.05%TFA B: 8 0.7min, to 95% A in 1.5 40 1.5 (2.0μm, 3.0*30mm) ACN+0.05%TFA 0.02 min, held for 0.08min From 90% A to 5% A in HALO 160A, ES‐ A: Water+0.025%TFA 7.99min, held for 2min, 9 C18(2.7μm, 1.2 40 11 B: ACN+0.025%TFA to 95% A in 0.1 min, 4.6*100mm) held for 0.9min From 70% A to 30% A in 1.69min, to 10% A in Shim‐pack Scepter A: Water / 5mM NH4HCO30.6 min, held for 0 C18‐120 (3.0μm, 1.5 40 3 B: Acetonitrile 0.5min, to 90% A in 3.0*33mm) 0.03 min, held for 0.17min From 80% A to 40% A Shim‐pack Scepter in 1.69min, to 10% A in A: 5mM NH4HCO3in C18‐ 0.6 min, held for 1 H2O / ACN (95:5, v:v); 1.5 40 3 120 (3.0μm, 0.5min, to 95% A in B: Acetonitrile 3.0*33mm) 0.03 min, held for 0.17min A: Water+0.1%FA From 95% A to 5% A in 1.5 40 1.5 Shimadzu LCMS- B: ACN+0.1%FA 0.84min, held for 2020 2 0.5min, to 95% A in HALO 90A C18 0.02 min, held for (2.0μm, 3.0*30mm) 0.13minA B C D E F G A: Water+0.05%TFA From 95% A to 0% A in 1.5 40 1.5 Shimadzu LCMS- B: ACN+0.05%TFA 0.84min, held for 2020 3 0.5min, to 95% A in HALO 90A C18 0.02 min, held for (2.0μm, 3.0*30mm) 0.13min Shimadzu LCMS- A: Water+0.05%TFA From 95% A to 0% A in 1.5 40 1.5 2020 B: ACN+0.05%TFA 0.39min, held for 4 HALO 90A C18 0.95min, to 95% A in (2.0μm, 3.0*30mm) 0.02 min, held for 0.13min Shimadzu LCMS- A: Water+0.1%FA From 90% A to 60% A 1.0 40 10 2020 B: ACN+0.1%FA in 6min, to 5% A in 2 5 HALO 90A C18 min，held for 2 min (2.7μm, 1300 bar 3.0*100mm) Shimadzu LCMS- A: 5mM NH4HCO3 in From 70% A to 30% A 1.0 40 8 2020 H2O / Acetonitrile (90:10, v:v); in 6min, to 5% A in 2 6 XBridge C18 B: Acetonitrile min， 600 bar (3.5μm, 3.0*100mm) A: Water / 5mM From 70% A to 50% A 1.5 40 3 Shimadzu LCMS- NH4HCO3 B: Acetonitril in 1.69min, to 10% A in 2020 e (95:5, v:v); 0.6 min, held for 7 Shim‐pack Scepter C18‐120 0.5min, to 90% A in (3.0μm, 0.03 min, held for 3.0*33mm) 0.17min Shimadzu LCMS- A: Water / 5mM From 90% A to 10% A 1.5 40 2 2020 NH4HCO3 B: Acetonitrile in 1.19min, held for 8 Shim‐pack Scepter 0.6min, to 90% A in C18‐120 (3.0μm, 0.02 min, held for 3.0*33mm) 0.18min Shimadzu LCMS- A: Water+0.1%FA From 95% A to 0% A in 1.5 40 1.2 2020 B: ACN+0.1%FA 0.84min, held for 9 Shim‐pack Velox 0.5min, to 95% A in SP‐C18 (2.7μm, 0.02 min, held for 3.0*300mm) 0.13minA B C D E F G A: Water / 6.5mM From 40% A to 20% A 1.2 40 3 Shimadzu LCMS- NH4HCO3 B: Acetonitril in 1.69min, to 10% A in 2020 e 0.6 min, held for 50 Shim-pack Scepter C18 0.5min, to 10% A in (3.0μm, 2.1*33mm) 0.03 min, held for 0.17min A: Water+0.05%TFA From 95% A to 0% A in 1.5 40 1.0 Shimadzu LCMS- B: ACN+0.05%TFA 0.54min, held for 2020 51 0.35min, to 95% A in HALO 90A C18 0.02 min, held for (2.0μm, 3.0*30mm) 0.08min Table II. List of abbreviations used in the experimental section: Abbreviation Definition Abbreviation Definition MeCN Acetonitrile DMSO dimethylsulfoxide AcOH acetic acid Ethylenediaminetetraacetic EDTA acid aq. Aqueous eq. equivalent atm Atmosphere EtOAc Ethyl acetate ATP adenosine 5´-triphosphate EtOH ethanol 9-borabicyclo(3.3.1) 9-BBN nonane (CAS# 280-64-8) h hour b.i.d. bis in die (twice a day) N,N,N′,N′-Tetramethyl-O- (7-azabenzotriazol-1-yl) Cpd compound HATU uronium hexafluorophos (Tributylphosphoranylidene) phate (CAS# 148893-10-1) CMBP acetonitrile high-performance liquid (CAS# 157141-27-0) HPLC chromatography d doublet IPA isopropanol DCM dichloromethane Int intermediate DCE dichloroethane liquid chromatography-mass diisopropyl azodicarbo LCMS DIAD spectrometry xylate (CAS# 2446-83-5) LDA lithium diisopropylamide N,N-diisopropylethyl DIPEA m multiplet amine (CAS# 7087-68-5) DMF N,N-dimethylformamide MeOH methanol min minuteAbbreviation Definition Abbreviation Definition mmol millimole q quartet MS mass spectrometry q.d. quaque die (once daily) Mtd method RT room temperature MW molecular weight Rt retention time NA not available s singlet sodium cyanoborohydride sat. saturated NaBH3(CN) (CAS# 25895-60-7) SM starting material sodium triacetoxyboro NaBH(OAc)3hydride (CAS# 56553-60-7) t triplet PBS phosphate-buffered saline TEA triethylamine PIN percentage inhibition Acid trifluoroacetic TFA (CAS# 76-05-1) p.o. per os (orally) THF tetrahydrofuran ppm parts-per-million GENERIC SYNTHESIS SCHEMES Scheme 1Scheme 1 describes the synthesis of a compound of general formula A7, starting from A1. Hal1and Hal2are halogens independently selected from chloro, bromo and iodo, so that they can be sequentially reacted, for example Hal1 is chloro and Hal2is iodo or alternatively Hal1 is bromo and Hal2is iodo. First, coupling of A1 and A2 is accomplished via carbon-carbon coupling, for example via a Sonogashira reaction in case Hal2is iodo and Hal1is either chloro or bromo, using Pd(PPh3)2Cl2 and CuI / TEA in DMSO at room temperature, resulting in intermediate A3. The PG2in A2 is a typical protecting groupused for an amine, for example -Boc. Further reaction of intermediate A3 in a carbon-nitrogen coupling with amine A4 (PG1is a protecting group for a carboxylic acid, for example methyl, ethyl or tert-butyl), can be done for example by conditions described for compound 27 if Hal1is chloro or as described for compounds 43 / 44 if Hal1is bromo, resulting in a compound A5. Sequential deprotection of PG1and PG2can be done pending on PG1and PG2used, for example if PG1is Methyl or Ethyl and PG2is -Boc, then PG1can be deprotected by treatment with NaOH in MeOH / H2O. In this case, PG2can for example be deprotected with HCl in dioxane. Alternatively, depending on PG1and PG2used, PG1and PG2can both be deprotected under the same conditions, for example in case PG1is tert-butyl and PG2is -Boc, deprotection can be done with TFA in dichloromethane or HCl in dioxane. This results in the formation of intermediate A6 Finally, formation of an amide bond can be performed by typical conditions like for example use of HATU / DIPEA in DMF, resulting in compound A7 from intermediate A6. Scheme 2Scheme 2 depicts an alternative towards intermediate A5. In this case, intermediate A3 is coupled with amine B1 (PG3is a protecting group for an alcohol, for example -TBDPS), via a carbon-nitrogen bond formation. For example, if Hal1is Bromide as described in the examples for compound 28 and compounds 35 / 36. In the resulting intermediate B2, PG3can be deprotected, for example, by using TBAF in THF if PG3is TBDPS, resulting in intermediate B3. Intermediate B3 is then converted in intermediate 5. For example, if Cy is a N-linked heterocycle (to L), via a Mitsunobu reaction using the CMBP reagent. Examples of such heterocycle are, but not limited to, ethyl 1H-imidazole-4-carboxylate, tert-butyl 1H-pyrazole-4-carboxylate, methyl 1H-pyrazole-4-carboxylate, ethyl 1H-pyrazole-3- carboxylate, methyl 1H-1,2,3-triazole-4-carboxylate, 3,4-diethyl 1H-pyrrole-3,4-dicarboxylate, 1H- pyrrole-3-carboxylate. Alternatively, the hydroxy function can be converted to a leaving group, like a mesylate, followed by substitution with a heterocycle like ethyl 1H-imidazole-4-carboxylate or tert-butyl 1H-pyrazole-3-carboxylate or ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate in the presence of a base, like for example K2CO3 in DMF. Scheme 3Scheme 3 depicts the synthesis of intermediate C4, a subclass of intermediate B2, where R1bis hydrogen. Here, a reductive amination between amine C1 and C2, results in intermediate C3, followed by a Sonogashira reaction, similar as described earlier, with alkyne A2, resulting in intermediate C4. Scheme 4Alternatively, an intermediate D2 can be formed from D1 (Hal3for example bromo), by a substitution, (for example di-tert-butyl iminodicarbonate PG2= -Boc). Compound D2 can then be converted to a compound A7, similarly as described in scheme 1 and scheme 2, for example as described for compound 33 in the examples. Scheme 5The intermediate A4 can be prepared as described in scheme 5, starting from E1 (PG4is a protecting group for an amine, like for example -Cbz or -Boc). Deprotection of PG3and formation of E3 can bedone by similar transformations as described in scheme 1 and scheme 2. An example of PG3is TBDPS, PG4can be -Cbz and PG1-tBu. In this case, PG4can be deprotected using Pd on carbon under hydrogen atmosphere. SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION Example 1. Preparation of intermediates towards illustrative compounds of the invention. 1.1. Int-1: 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-amine1.1.1. Step 1: 4-(2,2-dimethylhydrazineylidene)-1-methylpiperidine

[0220] To a solution of 1-methylpiperidin-4-one (CAS# 1445-73-4; 2.00 g, 17.7 mmol, 1.0 equiv) in toluene (20 mL) was added 1,1-dimethylhydrazine hydrochloride (1.88 g, 19.4 mmol, 1.1 equiv) and TEA (1.97 g, 19.4 mmol, 1.1 equiv) stirred at RT. The reaction mixture was stirred for 4 h at 110 °C. 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 crude title compound (1.99 g, 64% yield) as a yellow oil.

[0221] LCMS(ESI-MS) m / z = 156.0 [M+H]+

[0222] Rt 0.355 min; Method 22 1.1.2. Step 2: 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane

[0223] To a solution of 2-[2-(2-bromoethoxy)ethoxy]ethanol (CAS# 57641-67-5; 10.0 g, 46.9 mmol, 1.0 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. Thecrude 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.

[0224] LCMS(ESI-MS) m / z = 473.0, 475.0 [M+Na]+

[0225] Rt 1.175 min; Method 1

[0226] 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 – 3.52 (m, 8H), 1.00 (s, 9H). 1.1.3. Step 3: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin- 4-one

[0227] To a stirred mixture of 4-(2,2-dimethylhydrazineylidene)-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 EtOAc remaining). Then Citric acid solution (10% in H2O) was added. The mixture was stirred at RT 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 afford the title compound (5.2 g, 43%) as a light yellow solid.

[0228] LCMS(ESI-MS) m / z = 484.4 [M+H]+

[0229] Rt: 1.071 min; Method 20 1.1.4. Step 4: Intermediates Int-1 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-amine

[0230] To a stirred mixture of 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (CAS# 2127096-38-0; 3.0 g, 8.82 mmol, 1.0 equiv) and 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-one (5.55 g, 11.5 mmol, 1.3 equiv) in AcOH (36 mL) and DCE (18 mL) was added 4A molecular sieves (6.0 g) at RT. The mixture was stirred at 50 °C for 5 h. Then NaBH(OAc)3(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 concentrated under reduced pressure to afford crude product. Thecrude 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 afford the title compound (5.7 g, 75%) as a brown solid.

[0231] LCMS (ESI-MS) m / z = 808.3 [M+H]+

[0232] Rt: 0.846 min; Method 2 1.2. Int-2: 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

[0233] Int-2 was prepared similarly as described for Int-1, using 2-iodo-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-amine (CAS# 2903922-15-4) instead of 2-iodo-1-(2,2,2- trifluoroethyl)-1H-indol-4-amine (CAS# 2127096-38-0) in step 4.

[0234] In particular Int 2 was prepared as follows:

[0235] 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), 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-one (5.28 g, 10.9 mmol, 1.3 equiv) and 4A molecular sieves (6.0 g) in AcOH (48 mL) and DCE (24 mL) was stirred for 5 h at 50 °C. Then NaBH(OAc)3 (3.56 g, 16.8 mmol, 2.0 equiv) was added. The reaction mixture 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, 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 compound (2.9 g, 41% yield) as a brown solid.

[0236] LCMS (ESI-MS) m / z = 825.2 [M+H]+

[0237] Rt: 0.820 min; Method 21.3. Int-3: tert-butyl (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

[0238] Described in the synthesis of compound Cpd 1 (step 2)

[0239] LCMS(ESI-MS) m / z = 597.3 [M+H]+.

[0240] Rt: 0.700 min; Method 5 1.4. Int-4: methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazole-4-carboxylate

[0241] Described in the synthesis of compound Cpd 7B (step 1)

[0242] LCMS(ESI-MS) m / z = 706.5 [M+H]+

[0243] Rt: 1.062 min; Method 4 1.5. Int-5: methyl 2-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3- triazole-4-carboxylate

[0244] Described in the synthesis of compound Cpd 7B (step 1)

[0245] LCMS(ESI-MS) m / z = 706.4 [M+H]+.

[0246] Rt: 0.748 min; Method 61.6. Int-6: tert-butyl (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

[0247] Described in the synthesis of compound Cpd 2 (step 2)

[0248] LCMS(ESI-MS) m / z = 614.3 [M+H]+

[0249] Rt: 0.735 min; Method 6 1.7. Int-7: 2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl methanesulfonate

[0250] Described in the synthesis of compound Cpd 3A (step 1)

[0251] LCMS (ESI-MS) m / z = 675.3 [M+H]+

[0252] Rt: 0.932 min; Method 7 1.8. Int-8: 4-(2,2-dimethylhydrazineylidene)-1-methylpiperidine

[0253] Described in the synthesis of intermediates Int-1 (step 1)

[0254] LCMS(ESI-MS) m / z = 156.0 [M+H]+

[0255] Rt 0.355 min; Method 221.9. Int-9: rac-tert-butyl (3-(4-(((3R,4R)-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 & Int-10: rac-tert-butyl (3-(4-(((3R,4S)-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

[0256] Intermediates Int-3 was separated by prep-ACHIRAL-SFC column (Column: GreenSep Basic 3*15 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.3%-7M-NH3-MeOH); Flow rate: 75 mL / min; Gradient (B%): isocratic 16% B; Column Temperature (℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; 260-2B / RT1(min): 8.38; 260-2A / RT2(min): 10.48; Sample Solvent: MeOH; Injection Volume: 1.5 mL; Number Of Runs: 70). Purification resulted in title intermediates Int-9 with Rt1(min): 8.38 as yellow solid.

[0257] LCMS(ESI-MS) m / z = 597.3 [M+H]+

[0258] Rt: 0.654 min; Method 2

[0259] And title intermediates Int-10 with Rt2 (min): 10.48 as yellow semi-solid.

[0260] LCMS(ESI-MS) m / z = 597.3 [M+H]+

[0261] Rt: 0.695 min; Method 2 1.10. Int-11: rac-2-(2-(2-((3R,4R)-4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl methanesulfonate

[0262] To a solution of Int-9 (200 mg, 0.335 mmol, 1.0 equiv) in DCM (3.8 mL) was added triethylamine (42.4 mg, 0.419 mmol, 1.25 equiv) and methanesulfonyl chloride (49.9 mg, 0.436 mmol, 1.3 equiv) at RT. The reaction mixture was stirred for 1 h at RT and quenched with water (20 mL). The resulting mixture was extracted with DCM (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 title compound( 250 mg, crude) as a yellow solid.

[0263] LCMS (ESI-MS) m / z = 675.3[M+H]+

[0264] Rt: 0.753 min; Method 6 1.11. Int-12: 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine1.11.1. Step 1: ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate

[0265] To a stirred mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (CAS# 1038393- 19-9; 4.0 g, 14.8 mmol, 1.0 equiv) and ammonium thiocyanate (2.26 g, 29.7 mmol, 2.0 equiv) in MeOH (40 mL) was added N-Chlorosuccinimide (4.01 g, 30.0 mmol, 2.02 equiv). The reaction mixture was stirred for 2 h at RT and concentrated under reduced pressure, DCM (100 mL) was added. The resulting mixture was stirred for 30 min and filtered, filter cake was washed with DCM (100 mL), filtrate was collected, filtrate was washed with 10% NH4Cl (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude product. The residue was triturated with MTBE (100 mL) at 25 °C for 1 hour and filtered to provide title compound (4.3 g, 79% yield).

[0266] LCMS(ESI-MS) m / z = 327.9 [M+H]+

[0267] Rt: 0.599 min; Method 25 1.11.2. Step 2: ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate

[0268] To a stirred mixture of ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (24.0 g, 73.5 mmol, 1.0 equiv) and Cs2CO3 (35.9 g, 110 mmol, 1.5 equiv) in ACN (144 mL) and DMF (72 mL)was added trimethyl(trifluoromethyl)silane (12.5 g, 88.2 mmol, 1.2 equiv). The reaction mixture was stirred for 4 h at RT and concentrated under vacuum, diluted with H2O (1000 mL), extracted with EtOAc (1000 mL X 3). The organic layer was washed with brine (1000 mL), dried over Na2SO4 and filtered. The crude product was dissolved by DCM (700 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to provide the title compound (13 g, 43% yield).

[0269] LCMS(ESI-MS) m / z = 369.0 [M+H]+

[0270] Rt: 0.794 min; Method 6 1.11.3. Step 3: 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid

[0271] To a stirred mixture of ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2- carboxylate (13.0 g, 35.2 mmol, 1.0 equiv) in MeOH (93 mL) was added LiOH.H2O (2.96 g, 70.4 mmol, 2.0 equiv, in H2O (13 mL)). The reaction mixture was stirred for 1 h at RT. The mixture was adjusted to pH = 3 with hydrochloric acid (2 M) and filtered. Then the filter cake was washed with MeOH (100mL) to provide the crude title compound (10 g, 74%) as a solid. The crude product was used for next step directly.

[0272] LCMS(ESI-MS) m / z = 342.9 [M+H]+

[0273] Rt: 0.512 min; Method 18 1.11.4. Step 4: Int-12 - 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine

[0274] To a stirred mixture of 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (6.0 g, 17.5 mmol, 1.0 equiv) and K3PO4(7.80 g, 36.7 mmol, 2.09 equiv) in DMF (90 mL) was added Iodine (27.0 g, 106 mmol, 6.05 equiv). The reaction mixture was stirred for 6 h at 130 °C. The reaction mixture was cooled to 20°C, then poured into 10% sodium sulfite solution (300 mL). The resulting mixture was stirred for 0.5 h at RT and filtered. The filter cake was collected and re-dissolve with EtOAc (200 mL). The organic layer was washed with saturated NaHCO3 (200 mL) and then washed with brine (200 mL). The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was triturated with MTBE: PE = 1: 1 (100 mL) at 20 °C for 1 hour and filtered to provide title compound (4.6 g, 52%).

[0275] LCMS(ESI-MS) m / z = 422.9 [M+H]+

[0276] Rt: 0.833 min; Method 6 1.12. Int-13: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin- 4-one

[0277] Described in the synthesis of intermediates Int-1 (step 3)

[0278] LCMS(ESI-MS) m / z = 484.4 [M+H]+

[0279] Rt: 1.071 min; Method 20 1.13. Int-14: 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin- 4-one

[0280] To a stirred mixture of Int-13 (20.0 g, 41.3 mmol, 1.0 equiv), 4A molecular sieve and ammonium formate (52.1 g, 827 mmol, 20.0 equiv) in methanol (300 mL) was added formic acid (3.81 g, 82.7 mmol, 2.0 equiv) was stirred for 5 hours at 35°C. Then NaBH3CN (7.79 g, 124 mmol, 3.0 equiv) was added and the reaction mixture was stirred for 2 hours at 35 °C. The resulting mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 500 mL) and the organic layers were combined, washed with brine (2 x 250 mL), dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford crude product. The crude product was purified by reverse phase (Column:C18 column, 350 g, Mobile Phase A: Water(0.05% FA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 0% B to 50% B in 40 min; Wave Length: 220 nm; 35% - 40% B fractions were collected) to provide the title compound (10.0 g , 44.0% yield).

[0281] LCMS(ESI-MS) m / z = 485.3 [M+H]+

[0282] Rt: 0.542 min; Method 2 1.14. Int-15 - 1-(7-amino-2-iodobenzo[b]thiophen-3-yl)-2,2,2-trifluoroethan-1-ol1.14.1. Step 1: methyl 7-nitrobenzo[b]thiophene-2-carboxylate

[0283] To a solution of 2-chloro-3-nitrobenzaldehyde (CAS# 58755-57-0; 40.0 g, 216 mmol, 1.0 equiv) and potassium carbonate (35.8 g, 259 mmol, 1.2 equiv) in DMF (400 mL) was added methyl thioglycolate (27.5 g, 259 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred for 8 h at RT. The mixture was added to water (1000 mL) and filtered through a celite pad and washed with water (3 x 500 mL). The filter cake was dried under reduced pressure to afford crude title compound (47 g, 87% yield).

[0284] No Ms ionization. 1.14.2. Step 2: 7-nitrobenzo[b]thiophene-2-carboxylic acid

[0285] To a solution of methyl 7-nitrobenzo[b]thiophene-2-carboxylate (47.0 g, 187 mmol, 1.0 equiv) in MeOH (400 mL) was added aqueous NaOH (400 mL, 2 M) at 0 °C. The reaction mixture was stirred for 8 h at RT. The reaction mixture was concentrated under reduced pressure to remove MeOH. The mixture was acidified to PH = 2-3 with hydrochloric acid (6 M) at 0 °C. The mixture was extracted with EtOAc (3 x 1000 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title product (40.0 g, 91% yield).

[0286] LCMS(ESI-MS) m / z = 221.9 [M-H]-

[0287] Rt: 0.693 min; Method 5 1.14.3. Step 3: 7-nitrobenzo[b]thiophene

[0288] To a solution of 7-nitrobenzo[b]thiophene-2-carboxylic acid (40.0 g, 179 mmol, 1.0 equiv) in DMF (400 mL) was added cuprous oxide (12.8 g, 89.6 mmol, 0.5 equiv) at RT. The reaction mixture was stirred for 12 h at 120 °C. The mixture was added to water (1000 mL) and filtered through a celitepad and washed with water (3 x 500 mL). The filter cake was diluted with DCM / MeOH (5 / 1) and filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford crude title product (30.0 g, 88% yield).

[0289] No Ms. 1.14.4. Step 4: 7-nitrobenzo[b]thiophene-3-carbaldehyde

[0290] To a solution of 7-nitrobenzo[b]thiophene (30.0 g, 167 mmol, 1.0 equiv) in DCM (300 mL) was added dropwise Titanium tetrachloride (95.3 g, 502 mmol, 3.0 equiv) over 30 minutes under nitrogen atmosphere at 0 °C. After stirred for 20 minutes at 0 °C, dichloromethyl methyl ether (104 g, 904 mmol, 5.4 equiv) was added dropwise over 20 min keeping the reaction temperature below 0 °C. The reaction mixture was stirred for 3 h at RT. The reaction mixture was quenched with ice water (500 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL) and the organic layers were 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 (Column: 330 g x 2, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 80 mL / min; Gradient: 0% B to 40% B in 40 min; Wave Length: 220nm; Collected fractions: 18% - 23% B), the fraction was concentrated under reduced pressure to provide the title compound (25.7 g, 70% yield). 1.14.5. Step 5: 2,2,2-trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-ol

[0291] To a solution of 7-nitrobenzo[b]thiophene-3-carbaldehyde (2.00 g, 9.65 mmol, 1.0 equiv) in THF (13 mL) was added cesium fluoride (1.47 g, 9.65 mmol, 1.0 equiv). After stirred for 0.5 h under nitrogen at 0 °C, trimethyl(trifluoromethyl)silane (2.06 g, 14.5 mmol, 1.5 equiv, in 13 mL THF) was added. The reaction mixture was stirred overnight at RT and quenched with water (80 mL). The resulting mixture was extracted with ethyl acetate (3 x 150 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 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 30% B in 40 min; Wave Length: 254nm; Collected fractions: 13% - 18% B), the fraction was concentrated under reduced pressure to provide the title compound (1.92 g, 64% yield). 1.14.6. Step 6: 2,2,2-trifluoro-1-(2-iodo-7-nitrobenzo[b]thiophen-3-yl)ethan-1-ol

[0292] To a mixture of 2,2,2-trifluoro-1-(7-nitrobenzo[b]thiophen-3-yl)ethan-1-ol (3.75 g, 13.5 mmol, 1.0 equiv) in acetic acid (45 mL) was added N-Iodosuccinimide (3.65 g, 16.2 mmol, 1.2 equiv) and trifluoromethanesulfonic acid (9 mL) at 0 °C. The reaction mixture was stirred for 4 h at RT and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL) and the organic layers were combined, washed with brine (2 x 120 mL), dried over anhydrous sodium sulfateand 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 30% B in 40 min; Wave Length: 254 nm; Collected fractions: 10% - 15% B), the fraction was concentrated under reduced pressure to title compound (4.00 g, 66% yield). 1.14.7. Step 7: Int-15 - 1-(7-amino-2-iodobenzo[b]thiophen-3-yl)-2,2,2-trifluoroethan-1-ol

[0293] A mixture of 2,2,2-trifluoro-1-(2-iodo-7-nitrobenzo[b]thiophen-3-yl)ethan-1-ol (1.00 g, 2.48 mmol, 1.0 equiv) in ethanol (25 mL) was added H2O (5 mL), Fe powder (346 mg, 6.20 mmol, 2.5 equiv) and ammonium chloride (544 mg, 10.2 mmol, 4.1 equiv). The reaction mixture was stirred for 1.5 h at 70 °C. The mixture was filtered through a celite pad and washed with EtOH (3 x 30 mL). The filtrate was diluted with H2O (50 mL) extracted with ethyl acetate (3 x 80 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: 330 g, 100 - 200 mesh; Mobile Phase A: petroleum ether, Mobile Phase B: ethyl acetate; Flow rate: 80 mL / min; Gradient: 0% B to 40% B in 40 min; Wave Length: 254nm; Collected fractions: 23% - 28% B), the fraction was concentrated under reduced pressure to provide the title compound (800 mg, 77% yield).

[0294] LCMS(ESI-MS) m / z = 373.9 [M+H]+

[0295] Rt: 0.779 min; Method 5 1.15. Int-16: 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine1.15.1. Step 1: 7-chloro-2-iodopyrazolo[1,5-a]pyridine

[0296] To a stirred mixture of 2-iodopyrazolo[1,5-a]pyridine (CAS# 2226273-35-2; 1.0 g, 4.09 mmol, 1.0 equiv) in THF (15 mL) was added LiHMDS (6.0 mL, 0.002 mmol, 1.5 equiv, 1M in THF) dropwise at -78°C under nitrogen. The mixture was stirred for 1 h at -78 °C. Then the hexachloroethane (1.07 g, 4.50 mmol, 1.1 equiv, in THF (5 mL)) was added at -78 °C and warmed to room temperature. The mixture was stirred for 15 mins at room temperature under nitrogen and quenched with NH4Cl (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: 220 g, 100 - 200 mesh, Mobile Phase A: petroleum ether, Mobile Phase B: ethylacetate; Flow rate: 55 mL / min; Gradient: 0% B to 30% B in 30 min; Wave Length: 220 nm; 12% B fractions were collected) to provide the desired product 7-chloro-2-iodopyrazolo[1,5-a]pyridine (800 mg, 70% yield) as a white solid. LCMS(ESI-MS) m / z = 278.8 [M+H]+. Rt: 0.630 min (Method 2). 1.15.2. Step 2: 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine

[0297] To a stirred mixture of 7-chloro-2-iodopyrazolo[1,5-a]pyridine (800 mg, 2.87 mmol, 1.0 equiv) and 2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.22 g, 4.30 mmol, 1.5 equiv) in MeCN (8 mL) was added chlorotrimethylsilane (468 mg, 4.30 mmol, 1.5 equiv) dropwise at room temperature under nitrogen. The reaction mixture was stirred for 30 mins at 60 °C under nitrogen and concentrated under reduced pressure to afford the crude product. The crude product was quenched with NaOH solution (10 mL, 1 M) and extracted with DCM (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine (840 mg, 69% yield) as a white solid. LCMS (ESI-MS) m / z = 378.7 [M+H]+. Rt: 0.749 min (Method 2). 1.16. Int-17: tert-butyl 1-(2-(2-(2-(4-amino-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole- 4-carboxylate1.16.1. Step 1: benzyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-yl]carbamate

[0298] To a solution of 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-amine (6.00 g, 12.4 mmol, 1.0 equiv) in DCM (60 mL) was added benzyl 2,5- dioxopyrrolidin-1-yl carbonate (3.39 g, 13.6 mmol, 1.1 equiv) and Et3N (1.50 g, 14.9 mmol, 1.2 equiv) stirred at room temperature. The reaction mixture was stirred for 3 h at room temperature and quenched with water (300 mL). The resulting mixture was extracted with DCM (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 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 0% B in 5 min, 0% B to 15% B in 30 min; 254 nm; 10% B fractions were collected) to provide the desired product benzyl N-[3-(2,2- dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methylpiperidin-4-yl]carbamate (5.70 g, 61% yield) as a brown oil. LCMS(ESI-MS) m / z = 619.4 [M+H]+. Rt: 0.897 min (Method 6).1.16.2. Step 2: benzyl N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1-methylpiperidin-4-yl)carbamate

[0299] A solution of benzyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-yl]carbamate (5.70 g, 9.21 mmol, 1.0 equiv) in HCl (40 mL, 4.0 M in MeOH) was stirred at room temperature. The reaction mixture was stirred for 2 h at room temperature and concentrated under reduced pressure. Then added saturated aqueous NaHCO3 (10 mL). The solution was purified by C18 column (Column: 350 g; Mobile Phase A: Water(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 0% B in 5 min, 0% B to 100% B in 60 min; 254 nm; 20% B fractions were collected) to provide the desired product benzyl N-(3-{2-[2-(2- hydroxyethoxy)ethoxy]ethyl}-1-methylpiperidin-4-yl)carbamate (2.20 g, 47% yield) as a brown oil. LCMS(ESI-MS) m / z = 381.3 [M+H]+. Rt: 0.484 min (Method 6). 1.16.3. Step 3: tert-butyl 1-(2-{2-[2-(4-{[(benzyloxy)carbonyl]amino}-1-methylpiperidin-3- yl)ethoxy]ethoxy}ethyl)pyrazole-4-carboxylate

[0300] To a stirred mixture of benzyl N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1-methylpiperidin- 4-yl)carbamate (200 mg, 0.526 mmol, 1.0 equiv) and tert-butyl 1H-pyrazole-4-carboxylate (176 mg, 1.05 mmol, 2.0 equiv) in toluene (3 mL) was added 2-(tributyl-l^[5]-phosphanylidene)acetonitrile (380 mg, 1.57 mmol, 3.0 equiv) dropwise at 0 °C under nitrogen. The reaction mixture was stirred for 1 h at 100 °C under nitrogen 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 sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:11; Rf = 0.4; detection: UV) to provide the desired product tert-butyl 1-(2-{2-[2-(4-{[(benzyloxy)carbonyl]amino}-1-methylpiperidin- 3-yl)ethoxy]ethoxy}ethyl)pyrazole -4-carboxylate (200 mg, 71% yield) as a brown oil. LCMS(ESI-MS) m / z = 531.2 [M+H]+. Rt: 0.622 min (Method 2). 1.16.4. Step 4: tert-butyl 1-(2-(2-(2-(4-amino-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate

[0301] A stirred mixture of tert-butyl 1-(2-{2-[2-(4-{[(benzyloxy)carbonyl]amino}-1-methylpiperidin- 3-yl)ethoxy]ethoxy}ethyl)pyrazole-4-carboxylate (200 mg, 0.377 mmol, 1.0 equiv) in i-PrOH (6 mL) was added 10% palladium on activated carbon (104 mg). The reaction mixture was stirred for 2 h at room temperature under hydrogen. The resulting mixture was filtered, the filter cake was washed with DCM (6 mL x 3). The filtrate was concentrated under reduced pressure to the crude product tert-butyl 1-(2-(2-(2-(4-amino-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate (150 mg, crude) as a brown oil. LCMS(ESI-MS) m / z = 397.1 [M+H]+. Rt: 0.504 min (Method 2).1.17. Int-18: 12-iodo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane1.17.1. Step 1: 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-ol

[0302] To a solution of triethylene glycol (500 mL, 7.1 equiv) and py (74.8 g, 945 mmol, 2.0 equiv) was added TBDPSCl (130 g, 473 mmol, 1.0 equiv) dropwise at 0 °C. The reaction mixture was stirred 3 h at room temperature and quenched with water (1000 mL). The resulting mixture was extracted with EtOAc (3 x 1000 mL) and the organic layers were combined, washed with HCl (0.5 M, 3 x 500 mL) and brine (2 x 1000 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: 1.3 kg (glass column), 100 - 200 mesh; Mobile PhaseA: petroleum ether, Mobile Phase B: ethylacetate; Flow rate: 100 mL / min; Gradient: 0% B to 0% B in 30 min, 0% B to 40% B in 2h; 254 nm; 30% B fractions were collected) to provide the desired product 2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-ol (150 g, 73% yield) as a light yellow oil. LCMS(ESI-MS) m / z = 411.0 [M+Na]+. Rt: 0.822 min (Method 2). 1.17.2. Step 2: 12-iodo-2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane

[0303] To a solution of 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-ol (150 g, 386 mmol, 1.0 equiv) in DCM (1500 mL) was added Imidazole (34.2 g, 502 mmol, 1.3 equiv) and PPh3 (132 g, 502 mmol, 1.3 equiv) at 0 °C under nitrogen. After stirred for 0.5 h, Iodine (127 g, 502 mmol, 1.3 equiv) was added at 0 °C under nitrogen. The reaction mixture was stirred for 3 h at room temperature and quenched with saturated aqueous NaHSO3 (1500 ml). The resulting mixture was extracted with DCM (3 x 1500 mL) and the organic layers were combined, washed with brine (2 x 1500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by trituration with pentane (1500 mL) and was filtered through a celite pad. The filtrate was concentrated under reduced pressure to provide the desired product 12-iodo-2,2- dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane (150 g, 70% yield) as a colorless oil. LCMS(ESI- MS) m / z = 521.0 [M+Na]+. Rt: 0.939 min (Method 2).1.18. Int-19: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-amine1.18.1. Step 1: (1R)-N-(1-methylpiperidin-4-ylidene)-1-phenylethanamine

[0304] A solution of 1-methylpiperidin-4-one (20.0 g, 177 mmol, 1.0 equiv) and D-α- methylbenzylamine (21.4 g, 177mmol, 1.0 equiv) in toluene (500 mL) was stirred 3 h at reflux using a dean-stark trap. The reaction mixture was concentrated under reduced pressure to afford the crude product (1R)-N-(1-methylpiperidin-4-ylidene)-1-phenylethanamine (40 g, crude) as a light orange oil. 1.18.2. Step 2: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methyl- N-((R)-1-phenylethyl)piperidin-4-amine

[0305] To a solution of (1R)-N-(1-methylpiperidin-4-ylidene)-1-phenylethanamine (10.0 g, 32.4 mmol, 1.0 equiv, 70% pure) and diethylamine (3.08 g, 42.1 mmol, 1.3 equiv) in THF (54 mL) was dropwise added n-BuLi (26.3 mL, 42.1 mmol, 1.3 equiv, 1.6M in THF) stirred at -10 °C under nitrogen (keep the temperature at -10 °C). After stirred for 1 h at -10 °C, then 12-iodo-2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecane (18.8 g, 37.7 mmol, 1.17 equiv, in 18 mL THF) was added dropwise at - 80 °C under nitrogen. The reaction mixture was stirred for 1 h at -80 °C, NaBH4 (3.06 g, 80.9 mmol, 2.5 equiv) and EtOH (24 mL) was added, and the mixture was stirred overnight at -80 °C under nitrogen. The reaction mixture was concentrated under reduced pressure (about 20 °C) to remove THF (remove about 75% EtOH) and quenched with ice-water (50 mL). The resulting mixture was adjusted to Ph = 5 with hydrochloric acid (2 M) at 0 °C, then adjusted to Ph= 12 with NaOH (2 M) at 0 °C. 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. The crude product was chromatographed on a silica gel column (Column: 330 g, 100 - 200 mesh; Mobile PhaseA: DCM, Mobile Phase B:MeOH; Flow rate: 70 mL / min; Gradient: 0% B to 0% B in 8 min, 0% B to 20% B in 60 min; 254 nm; 7% B (cis isomers) and 15% B (desired product) fractions were collected) to provide the isomers cis-(3RS,4SR)-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-1-methyl-N-((R)-1-phenylethyl)piperidin-4-amine (7.0 g, crude) and the desired product (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methyl-N-((R)-1-phenylethyl)piperidin-4-amine (3.5 g, 16% yield) as a yellow oil. LCMS(ESI-MS) m / z = 589.4 [M+H]+. Rt: 0.687 min (Method 2). 1.18.3. Step 3: (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1- methylpiperidin-4-amine

[0306] To a solution of 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-1-methyl-N- [(1R)-1-phenylethyl]piperidin-4-amine (10.0 g, 17.0 mmol, 1.0 equiv) and HOAc (2.04 g, 34.0 mmol, 2.0 equiv) in EtOH (200 mL) was added 10% Palladium on activated carbon (20 g) in autoclave. The mixture was stirred for 20 hours at 45 °C under 25 atm hydrogen. The reaction mixture was cooled to room temperature and filtered to remove EtOH. The crude product was purified by a silica gel column (Column: 120 g x 2; Mobile Phase A: dichloromethane, Mobile Phase B: methanol; Flow rate: 100 mL / min; Gradient: 0% B to 100% B in 240 min; Wave Length: 220 nm; 25% - 100% B fractions were collected) to provide the desired product (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-1-methylpiperidin-4-amine (3.0 g, 32% yield) as a yellow oil. LCMS(ESI-MS) m / z = 485.3 [M+H]+. Rt: 0.605 min (Method 2). 1.19. Intermediates Int-20: tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)piperidine-1-carboxylate1.19.1. Step 1: tert-butyl 4-(2,2-dimethylhydrazin-1-ylidene)piperidine-1-carboxylate

[0307] 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. 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.

[0308] LCMS(ESI-MS) m / z = 242.2 [M+H]+

[0309] Rt 0.228 min; Method 1

[0310] 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).1.19.2. Step 2: tert-butyl 3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-4- oxopiperidine-1-carboxylate

[0311] 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 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 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.

[0312] LCMS(ESI-MS) m / z = 592.4 [M+H]+

[0313] Rt 0.915 min; Method 2 1.19.3. Step 3: Intermediate Int-20: tert-butyl 4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa- 3-siladodecan-12-yl)piperidine-1-carboxylate

[0314] 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 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 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.

[0315] LCMS(ESI-MS) m / z = 571.4 [M+H]+

[0316] Rt 0.703 min; Method 21.20. Int-21: tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoro-1- methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate1.20.1. Step 1: tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)carbamate

[0317] To a solution of 3-bromo-5-fluoropyridin-4-amine (23 g, 120 mmol, 1.0 equiv) in DCM (200 mL) was added Boc2O (65.7 g, 301 mmol, 2.5 equiv), DMAP (7.36 g, 60.2 mmol, 0.50 equiv) and Et3N (36.6 g, 361 mmol, 3.0 equiv) stirred at room temperature. The reaction mixture was stirred overnight at room temperature and diluted with DCM (200 mL) and washed twice with 10% citric acid solution (2 x 500mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)carbamate (47 g) as a brown solid. To a solution of tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)carbamate (47 g) in MeOH (300 mL) was added K2CO3 (49.9 g, 360 mmol, 3.0 equiv) stirred at room temperature. The reaction mixture was stirred for 4 h at 90 °C. The mixture was filtered through a celite pad and washed with DCM (3 x 200 mL). The filtrate was 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 100% B in 60 min; 254 nm; 60% B fractions were collected) to provide the desired product tert-butyl N-(3-bromo-5-fluoropyridin- 4-yl)carbamate (32 g, 82%yield) as a yellow solid. LCMS(ESI-MS) m / z = 291.0, 293.0 [M+H]+. Rt: 0.569 min (Method 18). 1.20.2. Step 2: tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5- fluoropyridin-4-yl]carbamate

[0318] To a solution of tert-butyl N-(3-bromo-5-fluoropyridin-4-yl)carbamate (4.80 g, 16.5 mmol, 1.0 equiv), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (642 mg, 1.32 mmol, 0.080 equiv), Pin2B2 (6.28 g, 24.7 mmol, 1.5 equiv), NaI (1.24 g, 8.24 mmol, 0.5 equiv) and K2CO3 (4.10 g, 29.7 mmol, 1.8 equiv) in N,N-dimethylacetamide (80 mL) was added 12-bromo-2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecane (8.93 g, 19.786 mmol, 1.2 equiv) stirred under nitrogen at room temperature. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was quenched with water (500mL). 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 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 100% B in 60 min; 254 nm; 35% B fractions were collected) to provide the desired product tert-butyl N-[3-(2,2-dimethyl- 3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoropyridin-4-yl]carbamate (3.8 g, 39%yield) as a white solid. LCMS(ESI-MS) m / z = 583.3 [M+H] +. Rt: 1.071 min (Method 6). 1.20.3. Step 3: 4-[(tert-butoxycarbonyl)amino]-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-5-fluoro-1-methylpyridin-1-ium iodide

[0319] To a solution of tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)- 5-fluoropyridin-4-yl]carbamate (1.4 g, 2.40 mmol, 1.0 equiv) in MeCN (21 mL) was added MeI (1.02 g, 7.21 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 50 °C for 16 h and concentrated under reduced pressure to give a crude product. The crude product was washed with pentane (20 mL) and filtered. The solid was collected and dried under reduced pressure to give a crude product 4-[(tert-butoxycarbonyl)amino]-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-5-fluoro-1-methylpyridin-1-ium iodide (1.12 g) as a yellow oil. LCMS(ESI-MS) m / z = 597.4 [M-I- ]+. Rt: 0.895 min (Method 6). 1.20.4. Step 4: tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)-5-fluoro-1- methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate

[0320] To a solution of 4-[(tert-butoxycarbonyl)amino]-3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3- siladodecan-12-yl)-5-fluoro-1-methylpyridin-1-ium iodide (5.25 g, 7.24 mmol, 1.0 equiv) in DCM (36 mL) and methanol (36 mL) was added Cerium(III) chloride heptahydrate (2.70 g, 7.24 mmol, 1.0 equiv), followed by addition of NaBH4 (5.48 g, 145 mmol, 20 equiv) in batches at 0°C. The mixture was stirred at 0 C for 30 min and HOAc (0.440 g, 7.24 mmol, 1.0 equiv) was added. The reaction mixture was stirred for 16 h at room temperature and quenched with water (150 mL) at 0 °C. The resulting mixture was extracted with EtOAc (4 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 afford the 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: 60 mL / min; Gradient: 0% B to 80% B in 30 min; Wave Length: 254 nm) 55% - 62% B fractions were collected to provide the desired product tert-butyl N-[3-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12- yl)-5-fluoro-1-methyl-3,6-dihydro-2H-pyridin-4-yl]carbamate (1.71 g, 35 %yield) as a yellow oil. LCMS(ESI-MS) m / z = 601.2 [M+H]+. Rt: 2.061 min (Method 50).1.21. Int-22: rac-methyl 1-[2-(2-{2-[(3S,4S)-4-amino-1-(2,2,2-trifluoroethyl)piperidin-3- yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate1.21.1. Step 1: rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate

[0321] To a stirred mixture of rac-tert-butyl (3S,4S)-4-amino-3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (650 mg, 1.22 mmol, 1.0 equiv) and Cbz-OSU (336 mg, 1.34 mmol, 1.1 equiv) in DCM (7 mL) was added TEA (148 mg, 1.47 mmol, 1.2 equiv). The reaction mixture was stirred for 4 h at room temperature and quenched with water (150 mL). The resulting mixture was extracted with DCM (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: 130 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; 20% B fractions were collected) to provide the desired product rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3- (2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (800 mg, 90% yield) as a colorless oil. LCMS(ESI-MS) m / z = 605.4 [M+H-Boc]+. Rt: 0.932 min (Method 2). 1.21.2. Step 2: rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-{2-[2-(2- hydroxyethoxy)ethoxy]ethyl}piperidine-1-carboxylate

[0322] A stirred mixture of rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-(2,2-dimethyl- 3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)piperidine-1-carboxylate (800 mg, 1.13 mmol, 1.0 equiv) in THF (8 mL) was added TBAF (1.36 mL, 0.034 mmol, 1.2 equiv, 1M in THF). The reaction mixture was stirred for 1 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 (6 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: 130 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; 16% B fractions werecollected) to provide the desired product rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-{2- [2-(2-hydroxyethoxy)ethoxy]ethyl}piperidine-1-carboxylate (450 mg, 76 %yield) as a colorless oil. LCMS(ESI-MS) m / z = 489.2 [M+Na]+. Rt: 0.603 min (Method 2). 1.21.3. Step 3: rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-[2-(2-{2-[4- (methoxycarbonyl)pyrazol-1-yl]ethoxy}ethoxy)ethyl]piperidine-1-carboxylate

[0323] To a stirred mixture of rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-{2-[2-(2- hydroxyethoxy)ethoxy]ethyl}piperidine-1-carboxylate (450 mg, 0.964 mmol, 1.0 equiv) and methyl 1H-pyrazole-4-carboxylate (243 mg, 1.92 mmol, 2.0 equiv) in Toluene (9 mL) was added CMBP (698 mg, 2.89 mmol, 3.0 equiv) dropwise at 0 °C under nitrogen. The reaction mixture was stirred for 1 h at 100 °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 product. The crude product was purified by TLC (Mobile phase:ethyl acetate / petroleum ether =1:1; Rf = 0.4; detection: UV) to provide the desired product rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}- 3-[2-(2-{2-[4-(methoxycarbonyl)pyrazol-1-yl]ethoxy}ethoxy)ethyl]piperidine-1-carboxylate (310 mg, 50% yield) as a colorless oil. LCMS(ESI-MS) m / z = 575.4 [M+H]+. Rt: 0.655 min (Method 2). 1.21.4. Step 4: rac-methyl 1-[2-(2-{2-[(3S,4S)-4-{[(benzyloxy)carbonyl]amino}piperidin-3- yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate

[0324] A stirred mixture of rac-tert-butyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-[2-(2-{2-[4- (methoxycarbonyl)pyrazol-1-yl]ethoxy}ethoxy)ethyl]piperidine-1-carboxylate (450 mg, 0.783 mmol, 1.0 equiv) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h at room temperature and concentrated under reduced pressure to afford the crude product rac-methyl 1-[2-(2-{2- [(3S,4S)-4-{[(benzyloxy)carbonyl]amino}piperidin-3-yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate (360 mg, crude) as a yellow semi-solid. LCMS(ESI-MS) m / z = 475.2 [M+H]+. Rt: 0.470 min (Method 2). 1.21.5. Step 5: rac-methyl 1-[2-(2-{2-[(3S,4S)-4-{[(benzyloxy)carbonyl]amino}-1-(2,2,2- trifluoroethyl)piperidin-3-yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate

[0325] To a stirred mixture of rac-methyl 1-[2-(2-{2-[(3S,4S)-4- {[(benzyloxy)carbonyl]amino}piperidin-3-yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate (260 mg, 0.548 mmol, 1.0 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (317 mg, 1.37 mmol, 2.5 equiv) in ACN (5 mL) was added Cs2CO3(535 mg, 1.64 mmol, 3.0 equiv). The reaction mixture was stirred overnight at room temperature and quenched with water (20 mL). 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 TLC (Mobile phase: ethyl acetate / petroleum ether=1:3; Rf = 0.4; detection: UV) to provide the desired product rac-methyl 1-[2-(2-{2-[(3S,4S)-4- {[(benzyloxy)carbonyl]amino}-1-(2,2,2-trifluoroethyl)piperidin-3-yl]ethoxy}ethoxy)ethyl]pyrazole-4- carboxylate (260 mg, 76% yield) as a colorless oil. LCMS(ESI-MS) m / z = 557.3 [M+H]+. Rt: 0.537 min (Method 2). 1.21.6. Step 6: rac-methyl 1-[2-(2-{2-[(3S,4S)-4-amino-1-(2,2,2-trifluoroethyl)piperidin-3- yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate

[0326] To a stirred mixture of rac-methyl 1-[2-(2-{2-[(3S,4S)-4-{[(benzyloxy)carbonyl]amino}-1- (2,2,2-trifluoroethyl)piperidin-3-yl]ethoxy}ethoxy)ethyl]pyrazole-4-carboxylate (240 mg, 0.431 mmol, 1.0 equiv) in i-PrOH (4 mL) was added 10% palladium on activated carbon (120 mg). The reaction mixture was stirred for 2 h at room temperature under Hydrogen. The resulting mixture was filtered, the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to afford the crude product rac-methyl 1-[2-(2-{2-[(3S,4S)-4-amino-1-(2,2,2-trifluoroethyl)piperidin-3- yl]ethoxy}ethoxy) ethyl]pyrazole-4-carboxylate (180 mg, crude) as a brown oil. LCMS(ESI-MS) m / z = 423.1 [M+H]+. Rt: 0.436 min (Method 2). Table III. Intermediates used towards the compounds of the invention. Mtd = Method, MS Mes’d = Measured mass, NA = not measured MS Int# Structure Name Mtd MW Mes’d N-(3-(2,2-dimethyl-3,3-diphenyl- 4,7,10-trioxa-3-siladodecan-12-yl)-1- 808.3 Int-1 methylpiperidin-4-yl)-2-iodo-1- 2 807.8 [M+H] (2,2,2-trifluoroethyl)-1H-indol-4-+amine 3-(2,2-dimethyl-3,3-diphenyl-4,7,10- trioxa-3-siladodecan-12-yl)-N-(2- Int-2 iodo-3-(2,2,2- - 824.9 - trifluoroethyl)benzo[b]thiophen-7- yl)-1-methylpiperidin-4-amine tert-butyl (3-(4-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1- 597.3 596.6 Int-3 methylpiperidin-4-yl)amino)-1-(2,2,2- 5 [M+H] 9 trifluoroethyl)-1H-indol-2-yl)prop-2-+yn-1-yl)carbamateMS Int# Structure Name Mtd MW Mes’d methyl 1-(2-(2-(2-(4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1- 706.5 yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- Int-4 4 705.8 [M+H] yl)amino)-1-methylpiperidin-3-+yl)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazole-4-carboxylate methyl 2-(2-(2-(2-(4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1- 706.4 yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- Int-5 6 705.8 [M+H] yl)amino)-1-methylpiperidin-3-+yl)ethoxy)ethoxy)ethyl)-2H-1,2,3- triazole-4-carboxylate tert-butyl (3-(7-((3-(2-(2-(2- hydroxyethoxy)ethoxy)ethyl)-1- 614.3 Int-6 methylpiperidin-4-yl)amino)-3-(2,2,2- 6 613.7 [M+H] trifluoroethyl)benzo[b]thiophen-2-+yl)prop-2-yn-1-yl)carbamate 2-(2-(2-(4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1- 675.3 yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- Int-7 7 674.8 [M+H] yl)amino)-1-methylpiperidin-3-+yl)ethoxy)ethoxy)ethyl methanesulfonate 156.0 4-(2,2-dimethylhydrazineylidene)-1- Int-8 22 155.2 [M+H] methylpiperidine+rac-tert-butyl (3-(4-(((3R,4R)-3-(2-(2- (2-hydroxyethoxy)ethoxy)ethyl)-1- 597.3 Int-9 methylpiperidin-4-yl)amino)-1-(2,2,2- 2 596.7 [M+H] trifluoroethyl)-1H-indol-2-yl)prop-2-+yn-1-yl)carbamate* rac-tert-butyl (3-(4-(((3R,4S)-3-(2-(2- (2-hydroxyethoxy)ethoxy)ethyl)-1- 597.3 Int-10 methylpiperidin-4-yl)amino)-1-(2,2,2- 2 596.7 [M+H] trifluoroethyl)-1H-indol-2-yl)prop-2-+yn-1-yl)carbamate*MS Int# Structure Name Mtd MW Mes’d rac-2-(2-(2-((3R,4R)-4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1- 675.3 yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- Int-11 6 674.8 [M+H] yl)amino)-1-methylpiperidin-3-+yl)ethoxy)ethoxy)ethyl methanesulfonate* 8-bromo-2-iodo-3- 422.9 Int-12 ((trifluoromethyl)thio)imidazo[1,2- 6 422.9 [M+H] a]pyridine+3-(2,2-dimethyl-3,3-diphenyl-4,7,10- 484.4 Int-13 trioxa-3-siladodecan-12-yl)-1- 20 483.7 [M+H] methylpiperidin-4-one+3-(2,2-dimethyl-3,3-diphenyl-4,7,10- 485.3 Int-14 trioxa-3-siladodecan-12-yl)-1- 2 484.8 [M+H] methylpiperidin-4-one+373.9 1-(7-amino-2-iodobenzo[b]thiophen-3- Int-15 5 373.1 [M+H] yl)-2,2,2-trifluoroethan-1-ol+7-chloro-2-iodo-3- 378.7 ((trifluoromethyl)thio)pyrazolo[1,5- Int-16 2 377.9 [M+H] a]pyridine + tert-butyl 1-(2-(2-(2-(4-amino-1- 397.1 methylpiperidin-3- Int-17 2 396.3 [M+H] yl)ethoxy)ethoxy)ethyl)-1H-pyrazole- + 4-carboxylate 521.0 12-iodo-2,2-dimethyl-3,3-diphenyl- Int-18 2 498.1 [M+Na 4,7,10-trioxa-3-siladodecane ]+. (3S,4S)-3-(2,2-dimethyl-3,3-diphenyl- 485.3 Int-19 4,7,10-trioxa-3-siladodecan-12-yl)-1- 2 484.3 [M+H] methylpiperidin-4-amine+MS Int# Structure Name Mtd MW Mes’d tert-butyl 4-amino-3-(2,2-dimethyl- 571.4 3,3-diphenyl-4,7,10-trioxa-3- Int-20 2 570.3 [M+H] siladodecan-12-yl)piperidine-1-+carboxylate tert-butyl N-[3-(2,2-dimethyl-3,3- diphenyl-4,7,10-trioxa-3-siladodecan- Int-21 50 600.3 601.2 12-yl)-5-fluoro-1-methyl-3,6-dihydro- 2H-pyridin-4-yl]carbamate rac-methyl 1-[2-(2-{2-[(3S,4S)-4- amino-1-(2,2,2- 423.1 Int-22 trifluoroethyl)piperidin-3- 2 422.2 [M+H] yl]ethoxy}ethoxy)ethyl]pyrazole-4- + carboxylate *stereochemistry arbitrarily assigned Example 2. Preparation of illustrative compounds of the invention 2.1. Compound 1: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28- yn-25-one2.1.1. Step 1: tert-butyl (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

[0327] To a stirred mixture of Int-1 (400 mg, 0.495 mmol, 1.0 equiv), tert-butyl N-(prop-2-yn-1- yl)carbamate (CAS# 92136-39-5; 144 mg, 0.931 mmol, 1.88 equiv), bis(triphenylphosphine)palladium(II) chloride (CAS# 13965-03-2; 38.2 mg, 0.054 mmol, 0.11 equiv) and cuprous iodide (25.4 mg, 0.134 mmol, 0.27 equiv) in DMSO (6 mL) was added TEA (200 mg, 1.98 mmol, 4.0 equiv). The reaction mixture was stirred for 2 h at RT 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: 120 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 0% B to 15% B in 40 min; Wave Length: 220nm nm; Collected fractions: 5% - 6% B) to afford the title compound (313 mg, 68% yield) as a brown semi-solid.

[0328] LCMS(ESI-MS) m / z = 835.6 [M+H]+.

[0329] Rt: 1.007 min; Method 6 2.1.2. Step 2: tert-butyl (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

[0330] To a stirred mixture of tert-butyl (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 (350 mg, 0.419 mmol, 1.0 equiv) in THF (4 mL) was added tetrabutylammonium fluoride (0.84 mL, 0.838 mmol, 2.0 equiv, 1M in THF). The reaction mixture was stirred for 1 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 (4 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: MeOH / DCM =1:6; Rf = 0.5; detection: UV) to afford the title compound (193 mg, 69% yield) as a brown semi-solid.

[0331] LCMS(ESI-MS) m / z = 597.3 [M+H]+.

[0332] Rt: 0.700 min; Method 5 2.1.3. Step 3: methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4- carboxylate

[0333] To a stirred mixture of tert-butyl (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 (180 mg, 0.302 mmol, 1.0 equiv), methyl 1H-pyrazole-4-carboxylate (CAS# 51105-90-9; 57.1 mg, 0.453 mmol, 1.5 equiv), 4A MS (400 mg) and triphenylphosphine (118 mg, 0.453 mmol, 1.5 equiv) in THF(1.8 mL) was added DIAD (91.5 mg, 0.453 mmol, 1.5 equiv) at 0°C. The reaction mixture was stirred for 1 h at RT under nitrogen 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 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: MeOH / DCM =1:6; Rf = 0.5; detection: UV) to afford the title compound (150 mg, 63% yield) as a yellow solid.

[0334] LCMS(ESI-MS) m / z = 705.3 [M+H]+.

[0335] Rt: 1.039,1.059 min; Method 4 2.1.4. Step 4: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4- carboxylic acid

[0336] To a stirred mixture of methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate (120 mg, 0.170 mmol, 1.0 equiv) in THF (1.2 mL) was added lithium hydroxide (16.3 mg, 0.680 mmol, 4.0 equiv, in H2O (1.2 mL)). The reaction mixture was stirred for 4 h at 50 °C. The mixture was adjusted to pH = 6 with hydrochloric acid (1 M) and extracted with EtOAc (3 x 50 mL) and concentrated under reduced pressure to afford crude title compound (110 mg, 84% yield) as a brown semi-solid.

[0337] LCMS(ESI-MS) m / z = 691.4 [M+H]+.

[0338] Rt: 0.691 min; Method 6 2.1.5. Step 5: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[0339] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylic acid (100 mg, 0.145 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at RT and concentrated under reduced pressure to afford the crude title compound (85 mg, crude) as a brown oil.

[0340] LCMS(ESI-MS) m / z = 591.3 [M+H]+.

[0341] Rt: 0.494 min; Method 27 2.1.6. Step 6: Compound 1 - 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexa zapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28-yn-25- one

[0342] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (94.0mg, 0.159 mmol, 1.0 equiv) and N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate (CAS# 207915-99-9; 58.1 mg, 0.207 mmol, 1.3 equiv) in ACN (9.4 mL) was added N-methylimidazole (CAS# 616-47-7; 78.4 mg, 0.954 mmol, 6.0 equiv). 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, 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 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: 26% B to56 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.5) to afford title compound (10.0 mg, 10% yield) as an off-white solid.

[0343] 1H NMR (400 MHz, DMSO) δ 8.69 – 8.58 (m, 1H), 8.23 – 8.16 (m, 1H), 7.92 – 7.86 (m, 1H), 7.23 – 7.05 (m, 1H), 7.04 – 6.93 (m, 1H), 6.76 – 6.65 (m, 1H), 6.27 – 6.07 (m, 1H), 5.46 – 5.23 (m, 1H), 5.18 – 4.96 (m, 1H), 4.97 – 4.81 (m, 1H), 4.39 – 4.23 (m, 3H), 4.21 – 4.08 (m, 1H), 3.80 – 3.64 (m, 2H), 3.55 – 2.99 (m, 6H), 2.91 – 2.65 (m, 2H), 2.60 – 2.49 (m, 1H), 2.22 – 2.08 (m, 3H), 2.07 – 1.92 (m, 2H), 1.89 – 1.52 (m, 4H), 1.46 – 0.93 (m, 1H).

[0344] LCMS(ESI-MS) m / z = 573.3 [M+H]+.

[0345] Rt: 0.919,0.929 min; Method 82.2. Compound 1A: (7R,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28- yn-25-one; Compound 1B: (7S,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28- yn-25-one; Compound 1C: (7S,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28- yn-25-one; Compound 1D: (7R,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28- yn-25-one

[0346] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (see step 5 for the synthesis of compound 1) (680 mg, 1.15 mmol, 1.0 equiv) and HATU (460 mg, 1.21 mmol, 1.05 equiv) in DMF (80 mL) was added DIPEA (1.34 g, 10.4 mmol, 9.0 equiv) at 0°C. The reaction mixture was stirred for 2 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 (5 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: MeOH / DCM =1:5; Rf = 0.5; detection: UV) to provide the desired product (280 mg, 80% pure).

[0347] The crude product was then purified by prep-Achiral-HPLC column (Column: GreenSep Basic 3*15 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH(1%-2M-NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 20% B; Column Temperature(℃): 35; Back Pressure(bar): 100; WaveLength: 220 nm; Rt1 (min): 10.13; Sample Solvent: MeOH; Injection Volume: 2 mL; Number Of Runs: 7) to result in a mixture of 4 isomers (160 mg, 97% pure).

[0348] The mixture of 4 isomers was separated by prep-SFC-HPLC column (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20mL / min; Gradient: isocratic 10; Wave Length: 254 / 220nm nm; Rt1 (min): 23.027; Rt2 (min): 27.711; Rt3 (min): 31.368; Sample Solvent: EtOH--HPLC; Injection Volume: 0.4 mL; Number Of Runs: 11).

[0349] Purification resulted in:

[0350] a mixture of Compound 1A & Compound 1D (45 mg, 95% pure),

[0351] Compound 1B (22.6 mg, 3.38% yield) ) as off-white solid: 1H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.9 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.05 (s, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 5.11 – 4.97 (m, 1H), 4.97 – 4.82 (m, 1H), 4.38 – 4.25 (m, 3H), 4.12 (m, 1H), 3.75 – 3.65 (m, 2H), 3.49 – 3.37 (m, 6H), 2.88 – 2.72 (m, 3H), 2.16 (s, 3H), 2.05 – 1.91 (m, 2H), 1.88 – 1.72 (m, 2H), 1.66 – 1.56 (m, 1H), 1.44 – 1.29 (m, 1H), 1.08 – 0.94 (m, 1H), LCMS (ESI-MS) m / z = 573.3 [M+H]+, Rt: 0.699 min; Method 7

[0352] Compound 1C (17.4 mg, 2.63%yield) ) as off-white solid,1H NMR (400 MHz, DMSO) δ 8.62 (t, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 5.33 – 5.25 (m, 1H), 5.15 – 5.00 (m, 1H), 4.85 (m, 1H), 4.37 – 4.23 (m, 3H), 4.16 (dd, J = 17.6, 5.3 Hz, 1H), 3.80 – 3.71 (m, 1H), 3.71 – 3.62 (m, 1H), 3.59 – 3.48 (m, 1H), 3.44 – 3.14 (m, 5H), 3.10 – 3.00 (m, 1H), 2.76 – 2.66 (m, 1H), 2.58 – 2.51 (m, 1H), 2.13 (s, 3H), 2.05 – 1.92 (m, 2H), 1.82 – 1.67 (m, 3H), 1.62 – 1.54 (m, 2H), LCMS (ESI-MS) m / z = 573.0 [M+H]+, Rt: 0.703 min; Method 7

[0353] The mixture of Compound 1A & Compound 1D was further separated by prep-SFC-HPLC column (Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220nm nm; Rt1 (min): 5.21; Rt2 (min): 7.06; Sample Solvent: EtOH--HPLC; Injection Volume: 0.6 mL; Number Of Runs: 3). Purification resulted in compound 1D (14.9 mg, 2% yield) ) as off-white solid;

[0354] 1H NMR (400 MHz, DMSO) δ 8.62 (t, J = 6.0 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 5.32 – 5.25 (m, 1H), 5.15 – 5.00 (m, 1H), 4.94 – 4.79 (m, 1H), 4.35 – 4.23 (m, 3H), 4.16 (dd, J = 17.7, 5.3 Hz, 1H), 3.80 – 3.71 (m, 1H), 3.71 – 3.63 (m, 1H), 3.57 – 3.48 (m, 1H), 3.44 – 3.17 (m, 5H), 3.09 – 3.00 (m, 1H), 2.75 – 2.66 (m, 1H), 2.58 – 2.52 (m, 1H), 2.12 (s, 3H), 2.06 – 1.93 (m, 2H), 1.84 – 1.65 (m, 3H), 1.63 – 1.52 (m, 2H), LCMS (ESI-MS) m / z = 573.4 [M+H]+, Rt: 0.708 min; Method 7; and

[0355] Compound 1A (18.3 mg, 2% yield) ) as off-white solid.

[0356] 1H NMR (400 MHz, DMSO) δ 8.65 (t, J = 5.9 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.05 (s, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.43 (d, J = 8.6 Hz, 1H), 5.11 – 4.97 (m, 1H), 4.97 – 4.82 (m, 1H), 4.38 – 4.25 (m, 3H), 4.12 (dd, J = 17.6, 5.3 Hz, 1H), 3.75 – 3.65 (m, 2H), 3.49 – 3.28 (m, 6H), 2.88 – 2.72 (m, 3H), 2.15 (s, 3H), 2.05 – 1.90 (m, 2H), 1.88 – 1.69 (m, 2H), 1.65 – 1.55 (m, 1H), 1.44 – 1.30 (m, 1H), 1.08 – 0.93 (m, 1H), LCMS (ESI-MS) m / z = 573.4 [M+H]+, Rt: 0.712 min; Method 7. 2.3. Compound 2: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26-penta zapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen-28-yn- 25-one

[0357] Compound 2 may be prepared based on similar methods as for Compound 1, starting from 2- iodo-3-(2,2,2-trifluoroethyl)-1-benzothiophen-7-amine (CAS# 2903922-15-4)

[0358] LCMS(ESI-MS) m / z = 590.2 [M+H]+. Rt: 1.346, 1.362 min; Method 12.

[0359] In particular, Compound 2 was prepared as follows:2.3.1. Step 1: tert-butyl (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

[0360] To a solution of Int-2 (600 mg, 0.727 mmol, 1.0 equiv), tert-butyl N-(prop-2-yn-1-yl)carbamate (CAS#92136-39-5; 212 mg, 1.37 mmol, 1.88 equiv), Pd(PPh3)2Cl2(CAS# 13965-03-2; 56.2 mg, 0.080 mmol, 0.11 equiv) and CuI (37.4 mg, 0.196 mmol, 0.27 equiv) in DMSO (6 mL) was added TEA (294 mg, 2.91 mmol, 4.0 equiv) at RT. The reaction mixture was stirred for 2 h at RT and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 40 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 (Column: 220 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 45 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220nm; Collected fractions: 9 % - 10 % B) to provide the title compound (520 mg,75% yield) as a yellow semi-solid.

[0361] LCMS(ESI-MS) m / z = 852.4 [M+H]+

[0362] Rt: 1.051 min; Method 6 2.3.2. Step 2: tert-butyl (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

[0363] To a solution of tert-butyl (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)carba mate (520 mg, 0.610 mmol, 1.0 equiv) in THF (6 mL) was added TBAF (1.3 mL, 1.34 mmol, 2.2 equiv, 1 M in THF) at RT. The reaction mixture was stirred for overnight at RT 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 (3 x 40 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) =1:7; Rf = 0.4; detection: UV) to afford the title compound (240 mg, 64% yield) as a brown semi-solid.

[0364] LCMS(ESI-MS) m / z = 614.3 [M+H]+

[0365] Rt: 0.735 min; Method 6 2.3.3. Step 3: methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate

[0366] To a solution of Int-6 (240 mg, 0.391 mmol, 1.0 equiv) in Toluene (4.8 mL) was added methyl 1H-pyrazole-4-carboxylate (CAS# 51105-90-9; 98.6 mg, 0.782 mmol, 2.00 equiv) and CMBP (CAS# 157141-27-0; 283 mg, 1.17 mmol, 3.0 equiv) at RT. The reaction mixture was stirred for 1 h at 110 °C and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL) and theorganic 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 (Column: 120 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 45 mL / min; Gradient: 0% B to 15% B in 30 min; Wave Length: 220nm; Collected fractions: 8 % - 10 % B) to provide the title compound (170 mg, 60% yield).

[0367] LCMS(ESI-MS) m / z = 722.4 [M+H]+

[0368] Rt: 0.804 min; Method 6 2.3.4. Step 4: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylic acid

[0369] To a solution of methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3- (2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate (170 mg, 0.236 mmol, 1.0 equiv) in MeOH (6.8 mL) was added NaOH (65.9 mg, 1.65 mmol, 7.0 equiv, in 6.8 mL H2O) and stirred at RT. The reaction mixture was stirred for 6 h at 50 °C and acidified to pH = 5 with HCL (1 N). The resulting mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound as a yellow semi-solid.

[0370] LCMS(ESI-MS) m / z = 708.4 [M+H]+

[0371] Rt: 0.639 min; Method 18 2.3.5. Step 5: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen- 7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[0372] A solution of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylic acid (170 mg, 0.240 mmol, 1.0 equiv) in hydrogen chloride (5 mL, 4.0 M in 1,4- dioxane) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure to provide crude title compound (145 mg, crude) as a brown semi-solid.

[0373] LCMS(ESI-MS) m / z = 608.3 [M+H]+

[0374] Rt: 0.499 min; Method 18 2.3.6. Step 6: compound 2 - 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen-28- yn-25-one

[0375] To a solution 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylic acid (150 mg, 0.247 mmol, 1.0 equiv) in DMF (5 mL) was added HATU (103 mg, 0.272 mmol, 1.1 equiv) and DIPEA (160 mg, 1.24 mmol, 5.0 equiv) at RT. The reaction mixturewas stirred for 1 h at RT and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 15 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 (10nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 45 % B in 10 min; Wave Length: 220nm; Rt1(min): 9.77) to provide the title compound (13.0 mg, 9% yield) as an off-white solid.

[0376] LCMS(ESI-MS) m / z = 590.2 [M+H]+

[0377] Rt: 1.346, 1.362 min; Method 12 2.4. Compound 2A: (7S,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia- 6,10,21,22,26-pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1(32),2,4,22,24(34),30(33)-hexaen-28-yn-25-one, Compound 2B: (7R,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen- 28-yn-25-one, Compound 2C: (7R,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen- 28-yn-25-one, Compound 2D: (7S,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen- 28-yn-25-one2.4.1. Step 1: tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate

[0378] To a solution of Int-6 (950 mg, 1.548 mmol, 1.0 equiv) in toluene (19 mL) was added tert-butyl 1H-pyrazole-4-carboxylate (521 mg, 3.096 mmol, 2.0 equiv) and CMBP (1.12 g, 4.644 mmol, 3.0equiv) , then the mixture was stirred for 1 h at 100 °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 crude product was chromatographed on a silica gel column (Column: 350 g, 100 - 200 mesh; Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 50 mL / min; Gradient: 0% B to 15% B in 40 min; Wave Length: 220nm; Collected fractions: 8 % B) to provide the title compound (590 mg, 49% yield) as a yellow semi-solid.

[0379] LCMS(ESI-MS) m / z = 764.4 [M+H]+

[0380] Rt (min) = 0.866 (Method 6) 2.4.2. Step 2: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen- 7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[0381] To a solution of tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-3- (2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylate (590 mg, 0.772 mmol, 1.0 equiv) in dichloromethane (27 mL) was added TFA (9 mL) at 0 °C. The reaction mixture was stirred for 1 h at RT and concentrated under reduced pressure to provide title compound (450 mg, crude).

[0382] LCMS(ESI-MS) m / z = 608.3 [M+H]+

[0383] Rt (min) = 0.588 (Method 6) 2.4.3. Step 3: Compound 2A: (7S,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia- 6,10,21,22,26-pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1(32),2,4,22,24(34),30(33)-hexaen-28-yn-25-one, Compound 2B: (7R,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen-28- yn-25-one, Compound 2C: (7R,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen-28- yn-25-one, and Compound 2D: (7S,12R)-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-31-thia-6,10,21,22,26- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30(33)-hexaen-28- yn-25-one

[0384] To a stirred solution of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)benzo[b]thiophen-7-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-4-carboxylic acid (520 mg, 0.856 mmol, 1.0 equiv) in DMF (8 mL) was added HATU (358 mg, 0.942 mmol, 1.1 equiv) and DIPEA (553 mg, 4.280 mmol, 5.0 equiv) at RT. The reaction mixture was stirred for 1 h at RT and quenched with water (30 mL). The resulting mixture was extracted withEtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 25 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 / 12) to provide the desired product (235mg, 95% pure).

[0385] Then the desired product was separated by prep-SFC-HPLC column (Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 8; Wave Length: 220nm; Rt1 (min): 10.497; Rt2 (min): 15.026; Rt3(min): 19.616; Sample Solvent: EtOH--HPLC; Injection Volume: 1.3 mL; Number Of Runs: 4).

[0386] Purification resulted in title Compound 2A with Rt1 (min): 10.497 (46.3 mg, 9% yield) ) as a light yellow solid, title Compound 2B with Rt2 (min): 15.026 (47.7 mg, 9%yield) as a light yellow solid, and a mixture of Compound 2C and Compound 2D Rt3(min): 19.616.

[0387] Compound 2A:1H NMR (400 MHz, DMSO) δ 8.69 (t, J = 5.9 Hz, 1H), 8.23 (s, 1H), 7.89 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 5.15 (d, J = 9.1 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.25 – 4.14 (m, 1H), 3.96 – 3.78 (m, 2H), 3.77 – 3.67 (m, 2H), 3.53 – 3.32 (m, 6H), 2.98 – 2.86 (m, 1H), 2.85 – 2.71 (m, 2H), 2.16 (s, 3H), 2.01 – 1.84 (m, 3H), 1.82 – 1.72 (m, 1H), 1.71 – 1.61 (m, 1H), 1.49 – 1.36 (m, 1H), 1.19 – 1.08 (m, 1H).

[0388] LCMS(ESI-MS) m / z = 590.3 [M+H]+

[0389] Rt: 1.458 min; Method 12

[0390] Compound 2B was repurified by preparative HPLC (Column:220nm XBridge Prep OBD C18 Column, 5μm, 30*150 mm, Mobile Phase A:Water(10mmol / LNH4HCO3), Mobile Phase B: ACN 60 mL / min 27% B to57 % B in 10 min, Rt: 8.913) to provide (26.6 mg, 5% yield) as a white solid.

[0391] 1H NMR (400 MHz, DMSO) δ 8.68 (t, J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.13 (d, J = 9.1 Hz, 1H), 4.36 – 4.24 (m, 3H), 4.24 – 4.14 (m, 1H), 3.98 – 3.77 (m, 2H), 3.77 – 3.66 (m, 2H), 3.52 – 3.37 (m, 6H), 2.96 – 2.84 (m, 1H), 2.83 – 2.69 (m, 2H), 2.14 (s, 3H), 2.00 – 1.81 (m, 3H), 1.80 – 1.73 (m, 1H), 1.68 – 1.58 (m, 1H), 1.48 – 1.34 (m, 1H), 1.18 – 1.05 (m, 1H).

[0392] LCMS(ESI-MS) m / z = 590.3 [M+H]+

[0393] Rt: 0.723 min; Method 7

[0394] The mixture of Compound 2C and Compound 2D was separated by prep-SFC-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 (B%): isocratic 30; Wave Length: 220 nm; Rt1 (min): 10.542; Rt2 (min): 18.855; Sample Solvent: EtOH--HPLC; Injection Volume: 0.6 mL; Number Of Runs: 5), resulting in title compound 2C with Rt1 (min): 10.542 (23.9 mg, 4% yield))as a light yellow solid, and the title compound 2D with Rt2 (min): 18.855 (20.8 mg, 4% yield,) as a light yellow solid.

[0395] Compound 2C

[0396] 1H NMR (400 MHz, DMSO) δ 8.68 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.26 (d, J = 6.0 Hz, 2H), 6.82 (s, 1H), 5.01 (d, J = 9.1 Hz, 1H), 4.35 – 4.19 (m, 4H), 3.98 – 3.60 (m, 5H), 3.50 – 3.37 (m, 6H), 3.30 – 3.19 (m, 1H), 2.67 – 2.57 (m, 1H), 2.29 – 2.01 (m, 5H), 1.90 – 1.50 (m, 5H).

[0397] LCMS(ESI-MS) m / z = 590.3 [M+H]+

[0398] Rt: 1.451 min; Method 12

[0399] Compound 2D:

[0400] 1H NMR (400 MHz, DMSO) δ 8.68 (t, J = 5.8 Hz, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.26 (d, J = 6.1 Hz, 2H), 6.81 (d, J = 6.5 Hz, 1H), 5.01 (d, J = 9.1 Hz, 1H), 4.37 – 4.19 (m, 4H), 3.99 – 3.58 (m, 5H), 3.52 – 3.37 (m, 6H), 3.29 – 3.21 (m, 1H), 2.66 – 2.55 (m, 1H), 2.28 – 2.00 (m, 5H), 1.89 – 1.51 (m, 5H).

[0401] LCMS(ESI-MS) m / z = 590.3 [M+H]+

[0402] Rt: 1.448 min; Method 12 2.5. Compound 3: 10-methyl-34-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,23,27,34-hexazapenta cyclo[29.2.1.05,33.07,12.021,25]tetratriaconta-1,3,5(33),22,24,31-hexaen-29-yn-26-one2.5.1. Step 1: ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5

[0403] To a stirred mixture of Int-3 (170 mg, 0.285 mmol, 1.0 equiv) and ethyl 1H-imidazole-4- carboxylate (79.8 mg, 0.570 mmol, 2.0 equiv) in toluene (2 mL) was added CMBP (206 mg, 0.855 mmol, 3.0 equiv). The reaction mixture was stirred for 1 h at 100 °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 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product (contained traces of regioisomer). The crude product was purified by TLC (Mobile phase: MeOH / DCM =1:12; Rf = 0.4; detection: UV) to provide the title compound (150 mg, 65% yield) as a yellow semi-solid.

[0404] LCMS(ESI-MS) m / z = 360.3 [1 / 2M+H]+

[0405] Rt: 0.714 min; Method 52.5.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5- carboxylic acid

[0406] To a stirred mixture of ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-5-carboxylate (140 mg, 0.195 mmol, 1.0 equiv) in MeOH (1.4 mL) was added sodium hydroxide (31.1 mg, 0.780 mmol, 4.0 equiv) in H2O (1.4 mL).The reaction mixture was stirred for 2 h at 50 °C. The mixture was adjusted to pH = 6 with hydrochloric acid (2 M) and extracted with EtOAc (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (120 mg, 80% yield) as a yellow solid.

[0407] LCMS(ESI-MS) m / z = 691.4 [M+H]+

[0408] Rt: 0.711, 0.725 min; Method 6 2.5.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5-carboxylic acid

[0409] A stirred mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-5-carboxylic acid (110 mg, 0.159 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred for 1 h at RT and concentrated under reduced pressure to afford the title compound (94 mg, crude) as a brown oil.

[0410] LCMS(ESI-MS) m / z = 591.1 [M+H]+

[0411] Rt: 0.800, 0.833 min; Method 20 2.5.4. Step 4: compound 3 - 10-methyl-34-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,23,27,34- hexazapentacyclo[29.2.1.05,33.07,12.021,25]tetratriaconta-1,3,5(33),22,24,31-hexaen-29-yn-26- one

[0412] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5-carboxylic acid (110 mg, 0.186 mmol, 1.0 equiv) and HATU (74.3 mg, 0.195 mmol, 1.05 equiv) in DMF (2 mL) was added DIPEA (216 mg, 1.67 mmol, 9.0 equiv). 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 (4 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 =1:5; Rf = 0.4; detection: UV) to provide the desired 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: 28% B to 45 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 8.6) to provide the title compound (10.9 mg, 9%) as an off-white solid.

[0413] LCMS(ESI-MS) m / z = 573.3 [M+H]+

[0414] Rt: 1.167, 1.210 min; Method 12 2.6. Compound 3A: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,23,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yn-25-one2.6.1. Step 1: Intermediates Int-7

[0415] A solution of Int-3 (220 mg, 0.369 mmol, 1.0 equiv) in DCM (4.5 mL) was added TEA (46.6 mg, 0.461 mmol, 1.25 equiv) and methanesulfonyl chloride (54.9 mg, 0.480 mmol, 1.3 equiv) at 0°C.The resulting mixture was stirred for 1 h at RT and quenched with water (50 mL). The resulting mixture was extracted with DCM (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 title compound (quantitative) as a yellow oil.

[0416] LCMS (ESI-MS) m / z = 675.3 [M+H]+

[0417] Rt: 0.932 min; Method 7 2.6.2. Step 2: ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-4- carboxylate and ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5- carboxylate

[0418] A solution of Int-7 (294 mg, 0.436 mmol, 1.0 equiv) and ethyl 1H-imidazole-4-carboxylate (67.2 mg, 0.480 mmol, 1.1 equiv) in DMF (9.0 mL) was added K2CO3 (265 mg, 1.92 mmol, 4.4 equiv) at RT. The resulting mixture was stirred for 60 h at RT 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 to afford crude product. The crude product was purified by TLC (MeOH / DCM = 1 / 10; Rf = 0.5; detection: UV) to provide the mixture of title compounds (150 mg, 43%yield) as a yellow oil.

[0419] LCMS (ESI-MS) m / z = 719.4 [M+H]+

[0420] Rt1: 0.912 min, Rt2: 0.950 min; Method 7 2.6.3. Step 3: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-4- carboxylic acid and 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5- carboxylic acid

[0421] To a mixture of ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-4-carboxylate and ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-5-carboxylate (136 mg, 0.189 mmol, 1.0 equiv) in MeOH (2.7 mL) and H2O (2.7 mL) was added NaOH (30.3 mg, 0.756 mmol, 4.0 equiv) at RT. The reaction mixture was stirred for 2 h at 50°C and concentrated under reduced pressure to remove MeOH. The resulting was adjusted to PH = 5 with hydrochloric acid (1 M). 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, filteredand concentrated under reduced pressure to afford crude mixture of title compounds (130 mg, crude) as a yellow solid.

[0422] LCMS (ESI-MS) m / z = 346.3 [1 / 2M+H]+

[0423] Rt: 0.728 min, 0.741 min; Method 11 2.6.4. Step 4: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-4-carboxylic acid / 1-(2-(2- (2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5-carboxylic acid

[0424] To stirred a mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-4-carboxylic acid and 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- imidazole-5-carboxylic acid (126 mg, 0.182 mmol, 1.0 equiv) in DCM (1.2 mL) was added TFA (0.4 mL) at RT. The reaction mixture was stirred for 1 h at RT and concentrated under reduced pressure to afford crude mixture of title compounds (quantitative) as a yellow oil.

[0425] LCMS (ESI-MS) m / z = 591.3 [M+H]+

[0426] Rt: 0.460 min; Method 27 2.6.5. Step 5: Compound 3A: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,23,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn- 25-one / Compound 3: 10-methyl-34-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,23,27,34- hexazapentacyclo[29.2.1.05,33.07,12.021,25]tetratriaconta-1,3,5(33),22,24,31-hexaen-29-yn-26- one (289-0)

[0427] To a mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-imidazole-4-carboxylic acid / 1-(2-(2-(2- (4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3- yl)ethoxy)ethoxy)ethyl)-1H-imidazole-5-carboxylic acid (107 mg, 0.181 mmol, 1.0 equiv) in DMF (2.0 mL) was HATU (82.7 mg, 0.217 mmol, 1.2 equiv), DIPEA (140 mg, 1.09 mmol, 6.0 equiv) and 4A MS (214 mg) at 0°C. The resulting mixture was stirred for 2 h at RT 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 to afford crude product. The crude product was purified by TLC (MeOH / DCM =1 / 10; Rf = 0.4; detection: UV) to provide the desired product (34 mg, ~90% pure). The 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 (B%): 3% B to 30% B in 10min; Wave Length: 220nm; Rt1 (min) 7.5, 8.17 for title compound 3 and Rt2 (min) 9.5 min for title compound 3A (2.0 mg, 1%yield) as a yellow solid.

[0428] Compound 3A:

[0429] LCMS(ESI-MS) m / z = 573.4 [M+H]+

[0430] Rt: 1.013 min; Method 8 2.7. Compound 4: mixture of 10,23-dimethyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,22,26,33-hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1,3,5(32),22,24(34),30-hexaen-28-yn-25-one and 10,34-dimethyl-33-(2,2,2-trifluoroethyl)-15,18- dioxa-6,10,21,22,26,33-hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1,3,5(32),22,24(34),30-hexaen-28-yn-25-one2.7.1. Step 1: methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl-1H- pyrazole-4-carboxylate / methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5- methyl-1H-pyrazole-4-carboxylate

[0431] To a solution of Int-3 (180 mg, 0.302 mmol, 1.0 equiv) and methyl 3-methyl-1H-pyrazole-4- carboxylate (85.0 mg, 0.604 mmol, 2.0 equiv) in toluene (4.0 mL) was added CMBP(218 mg, 0.906 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred for 2 h at 100 °C. The resulting mixture was quenched with waster (20 mL) and extracted with EtOAc (3 x 20 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 purified by TLC (Mobile phase: MeOH / DCM = 1 / 10; Rf = 0.5; detection: UV) to provide the mixture of title compounds as regioisomer (170 mg, 70% yield) as a brown solid.

[0432] LCMS (ESI-MS) m / z = 719.4 [M+H]+

[0433] Rt: 0.808 min; Method 6 2.7.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl-1H- pyrazole-4-carboxylic acid / 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-methyl- 1H-pyrazole-4-carboxylic acid

[0434] To a mixture of methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl- 1H-pyrazole-4-carboxylate / methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-methyl- 1H-pyrazole-4-carboxylate (170 mg, 0.236 mmol, 1.0 equiv) in MeOH (7.0 mL) and water (7.0 mL) was added sodium hydroxide (38.0 mg, 0.944 mmol, 4.0 equiv). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was diluted with waster (20 mL), 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 title compounds as regioisomer mixture (150 mg) as a brown solid.

[0435] LCMS (ESI-MS) m / z = 705.4 [M+H]+

[0436] Rt: 0.703 min; Method 62.7.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl-1H-pyrazole-4-carboxylic acid / 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-methyl-1H-pyrazole-4-carboxylic acid

[0437] A mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl-1H- pyrazole-4-carboxylic acid / 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-methyl- 1H-pyrazole-4-carboxylic acid (150 mg, 0.213 mmol, 1.0 equiv) hydrogen chloride (2.0 mL, 4 M in dioxane) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure to afford crude mixture of title compounds (128 mg, crude) (regioisomer mixture) as a brown solid.

[0438] LCMS (ESI-MS) m / z = 605.3 [M+H]+

[0439] Rt: 0.467, 0.494 min; Method 1 2.7.4. Step 4: Compound 4: - mixture of 10,23-dimethyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10, 21,22,26,33-hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30- hexa en-28-yn-25-one and 10,34-dimethyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexaza pentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn-25-one

[0440] To a mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-methyl-1H-pyrazole-4-carboxylic acid / 1- (2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-methyl-1H-pyrazole-4-carboxylic acid (120 mg, 0.198 mmol, 1.0 equiv) (mixture) and HATU (80.0 mg, 0.208 mmol, 1.05 equiv) in DMF (3.0 mL) was added DIPEA (154 mg, 1.19 mmol, 6.0 equiv) at 0 °C. The reaction mixture was stirred for 2 h at RT. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 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 purified by preparative HPLC (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to38 % B in 10 min; Wave Length: 254nm / 220nm; Rt1(min): 8.34) to afford title compounds as regioisomer mixture (12.2 mg, 10.0% yield) as a yellow solid.

[0441] LCMS (ESI-MS) m / z = 587.3 [M+H]+

[0442] Rt: 0.678 min; Method 72.8. Compound 5: 23-chloro-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yn-25-one, and Compound 5A: 34-chloro-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yn-25-one2.8.1. Step 1: ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-chloro-1H- pyrazole-4-carboxylate / ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-chloro- 1H-pyrazole-4-carboxylate

[0443] To a solution of Int-3 (170 mg, 0.285 mmol, 1.0 equiv) in toluene (4 mL) was added ethyl 3- chloro-1H-pyrazole-4-carboxylate (99.5 mg, 0.570 mmol, 2.0 equiv) and CMBP (206 mg, 0.855 mmol,3.0 equiv) at RT. The mixture was stirred for 1 h at 100 °C under nitrogen and quenched with water (25 mL). The resulting mixture was extracted with EtOAc (3 x 25 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 TLC (Mobile phase: MeOH / DCM) =1:12; Rf = 0.4; detection: UV) to provide the title compounds (200 mg, 87% yield) (regioisomer mixture) as a brown semi-solid.

[0444] LCMS (ESI-MS) m / z = 753.4 [M+H]+

[0445] Rt: 0.800 min; Method 6 2.8.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-chloro-1H- pyrazole-4-carboxylic acid / 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-chloro- 1H-pyrazole-4-carboxylic acid

[0446] To a solution of mixture of ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn- 1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3- chloro-1H-pyrazole-4-carboxylate and ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1- yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)- 5-chloro-1H-pyrazole-4-carboxylate (200 mg, 0.266 mmol, 1.0 equiv) in MeOH (8 mL) was added NaOH (53.1 mg, 1.330 mmol, 5.0 equiv, in H2O (8 mL)) at RT. The reaction mixture was stirred for 6 h at 50 °C. The mixture was acidified to pH = 5 with HCl (1 N). The resulting mixture was extracted with EtOAc (3 x 40 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compounds (180 mg, crude) (regioisomer mixture) as a brown solid.

[0447] LCMS (ESI-MS) m / z = 725.4 [M+H]+

[0448] Rt: 0.730 min; Method 6 2.8.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-chloro-1H-pyrazole-4-carboxylic acid / 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-chloro-1H-pyrazole-4-carboxylic acid

[0449] A solution of mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-chloro- 1H-pyrazole-4-carboxylic acid and 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-chloro- 1H-pyrazole-4-carboxylic acid (180 mg, 0.248 mmol, 1 equiv) and HCl (5 mL, 4.0 M in 1,4-dioxane)was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure to provide title compound (145 mg) (regioisomer mixture) as a brown semi-solid.

[0450] LCMS (ESI-MS) m / z = 725.4 [M+H]+

[0451] Rt: 0.730 min; Method 6 2.8.4. Step 4: Compound 5: 288-0: 23-chloro-10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,22,26,33-hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1,3,5(32),22,24(34),30-hexaen-28-yn-25-one, & Compound 5A: 288-0A: 34-chloro-10-methyl-33- (2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn- 25-one

[0452] To a solution of mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-chloro-1H-pyrazole-4- carboxylic acid and 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-chloro-1H-pyrazole-4-carboxylic acid (190 mg, 0.304 mmol, 1.0 equiv) in DMF (6 mL) was added HATU (127 mg, 0.334 mmol, 1.1 equiv) and DIPEA (196 mg, 1.520 mmol, 5.0 equiv), then the mixture was stirred for 1 h at RT. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 30 mL), the organic layers were combined, washed with brine (2 x 25 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 ; Gradient: 5% B to 35% B in 10 min; Wave Length: 220 nm; Rt1 (min): 9.87 ) to provide the mixture product (38 mg, 20% yield) (regioisomer mixture as an off-white solid. The mixture was separated by Achiral SFC ( Column: DAICEL DCpak P4VP 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: IPA(1%-2M-NH3-MeOH); Flow rate: 65 mL / min; Gradient: isocratic 36% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Rt1 (min): 7.52; Rt2 (min): 11.86; Sample Solvent: MeOH; Injection Volume: 1.5 mL) to provide the title compound 5 (Rt2: 11.86 min) (9.1 mg, 28% yield) as a light yellow solid.

[0453] LCMS(ESI-MS) m / z = 607.3 [M+H]+

[0454] Rt: 0.713 min; Method 7

[0455] And the title compound 5A (Rt1: 7.52 min) (10.3 mg, 32% yield) as a light yellow solid.

[0456] LCMS(ESI-MS) m / z = 607.3 [M+H]+

[0457] Rt: 0.692 min; Method 72.9. Compound 6: 10-methyl-34-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,27,34- hexazapentacyclo[29.2.1.05,33.07,12.021,25]tetratriaconta-1,3,5(33),22,24,31-hexaen-29-yn-26- one2.9.1. Step 1: ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5- carboxylate / ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3- carboxylate

[0458] To a stirred mixture of Int-3 (300 mg, 0.503 mmol, 1.0 equiv) and ethyl 1H-pyrazole-3- carboxylate (141 mg, 1.01 mmol, 2 equiv) in toluene (3 mL) was added CMBP (364 mg, 1.51 mmol, 3.0 equiv). The reaction mixture was stirred for 2 h at 100°C under nitrogen and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (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 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: 51% B to72 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 6.5, 7.1; Rt2 (min): 7.7, 8.4) to provide the desired product. Purification resulted in isomer 1, title compound ethyl 1-(2-(2-(2-(4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (Rt1 (min): 6.5, 7.1) (180 mg, 47% yield)) as a white solid and isomer 2, ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3- yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate (Rt2 (min): 7.7, 8.4) (60 mg, 13% yield,)) as white solid (These two structures were confirmed by NOESY NMR).

[0459] Isomer 1: ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5- carboxylate

[0460] LCMS(ESI-MS) m / z = 719.8 [M+H]+.

[0461] Rt: 1.225 min; Method 4 2.9.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5- carboxylic acid

[0462] To a stirred mixture of ethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-5-carboxylate (170 mg, 0.236 mmol, 1.0 equiv) in MeOH (1.7 mL) was added sodium hydroxide (37.8 mg, 0.944 mmol, 4.0 equiv, in H2O (1.7 mL)). The resulting mixture was stirred for 2 h at 50°C. The mixture was adjusted to PH = 6 with hydrochloric acid (2 M) and extracted with EtOAc (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (155 mg, 85%) as an off-white solid.

[0463] LCMS(ESI-MS) m / z = 691.5 [M+H]+

[0464] Rt: 0.829 min; Method 26 2.9.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid

[0465] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-5-carboxylic acid (150 mg, 0.217 mmol, 1.0 equiv) in DCM (3 mL) was added trimethylsilyl trifluoromethanesulfonate (241 mg, 1.08 mmol, 5.0 equiv) and DIPEA (168 mg, 1.30 mmol, 6.0 equiv). The reaction mixture was stirred for 2 h at RT and quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (127 mg, crude) as a yellow semi-solid.

[0466] LCMS(ESI-MS) m / z = 591.1 [M+H]+

[0467] Rt: 0.785, 0.800 min; Method 262.9.4. Step 4: Compound 6 - 10-methyl-34-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,27,34- hexazapentacyclo[29.2.1.05,33.07,12.021,25]tetratriaconta-1,3,5(33),22,24,31-hexaen-29-yn-26- one

[0468] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (120 mg, 0.203 mmol, 1.0 equiv) and HATU (81.1 mg, 0.213 mmol, 1.05 equiv) in DMF (1.5 mL) was added DIPEA (157 mg, 1.218 mmol, 6.0 equiv) at 0 °C. The reaction mixture was stirred for 2 h at RT and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (4 x 15 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: 29% B to 59 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 8.4) to provide the title compound (19.5 mg, 16% yield) as an off-white solid.

[0469] LCMS(ESI-MS) m / z = 573.3 [M+H]+

[0470] Rt: 2.459, 2.528 min; Method 33 2.10. Compound 6A: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33,34- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yn-25-one2.10.1. Step 1: tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5- carboxylate (isomer 1) / tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-3-carboxylate (isomer 2)

[0471] To a stirred mixture of Int-7 (200 mg, 0.296 mmol, 1.0 equiv) and tert-butyl 1H-pyrazole-3- carboxylate (54.8 mg, 0.326 mmol, 1.1 equiv) in DMF (4 mL) was added K2CO3(122 mg, 0.888 mmol, 3.0 equiv). The reaction mixture was stirred for 2 days at RT. The mixture was filtered through a celite pad and washed with EtOAc (3 x 80 mL). The filtrate was washed with brine (3 x 50 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(10nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 54% B to68 % B in 15 min; Wave Length: 254 nm / 220nm; Rt1 (min): 9.22, Rt2 (min): 11.47). Purification resulted in title compounds isomer 2 with Rt1 (min): 9.22, title compound tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate (47 mg, 20% yield)) as a brown semi-solid and isomer 1 / Rt2 (min): 11.47, title compound tert-butyl 1-(2-(2-(2-(4- ((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (70 mg, 30% yield)) as a brown semi-solid.

[0472] Isomer 2: tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3- carboxylate

[0473] LCMS(ESI-MS) m / z = 747.5 [M+H]+

[0474] Rt (min) = 0.891 (Method 7) 2.10.2. Step 2: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylic acid

[0475] To a stirred mixture of tert-butyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn- 1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrazole-3-carboxylate (47.0 mg, 0.063 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred for 1 h at RT and concentrated under reduced pressure to afford the crude title compound (37 mg, crude) as a brown oil.

[0476] LCMS(ESI-MS) m / z = 591.3 [M+H]+

[0477] Rt (min) = 0.502 (Method 6)2.10.3. Step 3: compound 6A - 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33,34- hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn- 25-one

[0478] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylic acid (35.0 mg, 0.059 mmol, 1.0 equiv) and HATU (30.4 mg, 0.080 mmol, 1.05 equiv) in DMF (4 mL) was added DIPEA (59.1 mg, 0.456 mmol, 6.0 equiv). The reaction mixture was stirred for 1 h at RT and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL) and the organic layers were combined, washed with brine (2 x 15 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: CAN; Flow rate: 60 mL / min; Gradient: 28% B to58 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 8.6) to provide the title compound (7.0 mg, 15% yield) as an off-white solid.

[0479] LCMS(ESI-MS) m / z = 573.3 [M+H]+

[0480] Rt (min) = 1.713, 1.739; Method 362.11. Compound 7B: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33,34- heptazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yn-25-one2.11.1. Step 1: Intermediates Int-4: methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop- 1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3- yl)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylate, Intermediates Int-5: methyl 2-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3- triazole-4-carboxylate, and methyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-5- carboxylate

[0481] To a stirred mixture of Int-3 (250 mg, 0.419 mmol, 1.0 equiv) and methyl 1H-1,2,3-triazole-4- carboxylate (106 mg, 0.838 mmol, 2.0 equiv) in toluene (2.5 mL) was CMBP (303 mg, 1.25 mmol, 3.0equiv). The reaction mixture was stirred for 2 h at 100°C under nitrogen 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 150 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: Shim-pack Scepter C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 70% B in 12min; Wave Length: 254nm / 220nm; Rt1 (min): 8.8; 9.6) to provide the product.

[0482] Purification resulted in Int-4 (20 mg, 6 % yield) brown semi-solid (This structure was confirmed by NOESY NMR.) and mixture A (Int-5 and isomer) (150 mg, 95% pure). The mixture A was separated by prep-Achiral SFC-HPLC column (Column: Torus Diol OBD 3*25 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: IPA: HEX=1: 1(1%-2M-NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 28% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Rt1 (min): 7.73; Rt2 (min): 9.8; Sample Solvent: MeOH; Injection Volume: 2 mL). Purification resulted in Int-5 (Rt1 (min): 7.73) (50 mg, 16%)) as brown semi-solid and isomer (Rt2 (min): 9.8) (33 mg, 10% yield)) as a brown semi-solid (These two structures were confirmed by C NMR and HSQC NMR).292-1B / 2.11.2. Step 2: 2-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3- triazole-4-carboxylic acid

[0483] To a stirred mixture of Int-5 (95.0 mg, 0.135 mmol, 1.0 equiv) in MeOH (1 mL) was added sodium hydroxide (21.5 mg, 0.540 mmol, 4.0 equiv, in H2O (1 mL)). The resulting mixture was stirred for 2 h at 50°C. The mixture was adjusted to PH = 6 with hydrochloric acid (2 M) and extracted with EtOAc (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (85.0 mg, 86%) as an off-white solid.

[0484] LCMS(ESI-MS) m / z = 692.4 [M+H]+

[0485] Rt: 0.716 min; Method 6 2.11.3. Step 3: 2-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3-triazole-4-carboxylic acid

[0486] To a stirred mixture of 2-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3- triazole-4-carboxylic acid (80.0 mg, 0.116 mmol, 1.0 equiv) in DCM (2.5 mL) was added trimethylsilyl trifluoromethanesulfonate (128 mg, 0.580 mmol, 5.0 equiv) and DIPEA (89.6 mg, 0.696 mmol, 6.0 equiv). The reaction mixture was stirred for 2 h at RT and quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (68 mg, 89%) as a yellow semi-solid.

[0487] LCMS(ESI-MS) m / z = 592.1 [M+H]+

[0488] Rt: 0.770 min, 0.788 min; Method 26 2.11.4. Step 4: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,26,33,34-heptazapenta cyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn-25-one

[0489] To a stirred mixture of 2-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-2H-1,2,3-triazole-4-carboxylic acid (85.0 mg, 0.144 mmol, 1.0 equiv) and HATU (57.3 mg, 0.151 mmol, 1.05 equiv) in DMF (8.5 mL) was added DIPEA (111 mg, 0.864 mmol, 6.0 equiv) at 0°C. The reaction mixture was stirred for 1 h at RT and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL) and the organic layers were combined, washed with brine (4 x 15 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 Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to51 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 9.8) to provide the title compound (9.5 mg, 11% yield) as a white solid.

[0490] LCMS(ESI-MS) m / z = 574.2 [M+H]+

[0491] Rt: 1.428 min, 1.450 min; Method 12 2.12. Compound 7A: 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,22,23,26,33-hepta zapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yn-25- one2.12.1. Step 1: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazole-4-carboxylic acid

[0492] To a stirred mixture of Int-4 (60.0 mg, 0.085 mmol, 1.0 equiv) in MeOH (0.6 mL) was added NaOH (13.6 mg, 0.340 mmol, 4.0 equiv, in H2O (0.6 mL)). The reaction mixture was stirred for 2 h at 50°C and adjusted to PH = 6 with hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (3 x 30 mL) and concentrated under reduced pressure to afford the crude title compound (50 mg, 76% yield) as a yellow solid.

[0493] LCMS(ESI-MS) m / z = 692.4 [M+H]+

[0494] Rt (min) = 0.779; Method 6) 2.12.2. Step 2: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylic acid

[0495] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3- triazole-4-carboxylic acid (50.0 mg, 0.072 mmol, 1.0 equiv) in DCM (1 mL) was added DIPEA (56.1 mg, 0.432 mmol, 6.0 equiv) and TMSOTf (80.3 mg, 0.360 mmol, 5.0 equiv). The reaction mixture was stirred for 2 h at RT and quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (42 mg, crude) as a brown semi- solid.

[0496] LCMS(ESI-MS) m / z = 592.1 [M+H]+

[0497] Rt (min) = 0.788; Method 26 2.12.3. Step 3: Compound 7A - 10-methyl-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,22,23,26,33-heptazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1,3,5(32),22,24(34),30-hexaen-28-yn-25-one

[0498] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (50.0 mg, 0.085 mmol, 1.0 equiv) and HATU (33.7 mg, 0.089 mmol, 1.05 equiv) in DMF (5 mL) was added DIPEA (65.5 mg, 0.510 mmol, 6.0 equiv). The reaction mixture was stirred for 2 h at RT 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: 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 (B%): 30% B to45% B in 10min; Wave Length: 254nm / 220nm; Rt1 (min): 8.17) to provide the title compound (1.0 mg, 2% yield) as an off-white solid.

[0499] LCMS(ESI-MS) m / z = 574.3 [M+H]+

[0500] Rt (min) = 0.702; Method 7 2.13. Compound 8: ethyl 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-23-carboxylate2.13.1. Step 1: diethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrrole-3,4- dicarboxylate

[0501] To a stirred mixture of Int-3 (400 mg, 0.670 mmol, 1.0 equiv) and 3,4-diethyl 1H-pyrrole-3,4- dicarboxylate (283 mg, 1.34 mmol, 2.0 equiv) in toluene (4 mL) was added CMBP (485 mg, 2.01 mmol, 3.0 equiv) at 0 °C under nitrogen. The reaction mixture was stirred for 2 h at 100 °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 product. The crude product was purified by TLC (Mobile phase: MeOH / DCM=1:12; Rf = 0.4; detection: UV) to provide the title compound (400 mg, 77% yield) as a brown solid.

[0502] LCMS(ESI-MS) m / z = 790.3 [M+H]+

[0503] Rt: 0.717 min; Method 2.2.13.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-4- (ethoxycarbonyl)-1H-pyrrole-3-carboxylic acid

[0504] To a stirred mixture of diethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H- pyrrole-3,4-dicarboxylate (260 mg, 0.377 mmol, 1.0 equiv) in EtOH (3 mL) was added NaOH (15 mg, 0.377 mmol, 1.0 equiv, in H2O (3 mL)). The reaction mixture was stirred for 2 days at 50 °C and adjusted to pH=3 with 2M HCl. The resulting mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (180 mg, crude) as a brown solid.

[0505] LCMS(ESI-MS) m / z = 762.6 [M+H]+

[0506] Rt: 0.843 min; Method 20 2.13.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-4-(ethoxycarbonyl)-1H-pyrrole-3- carboxylic

[0507] A stirred mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-4- (ethoxycarbonyl)-1H-pyrrole-3-carboxylic acid (180 mg, 0.236 mmol, 1.0 equiv) and hydrogen chloride (2 mL, 4.0 M in 1,4-dioxane) was stirred for 30 mins at RT. The reaction mixture was concentrated under reduced pressure to afford the crude title compound (140 mg, crude) as a brown semi-solid.

[0508] LCMS(ESI-MS) m / z = 662.5 [M+H]+

[0509] Rt: 0.654 min; Method 20 2.13.4. Step 4: ethyl 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-23-carboxylate

[0510] To a stirred mixture of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-4-(ethoxycarbonyl)-1H-pyrrole-3- carboxylic (140 mg, 0.212 mmol, 1.0 equiv) and HATU (96.0 mg, 0.254 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (164 mg, 1.27 mmol, 6.0 equiv) dropwise at 0°C. The reaction mixture was stirred for 1 h at RT 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 sodium sulfate, filtered and concentrated under reduced pressure to afford title compound (100 mg, crude) as a brown solid.

[0511] LCMS(ESI-MS) m / z = 644.5 [M+H]+

[0512] Rt: 0.982 min; Method 202.13.5. Step 5: 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-23-carboxylic acid

[0513] To a stirred mixture of ethyl 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,26,33-pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30- hexaen-28-yne-23-carboxylate (90.0 mg, 0.140 mmol, 1.0 equiv) in MeOH (1 mL) was added NaOH (22.3 mg, 0.560 mmol, 4.0 equiv, in H2O (1 mL)). The reaction mixture was stirred for 2 h at 50 °C and adjusted to PH=3 with 2M HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, 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, 48 g; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 40 min; Wave Length: 220nm; Collected fractions: 43 % B) to provide the title compound (40 mg, 41%yield) as a yellow solid.

[0514] LCMS(ESI-MS) m / z = 616.2 [M+H]+

[0515] Rt: 0.641 min; Method 2 2.13.6. Step 6: Compound 8 - 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,26,33-pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30- hexaen-28-yne-23-carboxamide

[0516] To a stirred mixture of 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yne-23- carboxylic acid (40 mg, 0.065 mmol, 1.0 equiv), NH4Cl (24 mg, 0.455 mmol, 7.0 equiv) and HATU (29 mg, 0.078 mmol, 1.2 equiv) in DMF (2 mL) was added DIEA (50 mg, 0.390 mmol, 6.0 equiv) dropwise at 0°C. The reaction mixture was stirred for 1 h at RT and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL) and the organic layers were combined, washed with brine (2 x 15 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: 24% B to54 % B in 10 min; Wave Length: 254nm / 220nm; Rt1 (min): 8.72 to provide the title compound (11.9 mg, 28%yield) as a yellow solid.

[0517] LCMS(ESI-MS) m / z = 615.3 [M+H]+

[0518] Rt: 1.375, 1.387 min; Method 122.14. Compound 9: : N,10-dimethyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-23-carboxamide2.14.1. Step 1: N,10-dimethyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-23-carboxamide

[0519] To a stirred mixture of 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yne-23- carboxylic acid (45.0 mg, 0.073 mmol, 1.0 equiv) and Methylamine hydrochloride (4.9 mg, 0.073 mmol, 1.0 equiv), HATU (33.3 mg, 0.088 mmol, 1.2 equiv) in DMF (2 mL) was added DIPEA (37.7 mg, 0.292 mmol, 4.0 equiv) dropwise at 0 °C. The reaction mixture was stirred for 1 h at RT and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL) and the organic layers were combined, washed with brine (2 x 15 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 = 0.4; detection: UV) to provide the crude product. The crude product was purified by preparative HPLC Column: Xbridge Prep OBD Shield RP18, 19*250 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MEOH; Flow rate: 25 mL / min; Gradient: 11% B to41 % B in 15 min; Wave Length: 254nm / 220nm; Rt1 (min): 12.33 to provide the title compound (7.2 mg, 14% yield) as a light yellow solid.

[0520] LCMS(ESI-MS) m / z = 629.3 [M+H]+

[0521] Rt: 0.656 min; Method 72.15. Compound 10: 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-22-carboxylic acid2.15.1. Step 1: diethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrrole-2,4- dicarboxylate

[0522] To a solution of Int-3 (550 mg, 0.922 mmol, 1.0 equiv) in toluene (9 mL) was added 2,4-diethyl 1H-pyrrole-2,4-dicarboxylate (389 mg, 1.84 mmol, 2.0 equiv) and CMBP (667.42 mg, 2.766 mmol, 3.0 equiv, in toluene (1mL)) stirred at RT under nitrogen. The resulting mixture was stirred for 3 h at 100 °C and quenched with water (15 mL). 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 chromatographed on a silica gel column (Column: 90 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 min; Wave Length: 220 nm; 8% - 9% B fractions were collected ) to provide the title compound (550 mg, 68% yield) as a brown solid.

[0523] LCMS(ESI-MS) m / z = 790.5 [M+H]+

[0524] Rt: 0.686 min; Method 22.15.2. Step 2: 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5- (ethoxycarbonyl)-1H-pyrrole-3-carboxylic acid

[0525] To a solution of diethyl 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-1H-pyrrole- 2,4-dicarboxylate (470 mg, 0.595 mmol, 1.0 equiv) in EtOH (9.4 mL) was added NaOH (119 mg, 2.97 mmol, 5.0 equiv, in H2O (9.4 mL)) stirred at RT. The resulting mixture was stirred for 3 h at 45 °C and diluted with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 25 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, separated out by prep-Achiral SFC column (Column: GreenSep Basic 3*15 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: ACN: MeOH=4: 1(1% 2M NH3-MeOH); Flow rate: 70 mL / min; Gradient: isocratic 48% B; Column Temperature (℃): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Rt1 (min): 4.17; Rt2 (min): 6.16; Sample Solvent: MeOH; Injection Volume: 3 mL). Purification resulted in the title compound (300 mg, 59% yield, Rt1 (min): 4.17) as a brown solid.

[0526] LCMS(ESI-MS) m / z = 762.5 [M+H]+

[0527] Rt: 0.620 min; Method 2 2.15.3. Step 3: 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-(ethoxycarbonyl)-1H-pyrrole-3- carboxylic acid

[0528] A mixture of 1-(2-(2-(2-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5- (ethoxycarbonyl)-1H-pyrrole-3-carboxylic acid (300 mg, 0.394 mmol, 1.0 equiv) and hydrogen chloride (3 mL, 4.0 M in 1,4-dioxane) was stirred at RT. The resulting mixture was stirred for 1 h at RT and concentrated under reduced pressure to afford crude title compound (260 mg, crude). The crude product was used in the next step directly without further purification.

[0529] LCMS(ESI-MS) m / z = 662.2 [M+H]+

[0530] Rt: 0.551 min; Method 2 2.15.4. Step 4: ethyl 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-22-carboxylate

[0531] To a solution of 1-(2-(2-(2-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-(ethoxycarbonyl)-1H-pyrrole-3-carboxylic acid (260 mg, 0.393 mmol, 1.0 equiv) and HATU (164.34 mg, 0.432 mmol, 1.1 equiv) in DMF (2.6 mL) was added DIPEA (253 mg, 1.96 mmol, 5.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 2 h at RT and quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 7 mL)and the organic layers were combined, washed with brine (2 x 7 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (250 mg, crude). The crude product was used in the next step directly without further purification.

[0532] LCMS(ESI-MS) m / z = 644.3 [M+H]+

[0533] Rt: 0.641, 0.675 min; Method 2 2.15.5. Step 5: 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-22-carboxylic acid

[0534] To a solution of ethyl 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yne-22- carboxylate (250 mg, 0.388 mmol, 1.0 equiv) in MeOH (1 mL) was added NaOH (62.1 mg, 1.55 mmol, 4.0 equiv, in H2O (1 mL)) stirred at RT. The reaction mixture was stirred at 50 °C overnight and diluted with H2O (3 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL) and the aqueous phase was acidified to pH 5~6 with hydrochloric acid (1 M). The aqueous phase was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (200 mg, crude). The crude product was used in the next step directly without further purification.

[0535] LCMS(ESI-MS) m / z = 616.4 [M+H]+

[0536] Rt: 0.519 min; Method 2 2.15.6. Step 6: compound 10 - 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa- 6,10,21,26,33-pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30- hexaen-28-yne-22-carboxamide

[0537] To a solution of 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yne-22- carboxylic acid (90.0 mg, 0.146 mmol, 1.0 equiv), HATU (66.7 mg, 0.175 mmol, 1.2 equiv) and NH4Cl (54.7 mg, 1.022 mmol, 7.0 equiv) in DMF (1 mL) was added DIPEA (113.36 mg, 0.876 mmol, 6.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 1 h at RT and quenched with water (2 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL) and the organic layers were combined, washed with brine (2 x 5 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 / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 46% B in 6.5 min; Wave Length: 254 nm / 220 nm; Rt1 (min): 5.43) to provide the title compound (6.8 mg, 6% yield) as a light yellow solid.

[0538] LCMS(ESI-MS) m / z = 615.3 [M+H]+

[0539] Rt: 1.308 min, 1341 min; Method 12 2.16. Compound 11: N,10-dimethyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-22-carboxamide2.16.1. Step 1: N,10-dimethyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28- yne-22-carboxamide

[0540] To a solution of 10-methyl-25-oxo-33-(2,2,2-trifluoroethyl)-15,18-dioxa-6,10,21,26,33- pentazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1,3,5(32),22,24(34),30-hexaen-28-yne-22- carboxylic acid (90.0 mg, 0.146 mmol, 1.0 equiv) in DMF (1 mL) was added HATU (66.70 mg, 0.175 mmol, 1.2 equiv), Methylamine hydrochloride (24.6 mg, 0.365 mmol, 2.5 equiv) and DIPEA (56.6 mg, 0.438 mmol, 3.0 equiv) stirred at 0 °C. The reaction mixture was stirred for 1 h at RT and quenched with water (2 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL) and the organic layers were combined, washed with brine (2 x 5 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: Kinetex EVO C18, 30*150 mm, 5 μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MeOH; Flow rate: 25 mL / min; Gradient: 26% B to 47 % B in 15 min; Wave Length: 254 nm / 220 nm; Rt1 (min): 13.86) to provide the title compound (6.3 mg, 6% yield) as a light yellow solid.

[0541] LCMS(ESI-MS) m / z = 629.3 [M+H]+

[0542] Rt: 1.335 min, 1.369 min; Method 122.17. Compound 12: 10-methyl-33-(2,2,2-trifluoroethyl)-6,10,21,22,26,33-hexaza pentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28-yn-25- one2.17.1. Step 1: ((8-bromooctyl)oxy)(tert-butyl)diphenylsilane

[0543] To a solution of 8-bromooctan-1-ol (10.0 g, 47.8 mmol, 1.0 equiv) in DMF (100 mL) were added Imidazole (8.14 g, 120 mmol, 2.5 equiv) and tert-butyl(chloro)diphenylsilane (17.1 g, 62.2 mmol, 1.3 equiv) at RT. The reaction mixture was stirred overnight at RT and quenched with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (3 x 70 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: EtOAc; Flow rate: 80 mL / min; Gradient: 0% B to 10% B in 30 min; Wave Length: 254 nm / 220 nm; 3% - 5% B fractions were collected) to provide the title compound (15.8 g, 66% yield) as a colourless oil.

[0544] LCMS(ESI-MS): no MS 2.17.2. Step 2: 3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin-4-one

[0545] To a solution of Int-8 (2.50 g, 16.1 mmol, 1.0 equiv) in THF (85 mL) was added LDA (2.0 M in THF) (12.1 mL, 24.2 mmol, 1.5 equiv) at 0 °C under nitrogen. The mixture was stirred for 1.5 h at 0 °C. Then ((8-bromooctyl)oxy)(tert-butyl)diphenylsilane (7.93 g, 17.7 mmol, 1.1 equiv) in THF (20 mL) was added at 0 °C under nitrogen. The reaction mixture was stirred for 16 h at RT and quenched with saturated aq. NH4Cl (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL) and the organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude intermediate (50 mL EtOAc remaining). Then Citric acid solution (10% in H2O, 50 mL) was added. The mixture was stirred at RT for 2 h andadjusted to PH=9 with saturated NaHCO3 solution and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL) and the organic layers were combined, washed with 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 (Column: 120 g x 2, 100 - 200 mesh, Mobile Phase A: DCM, Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient: 0% B to 11% B in 30 min; Wave Length: 220 nm; 8% B fractions were collected) to provide the title compound (4.60 g, 51% yield) as a yellow oil.

[0546] LCMS(ESI-MS) m / z = 480.3 [M+H]+

[0547] Rt: 0.990 min; Method 6 2.17.3. Step 3: N-(3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2- trifluoroethyl)-1H-indol-4-amine

[0548] To a mixture of 3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin-4-one (1.02 g, 2.12 mmol, 1.2 equiv) and 2-iodo-1-(2,2,2-trifluoroethyl)indol-4-amine (600 mg, 1.76 mmol, 1.0 equiv) in methanol (12 mL) was added acetic acid (212 mg, 3.53 mmol, 2.0 equiv) and 4A MS (2.00 g) at RT. The mixture was stirred for 16 h at 30 °C. Then sodium cyanoborohydride (333 mg, 5.29 mmol, 3.0 equiv) was added at RT. The reaction mixture was stirred for 1 h at 30 °C and filtered. The solid was washed with DCM (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EA (200 mL), washed with saturated aq. NaHCO3 (60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (DCM / MeOH =15 / 1; Rf = 0.3; detection: UV) to provide the title compound (530 mg, 30% yield) as a brown oil.

[0549] LCMS(ESI-MS) m / z = 804.4 [M+H]+

[0550] Rt: 1.112 min; Method 6 2.17.4. Step 4: tert-butyl (3-(4-((3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin-4- yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate

[0551] To a mixture of N-(3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin-4-yl)-2-iodo-1- (2,2,2-trifluoroethyl)-1H-indol-4-amine (520 mg, 0.647 mmol, 1.0 equiv), tert-butyl N-(prop-2-yn-1- yl)carbamate (181 mg, 1.17 mmol, 1.8 equiv), Pd(PPh3)2Cl2 (CAS# 13965-03-2; 45.4 mg, 0.065 mmol, 0.1 equiv) and CuI (24.6 mg, 0.129 mmol, 0.2 equiv) in DMSO (11.5 mL) was added Et3N (262 mg, 2.59 mmol, 4.0 equiv) at RT. The reaction mixture was stirred for 2 h at RT under nitrogen and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (4 x 50 mL) and the organic layers were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by reverse phase purification (C18 spherical, 20 - 30 um, 100 A, 80 g; Mobile Phase A: water (0.05% FA), 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; 55% B fractions were collected) to provide the title compound (453 mg, 80% yield) as a yellow solid.

[0552] LCMS(ESI-MS) m / z = 831.5 [M+H]+

[0553] Rt: 1.107 min; Method 6 2.17.5. Step 5: tert-butyl (3-(4-((3-(8-hydroxyoctyl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate

[0554] To a solution of tert-butyl (3-(4-((3-(8-((tert-butyldiphenylsilyl)oxy)octyl)-1-methylpiperidin- 4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate (450 mg, 0.541 mmol, 1.0 equiv) in THF (5 mL) was added TBAF (1.0 M in THF) (0.65 mL, 0.649 mmol, 1.2 equiv) at RT. The reaction mixture was stirred for 1.5 h at RT. The reaction mixture was diluted with EtOAc (100 mL), washed with brine (8 x 25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (DCM / MeOH = 12 / 1; Rf = 0.2; detection: UV) to provide the title compound (300 mg, 93% yield) as a yellow solid.

[0555] LCMS(ESI-MS) m / z = 593.4 [M+H]+

[0556] Rt: 0.742 min; Method 6 2.17.6. Step 6: tert-butyl 1-(8-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)octyl)-1H-pyrazole-4-carboxylate

[0557] To a solution of tert-butyl (3-(4-((3-(8-hydroxyoctyl)-1-methylpiperidin-4-yl)amino)-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate (150 mg, 0.253 mmol, 1.0 equiv) and tert-butyl 1H-pyrazole-4-carboxylate (85.1 mg, 0.506 mmol, 2.0 equiv) in toluene (4.5 mL) was added CMBP (183 mg, 0.759 mmol, 3.0 equiv) at RT. The reaction mixture was stirred for 2 h at 100 °C under nitrogen and quenched with water (25 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 25 mL) and the organic layers were combined, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (DCM / MeOH =10 / 1; Rf = 0.3; detection: UV) to provide the title compound (170 mg, 80% yield) as a yellow semi-solid.

[0558] LCMS(ESI-MS) m / z = 743.5 [M+H]+

[0559] Rt: 0.697 min; Method 18 2.17.7. Step 7: 1-(8-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)octyl)-1H-pyrazole-4-carboxylic acid

[0560] To a solution of tert-butyl 1-(8-(4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)octyl)-1H-pyrazole-4-carboxylate (120 mg, 0.162 mmol, 1.0 equiv) in Dioxane (2.7 mL) was added hydrogen chloride (0.81 mL, 3.240 mmol, 20.0 equiv, 4 M in dioxane) at 0 °C. The reaction mixture was stirred for 2.5 h at RT. Then the mixture was cooled to 0 °C, neutralized by saturated sodium bicarbonate until PH~ 7 and diluted withwater (15 mL). The resulting mixture was extracted with EtOAc (10 x 15 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude title compound (86 mg, crude) as a yellow oil. The crude product was used for next step directly.

[0561] LCMS(ESI-MS) m / z = 587.4 [M+H]+

[0562] Rt: 0.579 min; Method 6 2.17.8. Step 8: compound 12 - 10-methyl-33-(2,2,2-trifluoroethyl)-6,10,21,22,26,33-hexazapenta cyclo[28.2.1.121,24.05,32.07,12]tetratriaconta-1(32),2,4,22,24(34),30-hexaen-28-yn-25-one

[0563] To a solution of 1-(8-(4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4- yl)amino)-1-methylpiperidin-3-yl)octyl)-1H-pyrazole-4-carboxylic acid (86.0 mg, 0.147 mmol, 1.0 equiv) in DMF (4.5 mL) were added HATU (61.3 mg, 0.162 mmol, 1.1 equiv) and DIPEA (114 mg, 0.882 mmol, 6.0 equiv) at RT. The reaction mixture was stirred for 1 h at RT and quenched with water (25 mL). The resulting mixture was extracted with EtOAc (4 x 25 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by TLC (DCM / MeOH = 9 / 1; Rf = 0.2; detection: UV) to provide crude product (27 mg, 89% pure). The crude product was further 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 (B%): 11% B to 41% B in 8 min; Wave Length: 254nm / 220nm; Rt: 7.5 min) to provide the title compound (6.2 mg, 6% yield) as a light yellow solid.

[0564] LCMS(ESI-MS) m / z = 569.3 [M+H]+

[0565] Rt: 1.444 min; Method 122.18. Compound 13: rac-(7S,12S)-10-methyl-33-(2,2,2-trifluoroethyl)-23-(trifluoromethyl)-15,18- dioxa-6,10,21,22,26,33-hexazapentacyclo[28.2.1.121,24.05,32.07,12]tetratriaconta- 1(32),2,4,22,24(34),30-hexaen-28-yn-25-one2.18.1. Step 1: rac-ethyl 1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3- (trifluoromethyl)-1H-pyrazole-4-carboxylate / rac-ethyl 1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0566] To a solution of Int-11 (250 mg, 0.370 mmol, 1.0 equiv) in DMF (7 mL) was added ethyl 3- (trifluoromethyl)-1H-pyrazole-4-carboxylate (84.8 mg, 0.407 mmol, 1.10 equiv) , K2CO3 (154 mg, 1.110 mmol, 3.0 equiv). The reaction mixture was stirred overnight at 50 °C 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 25 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) =1:15; Rf = 0.4; detection: UV) to provide the title compounds as regioisomer (245 mg, 84% yield).

[0567] LCMS (ESI-MS) m / z = 787.5[M+H]+

[0568] Rt: 0.843 min; Method 6 2.18.2. Step 2: rac-1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3- (trifluoromethyl)-1H-pyrazole-4-carboxylic acid / rac-1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0569] To a solution of mixture of rac-ethyl 1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-1- methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate / rac-ethyl 1-(2-(2-(2-((3R,4R)-4-((2-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxylate (245 mg, 0.311 mmol, 1.0 equiv) in methanol (9 mL) was added the solution of NaOH (62.3 mg, 1.555 mmol, 5.0 equiv, in H2O (9 mL)). The reaction mixture was stirred overnight at 50 °C and acidified to pH = 5 with HCl (1 N). The resulting mixture was extracted with EtOAc (3 x 40 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude the title compounds as regioisomer mixture (260 mg, crude) as a yellow solid.

[0570] LCMS (ESI-MS) m / z = 759.4[M+H]+

[0571] Rt: 0.734 min; Method 6 2.18.3. Step 3: rac-1-(2-(2-(2-((3R,4R)-4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H- indol-4-yl)amino)-1-methylpiperidin-3-yl)ethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazole-4- carboxylic acid / rac-1-(2-(2-(2-((3R,4R)-4-((2-(3-aminoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-4-yl)amino)-1-m...

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-; Each Z1 and Z2 is independently selected from C and 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, - C1-6alkyl, 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, - C5-12membered 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, - C1-4alkyl optionally substituted with one or more independently selected halo, - C1-4alkoxy 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 selected from N, CH, S or O; B is selected from CR5, or NR5; R5is C1-4alkyl or C1-4thioalkyl, each of which is 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, - -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 a 5 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, which heteroaryl is optionally substituted with one or more independently selected R8; Each R8is independently selected from - halo, - -CN, - 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 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,- Phenyl optionally substituted with one or more independently selected halo, -OH, -CN, 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, - 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, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo, - C1-4alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n, and - C1-4 alkynyl comprising 1 or 2 triple bonds, optionally substituted with one or more independently selected R12o; Y is -C(=O)NR7a- or -NR7bC(=O)-; Each R7a, and R7bis 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, 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, 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 C1-4 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 Z1 is C, Z2 is C, A is S, or O,wherein * represents the attachment point.

4. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein Z1 is C, Z2 is C, A is =CH-, and B is -NR5, and R5is, wherein * represents the attachment point.

5. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein Z1 is C, Z2 is N, A is =N- and B is =CR5and R5is, wherein * represents the attachment point.

6. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R4aand R4bare both H.

7. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 1-6, wherein Cy is pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with one, two or three independently selected R8.

8. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 7, wherein each R8is independently selected from F, Cl, I, -CN, -CH3, -CF3, -NH2, -C(=O)NH2, -C(=O)NH(CH)3, or cyclopropyl.

9. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 7, wherein each R8is independently selected from C1-4 alkenyl comprising 1 or 2 double bonds, optionally substituted with one or more independently selected halo, or R12n.

10. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 7, wherein each R8is independently selected from C1-4 alkynyl comprising 1 or 2 triple bonds, optionally substituted with one or more independently selected halo, or R12o.

11. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to claim 1-6 wherein Cy is:wherein * is attached to Y, and ** attached to L in Formula I.

12. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein L iswherein # is attached to Cy and ## is attached to -CR2aR2b- of Formula I.

13. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-12, 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, halo, C1-4 alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i.

14. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-12, 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, halo, C1-4alkyl optionally substituted with one or more independently selected halo, -NH2, -NHR11h, and -NR11hR11i.

15. 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 1-14.

16. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-14, or a pharmaceutical composition according to claim 15 for use in medicine.

17. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-14, or a pharmaceutical composition according to claim 15 for use in the prophylaxis and / or treatment of proliferative diseases.

Images